• Signed informed consent.
• Patients of either gender ≥ 18 years and ≤ 75 years of age.
• Patients with Crohn’s Disease (CD) diagnosed at least 6 months prior to Screening visit in accordance with accepted clinical, endoscopic, histological and/or radiological criteria.
• Presence of complex perianal fistula(s) with a maximum of 2 internal openings and a maximum of 3 external openings based on clinical assessment; a central reading of locally performed contrast  enhanced (gadolinium) pelvic MRI will be performed to confirm location of the fistula and potential associated perianal abscess(es). Fistula(s) must have been draining for at least 6 weeks prior to Screening visit. Actively draining simple subcutaneous fistula(s), at the time of Screening visit, are not allowed in this study. A complex perianal fistula is defined as a fistula that meets one or more of the following criteria:
  • High inter-sphincteric, high trans-sphincteric, extra-sphincteric or supra-sphincteric
  • Presence of ≥ 2 external openings;
  • Associated perianal abscess(es).
    • Note: Abscesses that are larger than 2 cm in at least 2 dimensions on MRI must be confirmed to have been drained adequately by the surgeon during the preparation curettage in order to be eligible.
• Clinically controlled, non active or mildly active CD, during the last six months prior to Screening visit with:
  • A PRO-2 score < 14 at Screening; and
  • A colonoscopy documenting the absence of ulcers larger than 0.5 cm in the colonic mucosa:
  • If colonoscopy data are not available within 6 months prior to Screening:
    • Simple Endoscopic Score for CD (SES-CD) ≤ 6 with absence of rectal ulcers larger than 0.5 cm must be documented in a colonoscopy performed at Screening before randomization.
  • If colonoscopy data are available within 6 months prior to Screening:
    • The absence of ulcers larger than 0.5 cm in the colonic mucosa must be documented, otherwise a new colonoscopy at Screening before randomization, will be  mandatory; and
    • The improvement or no worsening in abdominal pain and/or in the diarrhea, sustained for one week or more, since the last colonoscopy was performed in the clinical records until Screening visit; and 
    • No hemoglobin decrease greater than 2.0 g/dL or an unexplained rising C-reactive protein (CRP), greater than 5.0 mg/L to a concentration above the referenced ULN (unless the rise is due to a known process other than luminal Crohn’s Disease), since the last colonoscopy was performed as compared to results during the Screening visit; and
    • No initiation or intensification of treatment with corticosteroids, immunosuppressants or mAbs dose regimen since the last endoscopy up to Screening visit.
• Patients whose perianal fistulas were previously treated and have shown an inadequate response (absence of closure of part or all fistula tracts, or new fistula during induction treatment) or a loss of response (fistula relapse during maintenance treatment after initial fistula closure) while they were receiving either an immunosuppressive agent or TNF-α antagonist or vedolizumab or ustekinumab, or having documented intolerance (occurrence, at any time, of an unacceptable level of treatment-related side effects that makes necessary treatment discontinuation) to any of these treatments administered at least at approved or recommended doses during the minimum period mentioned:
  • Immunosuppressive agents: at least 3 months treatment with azathioprine (2-3 mg/kg/day), 6-mercaptopurine (1-1.5 mg/kg/day), or subcutaneous/intramuscular methotrexate (25  mg/week) prior to Screening for the study.
  • TNFα antagonists:
    • Infliximab: at least 14 weeks treatment at the approved doses for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: 1  intravenous dose of 5 mg/kg followed by the same dose 2 and 6 weeks after. For maintenance: 5-10 mg/kg intravenously every 8 weeks, or more frequently;
    • Adalimumab: at least 14 weeks treatment at the approved doses for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: 1 subcutaneous dose of 160 mg, followed by 80 mg 2 weeks after. For maintenance: 40 mg subcutaneously every other week, or weekly;
    • Certolizumab pegol: at least 14 weeks treatment at the approved doses for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: 1 subcutaneous dose of 400 mg, followed by the same dose 2 and 4 weeks after. For maintenance: 400 mg subcutaneously every 2 to 4 weeks;
  • Anti-integrin: at least 14 weeks treatment of the approved dose for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: vedolizumab 300 mg. For maintenance:  vedolizumab 300 mg every 4 to 8 weeks.
  • Anti-IL-12/23: at least 16 weeks treatment of the approved dose in Crohn´s disease prior to screening for the study. For induction: ustekinumab[40], approximately 6 mg/kg intravenously initially then followed by 90 mg subcutaneously every 8 weeks.
• Women of childbearing potential (WCBP) must have negative serum pregnancy test at Screening (sensitive to 25 IU human chorionic gonadotropin [hCG]). Both WCBP or male patients participating in this study, with a WCBP as partner, must agree to use an adequate method of contraception during the entire duration of the study. An adequate method of contraception is defined as complete, non-periodic sexual abstinence, single barrier method, vasectomy, adequate hormonal contraception (to have started at least 7 days prior to Screening visit), or an intrauterine device (to have been in place for at least 2 months prior to Screening visit).
• A WCBP, for the purposes of this study, is a sexually mature female; who is not surgically sterile by means of a prior hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; and has not been naturally postmenopausal for at least the last 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

• Concomitant rectovaginal or rectovesical fistula(s).
• Patient naïve to prior specific medical treatment for complex perianal fistula(s) including IS or anti-TNFs.
• Presence of a perianal collection >2 cm in at least two dimensions on the central reading MRI at Screening visit that was not adequately drained as confirmed by the surgeon during the preparation procedure.
• Severe rectal and/or anal stenosis and/or severe proctitis (defined as the presence of large [>0.5 cm diameter] ulcers in the rectum) that make impossible to follow the Surgery Procedure Manual.
• Patient with diverting stomas.
• Active, uncontrolled infection requiring parenteral antibiotics.
• Patient with ongoing systemic or rectal steroids for CD in the last 2 weeks prior to the Preparation visit.
• Patients with major alteration on any of the following laboratory tests or increased risk for the surgical procedure:
  • Serum creatinine levels > 1.5 times the ULN;
  • Total bilirubin > 1.5 times the ULN (unless predominantly non-conjugated due to documented history of Gilbert’s syndrome);
  • AST/ALT > 3 times the ULN;
  • Hemoglobin < 10.0 g/dL;
  • Platelets < 75.0 x 10^9/L;
  • Albuminemia < 3.0 g/dL.
• Suspected or documented infectious enterocolitis within 2 weeks prior to Screening visit.
• Any prior invasive malignancy diagnosed within the last 5 years prior to Screening visit. Patients with basal-cell carcinoma of the skin completely resected outside the perineal region can be included.
• Current or recent (within 6 months prior to the Screening visit) history of severe, progressive, and/or uncontrolled hepatic, haematological, gastrointestinal (other than CD), renal, endocrine, pulmonary, cardiac, neurological or psychiatric disease that may result in patients increased risk from study participation and/or lack of compliance with study procedures.
• Patients with primary sclerosing cholangitis.
• Patients with known chronically active hepatopathy of any origin, including cirrhosis and patients with persistent positive HBV surface antigen (HBsAg) and quantitative HBV polymerase chain reaction (PCR), or positive serology for HCV and quantitative HCV PCR within 6 months prior to Screening visit.
• Congenital or acquired immunodeficiencies, including patients known to be HIV carriers.
• Known allergies or hypersensivity to penicillin or aminoglycosides; DMEM (Dulbecco Modified Eagle’s Medium); bovine serum; local anaesthetics or gadolinium (MRI contrast).
• Contraindication to MRI scan (e.g., due to the presence of pacemaker, hip replacement or severe claustrophobia).
• Severe trauma within 6 months prior to Screening visit.
• Pregnant or breastfeeding women.
• Patients who do not wish to or cannot comply with study procedures.
• Patients currently receiving, or having received any investigational drug within 3 months prior to Screening visit.
• Patients previously treated with Cx601 or other allogeneic stem-cell therapy cannot be enrolled into this clinical study.
• Any major surgery of the GI tract (including one or more segments of the colon or terminal ileum) within 6 months prior to screening or any minor surgery of the GI tract within 3 months prior to screening.
• Patients who had local perianal surgery other than drainage for the fistula within 6 months prior to the Screening visit, or those who may need surgery in the perianal region for reasons other than fistulas at the time of inclusion in the study.
• Contraindication to the anaesthetic procedure.

• Subjects must satisfy the following criteria to be enrolled in the study:
  • Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
  • Subject has documented diagnosis of MM and measurable disease
  • Subject has received at least 2 but no greater than 4 prior MM regimens.
  • Subject has received prior treatment with DARA, a proteasome inhibitor and an immunomodulatory compound-containing regimen for at least 2 consecutive cycles.
  • Subject must be refractory to the last treatment regimen. Refractory is defined as documented progressive disease during or within 60 days (measured from the last dose of any drug within the regimen) of completing treatment with the last anti-myeloma regimen before study entry.
  • Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen.
  • Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 peripheral neuropathy.

• Subject has nonsecretory multiple myeloma (MM). 
• Subject has inadequate pulmonary function defined as oxygen saturation (SaO2) < 92% on room air. 
• Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years. 
• Subject has active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome or amyloidosis. 
• Subject with known central nervous system (CNS) involvement with myeloma. 
• Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation. 
• Subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal. 
• Subject has a history or presence of clinically relevant CNS pathology. 
• Subject was treated with DARA in combination with POM with or without dex (DP±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DPd as bridging therapy but may receive DVd or IRd as bridging as per Investigator's discretion if randomized to Treatment Arm A. 
• Subject was treated with DP±d as part of their most recent anti-myeloma treatment regimen, cannot receive DPd if randomized to Treatment Arm B but may receive DVd or IRd as per Investigator's discretion. 
• Subject was treated with DARA in combination with BTZ with or without dex (DV±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DVd as bridging therapy but may receive DPd or IRd as bridging as per Investigator's discretion if randomized to Treatment Arm A. 
• Subject was treated with DV±d as part of their most recent anti-myeloma treatment regimen, cannot receive DVd if randomized to Treatment Arm B but may receive DPd or IRd as per Investigator's discretion. 
• Subject was treated with IXA in combination with LEN with or without dex (IR±d) as part of their most recent anti-myeloma treatment regimen, cannot receive IRd as bridging therapy but may receive DPd or DVd as bridging as per Investigator's discretion if randomized to Treatment Arm A. 

• Male and female patients ≥ 12 and ≤ 20 years of age at informed consent signature.
• Total SARA score ≥ 1 at Baseline.

GM2:

• Genetically and biochemically confirmed diagnosis of Tay-Sachs or Sandhoff disease NA.

NP-C:

• Genetically confirmed diagnosis of NP-C;
• Miglustat-naïve patients unwilling or unable to take miglustat, OR, Patients who have discontinued miglustat because of confirmed gastrointestinal safety/tolerability issues. Miglustat must have been discontinued at least 1 month prior to Baseline visit.

• A male participant with a female partner of childbearing potential is eligible if he agrees to follow the contraceptive guidance.
• If a female participant is a WOCBP and is having a male partner, she must agree to follow the contraceptive guidance.
• Willing and able to complete protocol assessments.
• Parent and/or legal guardian is able to read, understand, and sign the informed consent. Where appropriate, assent will also be sought for patients who have not reached the age of majority or who are not able to sign the consent form. A consent maybe be sought for patients who have reached the age of majority (PI decision). No genetic test will be done as part of the study.

• Any abnormal conditions at baseline visit which in the opinion of the PI could interfere with study assessments (e.g., severe infection).
• History of medical conditions other than GM2 gangliosidosis/NP-C that in the opinion of the PI would confound scientific rigor or interpretation of results.
• Presence of another inherited neurologic disease.
• The dose of anti-epileptic treatment(s) was not stable and/or a new anti-epileptic treatment (drug or procedure) was prescribed during the last month before baseline.
• Patient with Gilbert syndrome and/or total bilirubin > 2 x ULN (isolated bilirubin > 2 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is < 35%).
• Platelet count < 100 x 10^9 /L.
• Presence of moderate or severe renal impairment (estimated GFR < 60 mL/min/1.73 m^2 )
• Prior participation in a clinical study with an investigational drug within 3 months prior to Baseline.
• Patient with a positive serum pregnancy test (tested only for women of childbearing potential) at baseline.
• Breast feeding ongoing at baseline or planned during the study.
• ECG with an average of triplicate QTcF interval > 440 msec.
• Received treatment with enantiomers of N-Acetyl-Leucine, gene therapy, stem cell transplantation, or with any other azasugars (iminosugars) compound with similar mechanism of action within 3 months before baseline (except for miglustat for which it is 1 month).
• Any known allergy to azasugars or any excipients.
• Evidence of suicidal ideation with intent (Type 4-5) on the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening. Only in patients judged by the PI cognitively capable to understand the concept of suicide.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 2/10/23. Questions regarding updates should be directed to the study team contact.

• Seizure refractory to at least three standard antiepileptic medications at adequate doses, failed for lack of effectiveness. This may include a rescue medication designated use as PRN.
• A minimum of 3 seizures per month for 2 months by patient diary started at intake interview.
• Subjects should have partial-onset seizures with or without secondary generalization.
• Subjects should have evidence suggesting the target lesion is the source of seizures by standard clinical criteria including at least the description of seizures, physical examination, neuroimaging, and video EEG monitoring capturing at least one seizure.
• Subjects must be taking 2 medications during the Baseline period and the dosage must be stable.
• A diagnosis of intractable epilepsy secondary to a dysplastic subcortical lesion which would include: Hypothalamic hamartoma, Periventricular nodular hetereotopia, Dysembryoplastic neuroepithelial tumor (DNET), Cortical dysplasia, or Tuberous sclerosis.

• Patients with standard contraindications for MR imaging such as non-MRI compatible implanted metallic devices including cardiac pacemakers, size limitations, etc.
• Individuals who are not able or willing to tolerate the required prolonged stationary supine position during treatment (can be up to 4 hrs of total table time.).
• Patients with malignant brain tumors.
• Patients with a known history of psychogenic non-epileptic spells in the last three years.
• Patients with a vagal nerve stimulator, deep brain stimulator, other implanted electronic device, or prior radiofrequency lesion techniques.
• Lesions in the brainstem or cerebellum.
• Subjects with symptomatic generalized epilepsy.
• Subjects with only simple partial seizures.
• Subjects who have had convulsive status epilepticus within 12 months prior to baseline.
• Subjects with a prior diagnosis of psychogenic/non-epileptic seizures within the last 5 years.
• Subjects who are candidates for traditional open surgery or elect to receive traditional open surgery are excluded.

• Participant must be at least 16 years of age, at the time of signing the informed consent or assent.
• Participants must have a documented pathogenic activating variant, or variant of uncertain significance, of the CASR gene associated with biochemical findings of hypoparathyroidism either present at Screening or a documented history of both:
  • cCa < 8.6 mg/dL (2.2 mmol/L) in participants 16 to < 18 years, or < 8.5 mg/dL (2.1 mmol/L) in participants ≥ 18 years iPTH < 40 pg/mL (4.2 pmol/L);
  • Note: A genetic analysis report for CASR will be acceptable. In the absence of any documentation for the CASR variant, participants must be willing to undergo CASR variant analysis. Participants who have undergone an allogeneic bone marrow transplant must provide either CASR variant analysis report performed prior to the bone marrow transplant or provide a buccal swab for variant analysis. Participants who have received a blood transfusion must wait 2 weeks following the blood transfusion before undergoing CASR variant analysis.
• Participants must have a documented history of symptoms or signs of ADH1. Symptoms of ADH1 include agitation, anxiety, back pain, brain fog, bronchospasm, blepharospasm, cardiac failure, cognitive impairment, difficulty focusing/concentration, esophageal spasm, facial spasm, headaches, hypoesthesia (including facial and oral), irritability, laryngospasm, muscle cramping, muscle fatigue, muscle spasms, muscle tightness, muscle twitching, musculoskeletal pain, musculoskeletal stiffness, myalgia, nephrolithiasis, nervousness, paresthesia (including oral), polydipsia, polyuria, seizure, tetany, throat tightness, or tremor. Signs of ADH1 include basal ganglia or other cerebral calcification, Chvostek sign, hypercalciuria, nephrocalcinosis, papilledema, premature cataracts, prolonged QT interval on ECG, pseudotumor cerebri, or Trousseau sign.
• Participants 16 to < 18 years old must have closed growth plates on hand radiograph.
• Participants treated with thiazide diuretics must discontinue thiazides for at least 14 days prior to Screening through Period 3 Week 24. When the thiazide is being used as an antihypertensive, alternative therapy will be prescribed by the Investigator as needed.
• Participants treated with phosphate binders must discontinue the phosphate binders at least one day prior to the Screening Visit.
• Participants treated with magnesium or potassium supplements must be willing to discontinue such treatment prior to the first dose of encaleret.
• Participants treated with potassium-sparing diuretics must be willing to discontinue such treatment prior to the first dose of encaleret.
• Participants must meet SoC Optimization criteria.
• Male participants must use highly effective contraceptive method (eg, condoms with spermicidal gel or foam) during vaginal intercourse and should not father a child nor donate sperm while taking encaleret and for 3 months after the last dose of encaleret. Condoms are not required if the participant is vasectomized or if the participant’s partner is not a female of childbearing potential.
• Postmenopausal females and females not of childbearing potential may participate in this study without use of contraception:
  • Females are considered postmenopausal if they have had 12 months of natural (spontaneous) amenorrhea without an alternative medical cause and must be confirmed with plasma FSH;
  • Females are considered not of childbearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy) or hysterectomy. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment, shall she be considered not of childbearing potential.

• Females of childbearing potential, defined as all females physiologically capable of becoming pregnant, must use two highly effective methods of contraception starting at Screening and for 3 months following the last dose of encaleret. Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Capable of giving signed informed consent or assent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

• cCa and 24-hr UCa both within the respective reference ranges (cCa = 8.6-10.5 mg/dL in participants 16 to < 18 years or 8.5-10.5 mg/dL in participants ≥ 18 years and UCa < 250 mg/day for women and < 300 mg/day for men) at Screening Visit.
  • Note: Exclusion Criteria only applies to participants on SoC who have not participated in CLTX-305-201.
• History of hypocalcemic seizure within the past 3 months preceding Screening.
• History of thyroid or parathyroid surgery.
• Pregnant or nursing (lactating) women, where pregnancy is confirmed by a positive β-hCG laboratory test.
• History of treatment with PTH 1-84 or 1-34 within the 2 months preceding Screening and requiring SoC doses exceeding > 1.2 × their pre-PTH treatment total daily doses or bone turnover markers, CTx and P1NP, > upper limit of normal for sex, age (men only) and menopausal status (women only).
• Received any investigational medicinal product other than encaleret within 30 days or 5 half-lives, whichever is longer, prior to the first day on study, or are in follow-up for another interventional clinical study during Screening. If the half-life of an investigational medicinal product is unknown, then 30 days prior to Screening.
• Blood 25-OH Vitamin D level < 25 ng/mL.
• If participant has a blood 25-OH Vitamin D level < 25 ng/mL at the Screening Visit, they will be prescribed cholecalciferol or ergocalciferol supplementation per the Investigator. Once the 25-OH Vitamin D level is > 25 ng/mL, the participant will be eligible to enroll in the study (if still within Screening period) or re-screen for the study.
• Estimated glomerular filtration rate < 30 mL/minute/1.73 m^2 using CKD-EPIcr_R (for participants < 18 years old the Bedside Schwartz equation should be used). 
• 12-lead resting ECG with clinically important abnormalities except for asymptomatic QTc prolongation clinically ascribed to hypocalcemia.
• Participants with positive HBsAg, Hepatitis A IgM, or HIV viral serology test at the Screening Visit. Participants who are in complete remission from Hepatitis C as evidence by sensitive assay ≥ 12 weeks after completion of HCV therapy may participate in the study.
• Male or female participants planning to conceive a child prior to the LTE.
• Hypersensitivity to any active substance or excipient of encaleret. 
• Presence or history of any disease or condition (eg, drug or alcohol dependency) that, in the view of the Investigator, would affect the participant’s safety or places the participant at high risk of poor treatment compliance or of not completing the study.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/30/22. Questions regarding updates should be directed to the study team contact.

• Subjects or their Legally Authorized Representative (LAR) must provide written informed consent to the study procedures prior to any study procedures.
• Subjects must have a caregiver/ study partner who in the opinion of the site principal investigator, has contact with the study subject for a sufficient number of hours per week to provide informative responses on the protocol assessments, oversee the administration of study drug, and is willing and able to participate in all clinic visits and some study assessments.
• Men or women 50-85 years of age (inclusive), meeting criteria for probable Dementia with Lewy Bodies (DLB).
• Men willing to comply with acceptable form of contraception or women of non-childbearing.
• Willingness to undergo a lumbar puncture (LP) during the screening period and at the end of the 6-month treatment period.
• Formal education of eight or more years.
• Subjects living at home or in an assisted living facility.
• Subjects shall be generally healthy with mobility, vision and hearing sufficient for compliance with testing procedures.
• Must be able to complete all screening evaluations.

• Any neurological condition that may be contributing to cognitive impairment above and beyond those caused by the subject's DLB, including any co-morbidities detected by clinical assessment or MRI (or CT scan due to contraindication of MRI, if approved by medical monitor).
• History of transient ischemic attacks or stroke within 12 months of screening.
• Parkinsonian (extrapyramidal) features with Modified Hoehn and Yahr stage 4 or higher or any diagnosis of Parkinson’s disease or parkinsonism that preceded cognitive decline by more than one year.
• Hospitalization (except for planned procedures) or change of chronic concomitant medication within one month prior to screening.
• Any major psychiatric diagnosis, including schizophrenia, bipolar disorder, and current major depressive disorder as per Diagnostic and Statistical Manual of Mental Disorders Fifth Edition.
• Geriatric Depression Scale score > 6. (Subjects with a GDS > 6 may be allowable if the investigator does not believe the subject is clinically depressed. Investigators should contact the medical monitor to discuss eligibility).
• Subjects living in a continuous care nursing facility.
• Contraindication to the MRI examination for any reason (CT scan may be substituted for an MRI if subjects are unable to tolerate an MRI or an MRI is contraindicated for medical reasons, if the proposed CT scan is discussed and approved by the medical monitor on a case-by-case basis).
• Screening MRI (or historical MRI or CT scan due to contraindication of MRI if approved by medical monitor) or historical MRI/CT scan, if applicable. of the brain indicative of significant abnormality, including, but not limited to, prior hemorrhage or infarct >1 cm3 , > 3 lacunar infarcts, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, space-occupying lesion (e.g., abscess or brain tumor such as meningioma). If a small incidental meningioma is observed, the medical monitor may be contacted to discuss eligibility.
• Clinical, laboratory findings or medical history consistent with:
  • Other primary degenerative dementia, (frontotemporal dementia, Huntington’s disease, Creutzfeldt-Jakob Disease, Down syndrome, etc.);
  • Other neurodegenerative condition (amyotrophic lateral sclerosis, etc.);
  • Seizure disorder;
  • Other infectious, metabolic or systemic diseases affecting the central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, other laboratory values etc.).
• Clinically significant, advanced or unstable disease that may interfere with outcome evaluations, such as:
  • Chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency (ALT, AST, alkaline phosphatase > 1.5 ULN, lactate dehydrogenase (LDH) > 1.5 x ULN);
  • Respiratory insufficiency which requires the use of supplemental oxygen;
  • Renal insufficiency eGFR < 50 mL/min based on the CKD‐EPI formula;
  • Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within six months before screening);
  • Bradycardia (100 beats/min.). If heart rate is below 50 beats/min or above 100 beats/min, the heart rate assessment may be repeated to assess eligibility;
  • Poorly managed hypertension (systolic > 160 mm Hg and/or diastolic > 95 mm Hg) or hypotension (systolic 7.5% in subjects with diabetes, only those subjects with known diabetes are required to get a HbA1c at screen.
• History of cancer within 3 years of screening with the exception of fully excised non-melanoma skin cancers or non-metastatic prostate cancer that has been stable for at least 6 months.
• Seropositive for human immunodeficiency virus (HIV).
• History of acute/chronic hepatitis B or C and/or carriers of hepatitis B (seropositive for hepatitis B surface antigen [HbsAg] or anti-hepatitis C [HCV] antibody).
• Clinically significant abnormalities in screening laboratory tests, including:
  • Hematocrit less than 35% for males and less than 32% for females, absolute neutrophil cell count of 1500/uL (with the exception of a documented history of a chronic benign neutropenia, absolute lymphocyte count 1.4 or other coagulopathy, confirmed by repeat assessment of:
  • Hematocrit;
  • Neutrophil count;
  • Lymphocyte count;
  • Platelet count.
• Disability that may prevent the subject from completing all study requirements (e.g., blindness, deafness, severe language difficulty, etc.).
• Within 4 weeks of screening visit or during the course of the study, concurrent treatment with antipsychotic agents, antiepileptics, centrally active antihypertensive drugs (e.g., clonidine, l-methyl dopa, guanidine, guanfacine, etc.), sedatives, opioids, mood stabilizers (e.g., valproate, lithium); or benzodiazepines, with the following exceptions:
  • At the discretion of the investigator, lorazepam or another anxiolytic may be administered as per local standard of care prior to MRI scan or optional lumbar puncture. Note neurocognitive testing should not be done within 24 hours of administration of conscious sedation;
  • Stable use of clonazepam for at least 30 days as indicated for REM Sleep Behavioral Disorder (RBD);
  • Stable use of atypical antipsychotics (e.g., quetiapine, pimavanserin) for at least 30 days as indicated for delusions and hallucinations secondary to DLB.
• Any disorder that could interfere with the absorption, distribution, metabolism, or excretion of drugs (e.g., small bowel disease, Crohn’s disease, celiac disease, or liver disease).
• Nootropic drugs except stable AD meds (acetylcholinesterase inhibitors or memantine).
• Suspected or known drug or alcohol abuse; i.e., more than approximately 60 g alcohol (approximately 1 liter of beer or 0.5 liter of wine) per day indicated by elevated MCV significantly above normal value at screening.
• Suspected or known allergy to any components of the study treatments.
• Enrollment in another investigational study or intake of investigational drug within the previous 30 days or five half-lives of the investigational drug, whichever is longer.
• Intake of drugs or substances potentially involved in clinically significant induction or inhibition of CYP3A4 or P-gp mediated drug interactions with CT1812, within 4 weeks or five half-lives of the interacting drug prior to administration of CT1812 and throughout the course of the study. Grapefruit juice should be avoided in the two weeks prior to dosing and throughout the course of the study. 
• Any prior exposure to immunomodulators, anti Aβ vaccines, or passive Aβ immunotherapies (e.g., monoclonal antibodies) and/or exposure to BACE inhibitors within the past 30 days.
• Any condition, which in the opinion of the investigator or the sponsor makes the subject unsuitable for inclusion.
• Any vaccination within one week of the baseline visit.

Eligibility last updated 5/23/23. Questions regarding updates should be directed to the study team contact.

 Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation of AFP above institutional normal or > 10 ng/mL or human chorionic gonadotropin (hCG) beta > 100 mIU/mL. Suprasellar, pineal and bifocal tumors are included. (CSF tumor markers and cytology must be within 21 days prior to enrollment and within 35 days prior to start of protocol therapy [repeat if necessary]. Serum tumor markers, AFP and hCGbeta must be within 7 days prior to enrollment and start of protocol therapy [repeat if necessary]). Basal ganglia or other primary sites are excluded.

- Patients with any of the following pathological elements are eligible: endodermal sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant elements listed above are present. Patients with only mature teratoma are excluded.
Patients with pure germinoma admixed with mature teratoma are excluded (would be eligible for pure germinoma protocols).

- Patients must have a cranial magnetic resonance imaging (MRI) with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post operative brain MRI with and without gadolinium. The post operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not
required (within 14 days prior to study enrollment).

- Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment. Spine MRI with and without gadolinium is recommended (within 14 days prior to study enrollment).

- Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days
following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery.

- Patients must have CSF tumor markers obtained prior to enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first.

- Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (within 7 days prior to enrollment).

- Platelet count ≥ 100,000/uL (transfusion independent) (within 7 days prior to enrollment).

- Hemoglobin ≥ 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment).

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):

- Age: Maximum serum creatinine (mg/dL);
- 3 to < 6 years: 0.8 (male), 0.8 (female);
- 6 to < 10 years: 1 (male), 1 (female);
- 10 to < 13 years: 1.2 (male), 1.2 (female);
- 13 to < 16 years: 1.5 (male), 1.4 (female)'
- ≥ 16 years: male (1.7), 1.4 (female).

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment).

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 135 U/L (within 7 days prior to enrollment).

- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L.

- Central nervous system function defined as:

- Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled;

- Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment.

- Protocol therapy must begin within 31 calendar days of definitive surgery or clinical diagnosis. If a biopsy only was performed, the biopsy date will be considered the date
of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.

- All patients and/or their parents or legal guardians must sign a written informed consent.

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

- NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:

- English-, Spanish-, or French- speaking;

- Note: Patients who speak a language other than English, Spanish, or French will be allowed to participate in ACNS2021 but will not complete the neurocognitive
and quality of life assessments.

- No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g., Down syndrome, fragile X, William syndrome, intellectual disability). Patients with
NF1 will be allowed to participate.

- Additional eligibility criteria for the COG Standardized Neuropsychological Battery only: must be at a site that has a psychologist to administer the battery.

- Note: If not eligible for the COG Standardized Battery, patients should still complete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior
Assessment System Third Edition (ABAS-3), and Behavior Assessment System for Children, Third Edition (BASC-3) questionnaires.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 8/30/22. Questions regarding updates should be directed to the study team contact.

• Subject must be ≥ 18 years and ≤ 75 years of age.
• Body weight of ≥ 40 kg (88.2 lb) at the time of signing the informed consent form (ICF)/assent form.
  • Note: Countries or sites with local restrictions that prohibit enrollment of adolescents (aged 12 to 17 years inclusive) will only enroll subjects who are 18 years of age or older. Enrollment of adolescent subjects will begin only after the applicable regulatory requirements for enrolling subjects in that age group have been satisfied and the necessary health authority approvals have been granted. Where national or regional guidelines for the definition of adolescence differ from the definition stated above, the national or regional guidelines may be used to determine eligibility.
• Subject has histologic evidence of EoE, defined as a peak count of ≥ 15 eosinophils per high-power field (hpf) at any 2 levels of the esophagus (proximal, mid, and/or distal) when off anti-inflammatory therapy (eg, corticosteroids, see Exclusion Criterion 7) for EoE. The histologic criterion for diagnosis of EoE must be confirmed by a centrally read histological assessment of an EGD specimen during the Screening Period prior to randomization.
• Subject has symptoms of dysphagia of at least 4 DD, as assessed with the mDSD instrument, over the last 2 consecutive weeks (14 days) prior to Day 1 when off anti- inflammatory therapy (eg, corticosteroids, see Exclusion Criterion 7) for EoE. Subjects are required to have at least 11 days of diary data out of the final 14-day period of screening mDSD collection in order to be enrolled in the study. During these 11 days, responses to questions 2 through 5 of the mDSD instrument must be complete.
• Subject must have previously received an adequate trial of proton-pump inhibitor (PPI) medication (8 weeks per guidance, Dellon, 2013) that did not provide complete response to EoE, or the subject remains symptomatic with continued use (Dellon, 2018b; Lucendo, 2017). Prospective subjects who discontinued use of a PPI must not have received a PPI for at least 4 weeks before their first Screening Visit and must agree not to restart a PPI during the study.  If a prospective subject is receiving a PPI medication at screening, he or she must have been receiving a stable dose for at least 4 weeks prior to the first Screening Visit and agree to continue the same dose throughout the study.
• Subject must either:
  • be naïve or have had an adequate response to corticosteroid therapy (i.e., classified as Steroid Responders/Naïve); or
  • have had an inadequate response to corticosteroid therapy and is not considered to be a candidate for continued corticosteroid therapy, or is intolerant to corticosteroid therapy. For subjects who have previously received systemic or swallowed topical corticosteroids for EoE, designation of the status of Steroid Inadequate Responders/Intolerant will include either of the following definitions. Note that if any of the below criteria are met, a subject will be deemed Steroid Inadequate Responders/Intolerant (approximately 70% of the study population) and cannot be classified as Steroid Responders/Naïve (approximately 30% of the study population).
    • Inadequate response to corticosteroid therapy (failed to respond or lost response) and not considered a candidate for continued corticosteroid therapy: subjects who have had a trial of at least 6 weeks of swallowed topical corticosteroid treatment; or
    • 4 weeks of systemic corticosteroids at doses in accordance to published guidelines for the management of EoE (Lucendo, 2017), or a trial for the treatment duration specified in the prescribing information for approved products and judged by the treating physician as not achieving clinical improvement or having clinical improvement initially but lost response while on therapy;
• • Intolerant to corticosteroid therapy: subjects who initiated systemic or swallowed topical corticosteroid treatment but were unable to achieve treatment durations or dose levels due to intolerance because of side effects, including intolerance from use of corticosteroids for conditions other than EoE, or subjects with underlying conditions in which corticosteroid use is not recommended or contraindicated.
• Documentation of type of therapy, treatment duration, and outcome details will be collected when possible.
• Subjects must agree to maintain a stable diet (including any food elimination diet for the treatment of food allergy or EoE) from the first Screening Visit and throughout the duration of the study, and subjects must have maintained a stable diet for at least 4 weeks prior to the first Screening Visit. Subjects must agree not to introduce any changes in their diet while participating in the study.
• Subjects currently receiving inhaled corticosteroids, leukotriene receptor antagonists (e.g., montelukast), or mast cell stabilizers (e.g., cromolyn sodium) for indications other than EoE, or medium potency topical corticosteroids (eg, mometasone furoate cream or lotion) for dermatologic conditions, must maintain stable doses/regimens for at least 4 weeks prior to the first Screening Visit and regimens must remain stable throughout the duration of the study. If recently discontinued, the medication must have been discontinued at least 4 weeks prior to the first Screening Visit.
• Female subjects of childbearing potential must agree to practice a highly effective method of contraception. Highly effective methods of contraception are those that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly.
• A female of childbearing potential (FCBP) is a female who:
  • has achieved menarche at some point;
  •  has not undergone a hysterectomy or bilateral oophorectomy; or
  •  has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) and must:
• • Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study and through the Final 16-week Safety Follow-up Visit. This applies even if the subject practices true abstinence* from heterosexual contact;
  • Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, highly effective contraception without interruption throughout the study and for 5 months after the last dose of IP. Acceptable methods of birth control in this study are the following (birth control must be effective by the time the FCBP subject is randomized into the study [e.g., hormonal contraception should be initiated at least 28 days before randomization]):
    • combined hormonal (estrogen and progestogen containing) contraception, which may be oral, intravaginal, or transdermal;
    • progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injectable, or implantable placement of an intrauterine device (IUD);
    • placement of an intrauterine hormone-releasing system (IUS);
    • bilateral tubal ligation; or bilateral tubal occlusion (if an implantable device was recently placed, the subject must use an additional effective method of birth control until full occlusion has been confirmed and documented);
    • vasectomized partner (vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual partner of the FCBP and has received medical assessment of the surgical success);
    • sexual abstinence.
• Subject is willing to receive weekly SC injections throughout the study.
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. For subjects less than 18 years of age, subject assent must be obtained, and parental/legal representative consent is required.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• True abstinence is acceptable when this is the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), and lactational amenorrhea method are not acceptable methods of contraception.

• Subject has clinical or endoscopic evidence of the presence of any other disease that may interfere with or affect the histologic, endoscopic, and clinical symptom endpoints for this study (eg, erosive esophagitis Los Angeles [LA] classification Grade B or above, Barrett's esophagus, esophageal lichen planus, upper gastrointestinal bleed, achalasia, inflammatory bowel disease, diagnosed eosinophilic gastroenteritis [clinical symptoms and/or EGD findings and confirmatory eosinophilia in gastric and/or duodenal mucosa], or significant hiatal hernia [> 3 cm], etc.).
• Subject demonstrates presence of esophageal varices.
• Subject has a known active Helicobacter pylori infection and/or is currently being treated for this condition.
• Subject has evidence of a severe endoscopic structural abnormality in the esophagus (e.g., high-grade stenosis where an 8- to 10-mm endoscope could not pass through the stricture without dilation at the time of the screening EGD).
• Subject had esophageal dilation for symptom relief during the Screening Period or within 8 weeks prior to the first Screening Visit, or esophageal dilation is anticipated to be performed within 48 weeks of dosing during the study.
• Subject demonstrates evidence of immunosuppression or is receiving systemic immunosuppressive or immunomodulating drugs (e.g., anti-IL-13 antibodies [except IP in this study], IL-4 receptor alpha antagonist antibodies [eg, dupilumab], anti-IL-5 antibodies, anti-IL-17 antibodies, anti-immunoglobulin E [IgE] antibodies, α4β7 integrin inhibitor antibodies, or any other monoclonal antibody, methotrexate, cyclosporine, azathioprine, mercaptopurine, interferon alpha [IFNα], tumor necrosis factor alpha [TNFα] inhibitors, etc.) within 5 drug half-lives prior to the first Screening Visit. Any use of these medications will be prohibited during the study.
• Subject is currently receiving systemic or swallowed topical corticosteroid medication. Prospective subjects with EoE previously treated with a corticosteroid must not have received a systemic corticosteroid within 8 weeks or swallowed topical corticosteroid within 4 weeks of the first Screening Visit.
• Subject is currently receiving a high potency topical corticosteroid (e.g., augmented betamethasone dipropionate, clobetasol propionate, etc.) for dermatologic use. Prospective subjects must not have received a high potency topical corticosteroid for dermatologic use within 8 weeks of the first Screening Visit. Any use will be prohibited during the study.
• Subject is currently receiving a leukotriene receptor antagonist (e.g., montelukast) or mast cell stabilizer (e.g., cromolyn sodium) for the indication of EoE. Subjects must not have received a leukotriene receptor antagonist or mast cell stabilizer for EoE within 4 weeks of the first Screening Visit. Any use for the treatment of EoE during the study will be prohibited.
• Subject is currently successfully treated for EoE with dietary modifications (e.g., food elimination diet) and is able to fully adhere to the diet resulting in a complete response to EoE (i.e., the subject does not meet the symptoms of dysphagia requirement of at least 4 DD and histologic criterion for diagnosis of EoE per Section 4.2, Inclusion Criteria 2 and 3).
• Subject has received oral or sublingual immunotherapy within 6 months of the first Screening Visit; any use will be prohibited during the study. Subjects receiving SC immunotherapy may participate but must be on stable doses for at least 3 months prior to the first Screening Visit and during the study.
• Subject is receiving concurrent treatment with another IP, including through participation in an interventional trial for COVID-19. Prospective subjects may not participate in a concurrent IP study or have received an IP within 5 drug half-lives prior to signing the ICF/assent for this study. Further, for subjects who received an investigational COVID-19 vaccine as part of a clinical trial prior to the first Screening Visit, enrollment must be delayed until the biologic impact of the vaccine is stabilized, as determined by discussion between the Investigator and the Clinical Trial Physician.
• Subject has received a live attenuated vaccine within one month prior to the first Screening Visit or anticipates the need to be vaccinated with a live attenuated vaccine during the course of the study. Administration of any live attenuated vaccine will be prohibited during the study through the Final 16-week Safety Follow-up Visit.
• Subject has previously received CC-93538 treatment (formerly known as RPC4046 and ABT-308) through participation in the Phase 2 Study, RPC02-201, or any Phase 1 clinical study.
• Subject has any other disease that would make conduct of the protocol or interpretation of the study results difficult or that would put the prospective subject at risk by participating in the study (eg, severe uncontrolled asthma, infection causing eosinophilia, hypereosinophilic syndrome, gastritis, colitis, celiac disease, Mendelian disorder associated with EoE, or cardiovascular condition, or neurologic or psychiatric illness that compromises the prospective subject's ability to accurately document symptoms of EoE).
• Subject has liver function impairment or persisting elevations of aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) that are 2 times the upper limit of normal (ULN), or total bilirubin 1.5 times the ULN. Subjects with elevations that are not clinically significant in total bilirubin associated with Gilbert’s syndrome may participate.
• Subject has an active parasitic/helminthic infection or a suspected parasitic/helminthic infection. Subjects with suspected infections may participate if clinical and laboratory assessments, if needed, rule out active infection prior to randomization.
• Subject has an ongoing infection (e.g., hepatitis B or C, human immunodeficiency virus [HIV], or tuberculosis as defined by standard medical guidelines).
• Subject had a previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 4 weeks prior to screening. Symptoms must have completely resolved and based on Investigator assessment in consultation with the Clinical Trial Physician, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment.
• Subject has known hereditary fructose intolerance (HFI).
• Subject is pregnant or lactating.
• Subject has a history of idiopathic anaphylaxis or a major immunologic reaction (such as anaphylactic reaction, anaphylactoid reaction, or serum sickness) to an immunoglobulin G (IgG) containing agent.
• Subject has a history of cancer or lymphoproliferative disease, other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma or adequately treated cervical carcinoma in situ, within 5 years of screening.
• Subject has a history of alcohol or drug abuse within 5 years prior to initiation of screening.
• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Subject has any condition that confounds the ability to interpret data from the study.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 5/9/23. Questions regarding updates should be directed to the study team contact.

• Failing surgically implanted bioprosthetic valve in the mitral position demonstrating ≥ moderate stenosis and/or ≥ moderate insufficiency.
• NYHA Functional Class ≥ II.
• Heart Team agrees that the patient is at intermediate surgical risk.
• Heart Team agrees valve implantation will likely benefit the patient.
• The study patient has been informed of the nature of the study, agrees to its provisions and has provided written informed consent as approved by the Institutional Review Board (IRB) of the respective clinical site.

• Index valve has ≥ mild paravalvular regurgitation where the surgical bioprosthesis is not securely fixed in the native annulus or is not structurally intact as determined by transesophageal echocardiography (TEE).
• Aortomitral angle <105°.
• Severe regurgitation or stenosis of any other valve.
• Severe right ventricle (RV) dysfunction.

• Male or female subjects age 18 years or older.
• Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses.
• EGPA diagnosis based on history or presence asthma and eosinophilia (> 1.0x10^9/L and/or >10% of leucocytes) and at least 2 of; biopsy with eosinophilic vasculitis or perivascular/granulomatous inflammation; mono-or polyneuropathy, non-fixed pulmonary infiltrates, sino-nasal abnormality; cardiomyopathy; glomerulonephritis; alveolar haemorrhage; palpable purpura; anti neutrophil cytoplasmic anti-body (ANCA) positivity (Myeloperoxidase or proteinease 3).
• History of relapsing (at least 1 confirmed EGPA relapse within last 2 years and > 12 weeks prior to screening, or refractory (failure to attain remission, defined as BVAS=0 and oral corticosteroid (OCS) dose ≤ 7.5 mg/day of prednisolone or equivalent, following standard induction regimen for at least 3 months and within 6 months prior to screening, or recurrence of symptoms upon OCS tapering at any dose of ≥ 7.5 mg/day prednisolone or equivalent. If induction with glucocorticoidsalone, patient must have failed to attain remission after 3 months and the glucocorticoid dose must be ≥ 15 mg/day prednisolone or equivalent for the 4 weeks prior to randomization.
• Must be on a stable dose of oral prednisolone or prednisone of ≥ 7.5 mg/day (but not > 50mg/day) for at least 4 weeks prior to randomization.
• If receiving immunosuppressive therapy (excluding cyclophosphamide) the dose must be stable for the 4 weeks prior to randomization and during the study (dose reductions for safety reasons will be permitted).
• QTc(F) < 450 msec or QTc(F) < 480 msec for patients with bundle branch block.
• Females of childbearing potential must use an acceptable method of birth control from signing the informed consent until 4 months after the last study drug administration.

• Diagnosed with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).
• Organ-threatening EGPA: organ-threatening EGPA as per the European League against Rheumatism criteria (Yates et al 2016); i.e., organ failure due to active vasculitis, creatinine > 5.8 mg/dL (> 513 μmol/L) within 3 months prior to screening (Visit 1) and through randomisation (Visit 2).
• Life-threatening EGPA: imminently life-threatening EGPA disease defined as any of the following within 3 months prior to screening (Visit 1) and through randomisation (Visit 2).
• Currently pregnant or breastfeeding, or planning to become pregnant during study participation.
  • Intensive care required;
  • Severe alveolar haemorrhage or haemoptysis requiring transfusion or ventilation or haemoglobin < 8 g/dL (< 80 g/L) or drop in haemoglobin > 2 g/dL (> 20 g/L) over a 48-hour period due to alveolar haemorrhage;
  • Rapidly progressive glomerulonephritis with creatinine > 2.5 mg/dL (> 221 μmol/L) or rise in creatinine > 2 mg/dL (> 177 μmol/L) over a 48-hour period;
  • Severe gastrointestinal involvement, for example, gangrene, bleeding requiring surgery;
  • Severe central nervous system involvement;
  • Severe cardiac involvement, for example, life-threatening arrhythmia, cardiac failure: ejection fraction < 20%, NYHA Class III/IV (NYHA 2012), acute myocardial infarction.
• Patients who have had basal cell carcinoma, localised squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to screening (Visit 1).
• Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained.
• Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones)
• Patients who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment including but not limited to:
  • Known ejection fraction < 30%, OR
  • Severe heart failure that meet NYHA Class IV (NYHA 2012), OR
  • Hospitalised in the 12 months prior to screening (Visit 1) for severe heart failure meeting NYHA Class III (NYHA 2012), OR
  • Angina diagnosed within 3 months prior to screening (Visit 1) and through randomisation (Visit 2).
• Chronic or ongoing active infectious disease requiring systemic treatment.
• A helminth parasitic infection diagnosed within 6 months prior to screening (Visit 1) and through randomisation (Visit 2) that has not been treated with or has failed to respond to standard of care therapy.
• Chronic stable hepatitis B and C (including positive testing for HBsAg or hepatitis C antibody), or other stable chronic liver disease are acceptable if patient otherwise meets eligibility criteria. Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis.
• A history of known immunodeficiency disorder including a positive HIV test.
• History of known allergy, intolerance, or anaphylaxis to any biologic therapy or vaccine.
• Known history of allergy or reaction to any component of the IP formulation.
• Patients who have known, preexisting, clinically significant endocrine, autoimmune, metabolic, neurologic, renal, gastrointestinal, hepatic, haematological, respiratory or any other system abnormalities that are not associated with EGPA and are uncontrolled with standard treatment. Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening/run-in period, which in the opinion of the Investigator, may put the patient at risk, because of his/her participation in the study, or may influence the results of the study, or the patients’ ability to complete entire duration of the study.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Previous randomisation in the present study.
• Participant is currently participating in any other interventional clinical study.
• For women only: Currently pregnant, breastfeeding, or lactating. Patients should not be enrolled if they plan to become pregnant during the time of study participation. A serum pregnancy test will be done for WOCBP at screening (Visit 1) and a urine pregnancy test must be performed for WOCBP at each treatment visit prior to IP administration. A positive urine test result must be confirmed with a serum pregnancy test, before proceeding with further IP dosing. If serum test is positive, the patient should be excluded.
• Other laboratory parameter exclusions at screening (Visit 1) and on repeat testing (if applicable) prior to Visit 2: 
  • Creatinine > 2.5 mg/dL (221 µmol/L);
  • WBC < 4 × 10^9 /L;
  • Platelet count < 120000/mm^3;
  • Haemoglobin < 8 g/dL (< 80 g/L).
• Alcohol/substance abuse: a history (or suspected history) or alcohol misuse or substance abuse within 2 years prior to screening (Visit 1).
• Other investigational non-biologic product: receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to screening (Visit 1), whichever is longer.
• Adherence: patients who have known evidence of lack of adherence to prescribed medications and/or ability to follow physician's recommendations.
• ALT or AST level ≥ 3 times the ULN confirmed during screening period, confirmed by repeated testing (if applicable) during screening period. Transient increase of AST/ALT level that resolves by the time of randomisation is acceptable if, in the Investigator’s opinion, the patient does not have an active liver disease and meets other eligibility criteria.
• Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening/run-in period, which in the opinion of the Investigator, may put the patient at risk, because of his/her participation in the study, or may influence the results of the study, or the patients’ ability to complete entire duration of the study. Any other medical illness that precludes study involvement.
• Receipt of blood products within 30 days prior to screening (Visit 1).
• Receipt of live attenuated vaccines 30 days prior to screening (Visit 1).

• Males and females, 18-80 years of age.
• Patients with cHP for ≥ 12 months at the time of screening.
• Two paired measurements of showing low parathyroid hormone (PTH) and serum calcium either below normal or within normal under standard of care.
• Requirement for therapy with calcitriol ≥0.5 mcg per day or alphacalcidol ≥1 mcg per day, and requirement for supplemental oral calcium treatment ≥ 1000 mg per day over and above patient's dietary calcium intake at Day 1 visit.
• Successful completion of the Optimization period based on two consecutive measurements of albumin-adjusted serum calcium at least 1 week apart within the range of 7.8 to 9.0 mg/dL and with no more than 25% of change in the daily dose of any of active vitamin D and oral calcium supplements between the two measurements.
• Thyroid-stimulating hormone (TSH) within the lower limit of normal and 1.5-fold of the upper limit of normal at screening; if on suppressive therapy for a history of thyroid cancer, TSH level must be ≥ 0.2 mIU/mL and thyroid medication should be stable for at least 6 weeks prior to treatment.
• Prior to start of treatment:
  • Magnesium level within laboratory normal limits;
  • 25(OH) vitamin D levels of 30-70 ng/mL (75-175 nmol/L);
  • eGFR ≥ 30 mL/min/1.73m² during screening.
• Able to perform daily subcutaneous self-injections of study drug (or have a designee to perform injections) via a pre-filled injection pen.
• Female patients of non-childbearing potential or using an effective method of contraception throughout the study. Women of childbearing potential should have a negative pregnancy test.
• Able and willing to provide written and signed informed consent in accordance with GCP.

• Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation.
• Clinically significant abnormal values at screening for hematology, clinical chemistry, coagulation or urinalysis.
• Abnormal arterial pressure at screening, defined as (1) systolic blood pressure < 100 mmHg, or (2) systolic blood pressure > 150 mmHg, and/or diastolic blood pressure > 100 mmHg.
• Heart rate at rest outside the range of 50-100 beats/minute at screening.
• Clinically significant abnormal standard 12-lead electrocardiogram indicative of severe cardiac disease.
• Known history of autosomal-dominant hypocalcemia or known pseudohypoparathyroidism (impaired responsiveness to PTH).
• Any current disease (other than hypoparathyroidism) that might affect calcium metabolism, calcium-phosphate homeostasis or PTH levels.
• Patients with increased risk for osteosarcoma.
• Current uncontrolled active disease processes that may adversely affect gastrointestinal absorption.
• History of cerebrovascular accident within 6 months prior to screening.
• History of active uncontrolled malignancy over the past 2 years at time of screening.
• History of any other cancer other than thyroid cancer (except basal cell skin cancer or squamous cell skin cancer) who have not been disease-free for a period of at least 2 years at the time of screening.
• Acute gout < 2 months prior to screening.
• Dependent on parenteral calcium infusions to maintain calcium homeostasis.
• Use of medications such as loop and thiazide diuretics, raloxifene hydrochloride, lithium, methotrexate, cardiac glycosides or systemic corticosteroids within 4 weeks prior to start of treatment.
• Previous treatment with PTH/parathyroid hormone-related protein-like drugs, including PTH(1-84) and PTH(1-34) within 3 months of screening.
• Use of other drugs known to influence calcium and bone metabolism within 4 weeks of screening.
• Use of oral bisphosphonates within 6 months of screening or intravenous bisphosphonate within 12 months of screening.
• Use of denosumab within 18 months of screening.
• Seizure disorder/epilepsy with history of a seizure within 6 months of screening.
• History of symptomatic urinary tract calculi within 3 months of screening.
• Irradiation to the skeleton within 2 years of screening.
• Pregnant or breastfeeding female patients.
• Participation in any other interventional study in which the patient received an investigational drug or device within 2 months or within 5 times the half-life of the investigational drug (whichever comes first) prior to screening.
• Any disease or condition that, in the opinion of the investigator, may require treatment or make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the study treatment or procedures, including treated malignancies that are likely to recur within the approximate duration of the trial.
• Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule.
• Known allergy or sensitivity to PTH or any of the excipients.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 4/27/23. Questions regarding updates should be directed to the study team contact.

• Adult ≥ 18 years of age.
• Able to provide informed consent.
• Stable heart failure (NYHA II-IV) on maximally-tolerated background therapy (as determined by the site Principle Investigator) for at least 2 weeks prior to randomization.
• Able and willing to perform a 6MWT at the time of randomization.
• Reduced left ventricular ejection fraction. Assessment must be performed at least 12 weeks after major cardiac surgical intervention including coronary artery bypass graft (CABG), valvular repair/replacement, or cardiac resynchronization
• therapy (CRT) device implantation.
  • Left ventricular ejection fraction ≤ 40% obtained during the screening visit OR either of the following:
    • Historical value of ejection fraction ≤ 40% within 24 months of screening visit;
    • Historical value of ejection fraction ≤ 30% within 36 months of screening visit.
• Hemoglobin > 9.0 g/dL and < 13.5 g/dL (females) or < 15.0 g/dL (males) within 28 days of randomization.
• Serum ferritin < 100 ng/mL or 100 to 300 ng/mL with TSAT < 20%. Patients with screening ferritin <15 ng/mL must have documentation of an appropriate evaluation, as determined by the Principle Investigator, within 3 months of screening and prior to randomization.
• Either documented hospitalization for heart failure within 12 months of enrollment or elevated N-terminal-pro-brain natriuretic peptide (NT-proBNP) within 90 days of randomization:
  • For patients in normal sinus rhythm: N-terminal-probrain natriuretic peptide (NT-proBNP) >600 pg/mL (or BNP > 200 pg/mL);
  • For patients in atrial fibrillation: NT-proBNP >1000 pg/mL (or BNP > 400 pg/mL.
    • NOTE: NT-proBNP must be used to confirm eligibility for patients taking sacubitril/valsartan.

• Known hypersensitivity reaction to any component of FCM.
• History of acquired iron overload, or the recent receipt (within 3 months) of erythropoietin stimulating agent, IV iron therapy, or blood transfusion.
• Acute myocardial infarction, acute coronary syndrome, transient ischemic attack, or stroke within 30 days of enrollment.
• Uncorrected severe aortic stenosis, severe valvular regurgitation, or left ventricular outflow obstruction requiring intervention.
• Current atrial fibrillation or atrial flutter with a mean ventricular response rate > 100 per minute (at rest).
• Current or planned mechanical circulatory support or heart transplantation.
• Hemodialysis or peritoneal dialysis (current or planned within the next 6 months).
• Documented liver disease, or active hepatitis (i.e., alanine transaminase or aspartate transaminase > 3 times the upper limit of normal range).
• Current or recent (within 3 years) malignancy with exception of basal cell carcinoma or squamous cell carcinoma of the skin, or cervical intraepithelial neoplasia.
• Active gastrointestinal bleeding.
• Female participant of child-bearing potential who is pregnant, lactating, or not willing to use adequate contraceptive precautions during the study and for up to 5 days after the last scheduled dose of study medication.
• Inability to return for follow up visits within the necessary windows.
• Concurrently in a study with an investigational product.

STEP 1 REGISTRATION
•DISEASE-RELATED CRITERIA

• All patients must have a histologically or cytologically proven diagnosis of adenocarcinoma of the prostate. Patients with pure small cell carcinoma* (SCC), sarcomatoid, or squamous cell carcinoma are not eligible. (*morphology must be consistent with SCC; synaptophysin or chromogranin positive by immunohistochemical staining is insufficient to diagnose SCC).
• Patients must have an intact prostate.
• Patients must have at least one of the following scans performed, showing evidence of metastatic disease:
  • technetium bone scan; OR
  • CT of abdomen & pelvis; OR
  • MRI of pelvis..
• Scans must be performed between 42 days prior to start of first hormonal therapy and 14 days following start of first hormonal therapy. Metastatic disease that is detected by PET scan only (NaF, PSMA, FACBC, C11) but not conventional imaging (Tc99 bone scan, CT or MRI) or solitary metastases by conventional imaging, must be confirmed histologically or cytologically.
• Patients with known brain metastases are not eligible. Brain imaging studies are not required for eligibility if the patient has no neurologic signs or symptoms suggestive of brain metastasis. If brain imaging studies are performed, they must be negative for disease.

STEP 1 REGISTRATION
•PRIOR/CONCURRENT THERAPY CRITERIA

• Patients must have received no more than 28 weeks of SST, as measured from the date of first hormonal therapy (LHRH agonist or LHRH antagonist) or surgical castration. SST is defined as current NCCN guidelines for metastatic prostate cancer.
• No prior local therapy for prostate adenocarcinoma is allowed (e.g., brachytherapy, HIFU, cryotherapy, laser ablative therapies). Any prior therapy for benign conditions, such as obstruction, are acceptable (e.g., transurethral resection of the prostate, greenlight laser ablation, microwave ablation).
• Patients must not have received any prior systemic therapy for prostate cancer, outside of line of SST to be used for duration of study.
• Patients must not have progressed while on SST.
• Patients with oligometastatic prostate cancer may receive metastasis directed therapy to up to four sites of disease prior to randomization.

STEP 1 REGISTRATION
•CLINICAL/LABORATORY CRITERIA:

• Patients must be ≥ 18 years of age.
• Patients must have a complete physical examination and medical history within 28 days prior to registration.
• Patients must have a documented PSA:
  • Prior to initiation of SST;
  • Within 28 days prior to registration;
  • Any additional PSAs measured while receiving SST should be recorded.
• Patients must have a testosterone lab documented within 28 days prior to registration. Any additional testosterone labs measured while receiving SST should be recorded as well as pretreatment initiation if available.
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated Stage 0, I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.

STEP 1 REGISTRATION
•SPECIMEN SUBMISSION CRITERIA

• Patients must be offered the opportunity to participate in translational medicine studies and specimen banking for future studies.

STEP 1 REGISTRATION - QUALITY OF LIFE CRITERIA

• Patients who can complete Patient-Reported Outcome instruments in English, Spanish or French, must participate in the quality of life studies.

STEP 1 REGISTRATION - REGULATORY CRITERIA

• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
• As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.

STEP 2 RANDOMIZATION
•DISEASE-RELATED CRITERIA

• Patients must have no evidence of disease progression during the 28 weeks of SST, as shown by:
  • PSA measure;
  • imaging (bone scan and one of the following: CT of abdomen & pelvis, MRI of abdomen & pelvis, CT of abdomen & MRI of pelvis) within 42 days prior to randomization.
• Patients must have no evidence of symptomatic deterioration (as defined by physician discretion) within 28 days prior to randomization.
• Patients must have consultation with a urologist and have surgically resectable disease regardless of definitive treatment intent or randomization.

STEP 2 RANDOMIZATION - PRIOR/CONCURRENT THERAPY CRITERIA

• Patients must have received at least 22 and no more than 28 weeks of SST, as measured from the date of first hormonal therapy (LHRH agonist or LHRH antagonist) or surgical castration. SST is defined by current NCCN guidelines for metastatic prostate cancer.
• Patients must not be planning to receive docetaxel after randomization.
• Any toxicities from SST must have resolved to ≤ Grade 1 (CTCAE Version 5.0) prior to randomization.
• Patients may have received elective metastasis directed therapy to oligometastatic sites (≤ 4 sites). All treatment must be completed prior to randomization.

STEP 2 RANDOMIZATION - CLINICAL/LABORATORY CRITERIA

• Patients must have a PSA performed within 28 days prior to randomization.
• Patients must have a testosterone < 50 ng/dL within 28 days prior to randomization.
• Patients must have a Zubrod performance status of 0 – 1 within 28 days prior to randomization.

For Substudy 1:

• Subject achieved clinical response in Study M14-431 or Study M14-433.
• Subject completed Week 12 (in subjects who achieve response at Week 12) or Week 24 (in subjects who achieve response at Week 24) visit and procedures in Study M14-431 or Study M14-433.
  • Note: Subjects completing Part 3/Cohort 3 of Study M14-431, who received open-label Extended Treatment, should enroll in Substudy 2.

For Substudy 2:

• Subject completed Week 52 of the maintenance period of Study M14-430 (Substudy 1).  Completion includes the Week 52 endoscopy of Substudy 1.
• Subject achieved clinical response at Week 24 and completed Week 24 visit and procedures in Part 3/Cohort 3 of Study M14-431.

Substudy 1 and 2:

• Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study.
• Subject who has a known hypersensitivity to upadacitinib or its excipients, or had an AE during Study M14-431, M14-433, or Substudy 1 of Study M14-430 that in the investigator's judgment makes the subject unsuitable for this study.
• Subject with any active or chronic recurring infections based on the investigator's assessment that makes the subject an unsuitable candidate for the study. Subjects with serious infections undergoing treatment may be enrolled BUT NOT dosed until the infection treatment has been completed, and the infection is resolved, based on the investigator's assessment.
• Subjects with high grade colonic dysplasia or malignancy diagnosed at the endoscopy performed at the final visit of Study M14-431, M14-433, or Substudy 1 of Study M14-430 (Week 52).

Substudy 1 and 2

• Subject is  considered by the  investigator, for any reason, to be an unsuitable candidate for the study.
• Subject who has a known hypersensitivity to upadacitinib or its excipients, or had an AE during Studies M14-431, M14-433, or Substudy 1 of Study M14-430 that, in the investigator's judgment, makes the subject unsuitable for this study.
• Anticipated requirement or receipt of any live vaccine during study participation including up to 30 days after the last dose of study drug.
• Female subjects with a confirmed positive pregnancy test at the final visit in Studies M14-431, M14-433, or Substudy 1 of Study M14-430, or who is considering becoming pregnant during the study.
• Subject is not in compliance with prior and concomitant medication requirements throughout Studies M14-431, M14-433, or Substudy 1 of Study M14-430.
• Subject with any active or chronic recurring infections based on the investigator's assessment makes the subject an unsuitable candidate for the study. Subjects with serious infections undergoing treatment may be enrolled BUT NOT dosed until the infection treatment has been completed, and the infection is resolved, based on the investigator's assessment.
• Current evidence of active or untreated latent tuberculosis.
• Subjects with high grade colonic dysplasia or malignancy diagnosed at the endoscopy performed at the final visit of Studies M14-431, M14-433, or Substudy 1 of Study M14-430 (Week 52).
• Current or history of malignancy or lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly; except for successfully treated non-metastatic cutaneous squamous cell, basal cell carcinoma, and/or localized carcinoma in situ of the cervix.
• Subject with a poorly controlled medical condition, such as uncontrolled diabetes, unstable ischemic heart disease, moderate or severe congestive heart failure, recent cerebrovascular accidents, and any other condition which, in the opinion of the investigator or sponsor, would put the subject at risk by participation in this study.
• Laboratory values from the visit immediately prior to the Week 0 Visit meeting the following criteria:
  • AST or ALT > 3 × upper limit of normal (ULN);
  • Estimated glomerular filtration rate (eGFR) by simplified 4-variable;
  • Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m2;
  • Total WBC count < 2,000/μL;
  • Absolute neutrophil count (ANC) < 1,000/μL;
  • Platelet count < 50,000/μL;
  • Absolute lymphocyte count < 500/μL;
  • Hemoglobin < 8 g/dL.
• Enrollment in another interventional clinical study while participating in this study.

• Informed consent obtained before any trial-related activity.
• Age ≥ 18 years and ≤ 90 years at Screening.
• Diagnosis of SBS and with the latest intestinal resection being at least 6 months prior to Screening and considered stable with regard to PS need. No restorative surgery planned in the trial period.
• Requiring PS at least 3 days per week.
• Willing to adhere to an individual pre-defined drinking menu during 48-hours measuring intervals.
• Willing to maintain a stable weight (± 5%) for the duration of the trial (24 weeks).
• Having:
  • A stoma; or
  • Colon-in-Continuity (CiC) with documented colonoscopy performed during Screening and which does not give rise to any safety concerns; and
  • Able to separate stool and urine during the 48 hours measuring intervals.
    • Note: A colonoscopy performed within 6 months prior to Screening and not giving rise to any safety concerns is accepted. For patients with a remnant colon, which is not connected to the passage of foods and is thereby dormant, a computerized tomography (CT) scan or magnetic resonance imaging (MRI) (if standard of care at site) will suffice at the discretion of the investigator.

• More than 2 SBS-related or PS-related hospitalizations within 6 months prior to Screening. No SBS-related hospitalizations within 30 days prior to randomization. 
• Poorly controlled inflammatory bowel disease that is moderately or severely active or fistula interfering with measurements or examinations required in the trial.
• Bowel obstruction. 
• Known radiation enteritis or significant villous atrophy.
• Cardiac disease defined as:
  • decompensated heart failure (New York Heart Association [NYHA] Class III-IV);
  • unstable angina pectoris; and/or
  • myocardial infarction within the last 6 months prior to Screening. 
• Clinically significant abnormal ECG.
• Repeated (2 or more consecutive measurements separated by at least 15 minutes) systolic blood pressure measurements > 180 mm Hg.
• Human immunodeficiency virus positive, acute liver disease, or unstable chronic liver disease. 
• Any history of colon cancer. History of any other cancers unless disease-free state for at least 5 years.
• Estimated creatinine clearance (CLcr; by the Cockcroft-Gault formula) < 30 mL/min.
• Hepatic impairment defined as:
  • Total bilirubin ≥ 2 × the upper limit of normal (ULN); or
  • Aspartate aminotransferase (AST) ≥ 5 × ULN; or
  • Alanine aminotransferase (ALT) ≥ 5 × ULN.
• Use of GLP-1, GLP-2, human growth hormone (HGH), somatostatin, or analogs thereof, within 3 months prior to Screening.
• Use of dipeptidyl peptidase (DPP)-4 inhibitors within 3 months prior to Screening.
• Systemic immunosuppressive therapy that has been introduced or has been unstable within 3 months prior to Screening.
• Unstable biological therapy (e.g., anti-TNF-α, natalizumab, etc.) within 6 months prior to Screening, including significant changes in doses or switch of drug.
• Females of childbearing potential, who are pregnant, breast-feeding, intend to become pregnant or are not using highly effective contraceptive methods. 
• Known or suspected hypersensitivity to glepaglutide or related products.
• Previous exposure to glepaglutide.
• Previous participation (randomization) in this trial.
• Current, or within 30 days prior to Screening, participation in another interventional clinical trial that includes administration of an active compound.
• Mental incapacity or language barriers which preclude adequate understanding or cooperation, or unwillingness to comply with trial requirements.
• Any condition or disease or circumstance that in the Investigator's opinion would put the patient at any undue risk, prevent completion of the trial, or interfere with the analysis of the trial results.
• Committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• An employee of the sponsor or Investigator or otherwise dependent on them.

• Males and females.
• Participants with severe Von Willebrand Disease with Type 3 VWD or VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 30% of pooled normal control plasma on more than one occasion.
• Participants with clinically severe VWD as defined by VWF:RCo or VWF:Ag ≤ 40% of normal with severe bleeding phenotype defined as requiring use of recurrent factor concentrates.
• Co-enrollment in the ATHN dataset.

Exclusion Criteria

• Diagnosis of platelet-type VWD;
• Diagnosis of acquired VWD (clinical diagnosis made by the hemophilia health care provider, typically based on association with hypothyroidism, lymphoproliferative and myeloproliferative disorders, malignancies and cardiovascular disease, typically aortic stenosis or LVAD).

Eligibility last updated 12/15/21. Questions regarding updates should be directed to the study team contact.

• Females or males diagnosed with pathologically (histologically) proven invasive mammary carcinoma (ductal, lobular or other) of the breast who have undergone either mastectomy or lumpectomy with any type of axillary surgery or axillary sampling.
• For patients who have undergone lumpectomy, any type of mastectomy and any type of reconstruction (including no reconstruction) are allowed.
• For patients who have undergone lumpectomy, there are no breast size limitations.
• Patients with non-metastatic breast cancer are eligible. This includes American Joint Committee on Cancer (AJCC) 7th edition left- or right-sided breast cancer clinical or pathologic stage I, II, III or loco-regionally recurrent at time of diagnosis. For patients that receive neoadjuvant chemotherapy, AJCC 7th edition left- or right-sided breast cancer pathologic stage yp 0, I, II, III are eligible.
• Bilateral breast cancer is permitted. Patients with bilateral breast cancer will be stratified as left-sided.
• Must be proceeding with breast/chest wall and nodal radiation therapy including internal mammary node treatment.
• Must have a pertinent history/physical examination within 90 days prior to registration.
• Age ≥ 21 years
• Negative pregnancy test by urine or serum or waiver of pregnancy testing per local institutional policy within 30 days prior to randomization according to local standards for women of childbearing potential.
• ECOG Performance Status 0
  •2 (asymptomatic to symptomatic but capable of self-care) within 45 days prior to randomization.
• Confirmation that the patient's health insurance will pay for the treatment in this study (patients may still be responsible for some costs, such as co-pays and deductibles). If the patient's insurance will not cover a specific treatment in this study and the patient still wants to participate, confirmation that the patient would be responsible for paying for any treatment received.
• Patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 180 days prior to registration as documented in the medical record. HIV testing is not required for eligibility for this protocol.
• The patient must provide study-specific informed consent prior to study entry.

Exclusion Criteria

• Definitive clinical or radiologic evidence of metastatic disease, as documented by the treating institution.
• Prior radiotherapy to the ipsilateral chest wall or ipsilateral breast or thorax. Individuals with prior radiotherapy in the contralateral breast or chest wall are eligible.
• Any radiation therapy for the currently diagnosed breast cancer prior to randomization.
• Dermatomyositis with a CPK level above normal or with an active skin rash or scleroderma.
• Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 12/13/22. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 12/13/22. Questions regarding updates should be directed to the study team contact.

• Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed.
• Men and women 18 years of age or older.
• For Phase 1, histologically and / or cytological confirmed unresectable or metastatic solid malignancy.
• For Phase 2, five cohorts will be enrolled:
  • Cohort A-1: NSCLC EXON 14 skip mutation (c-Met naïve) for first line treatment;
  • Cohort A-2: NSCLC EXON 14 skip mutation (c-Met naïve) pretreated subjects with no more than 3 lines of prior therapy in the metastatic setting;
  • Cohort B: NSCLC EXON 14 skip mutation (c-Met experienced; radiographic progression on prior c-Met inhibitor);
  • Cohort C: basket of tumor types with c-Met high level amplification (NSCLC EXON 14 skip mutation excluded);
  • Cohort D: basket of tumor type with c-Met fusions.
• Cohort A-1: EXON 14 Non-small-Cell Lung Cancer – c-Met inhibitor naïve:
  • Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations as determined by MI Transcriptome™ companion diagnostic (CDx) by central laboratory, Caris Life Sciences;
  • All histologies, including pulmonary sarcomatoid carcinoma and squamous;
  • Unresectable or metastatic disease (Stage 3b/4);
  • Treatment naïve subjects in first line;
  • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
• Cohort A-2: EXON 14 Non-Small-Cell Lung Cancer – c-Met inhibitor naïve (≥ 2L):
  • Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations;
  • All histologies, including pulmonary sarcomatoid carcinoma and squamous;
  • Unresectable or metastatic disease (Stage 3b/4);
  • Pretreated subjects refractory to or intolerable to standard therapies with no more than three lines of prior therapy in the metastatic setting;
  • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
• Cohort B: EXON 14 Non-Small-Cell Lung Cancer – c-Met inhibitor experienced:
  • Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations; 
  • All histologies, including pulmonary sarcomatoid carcinoma and squamous;
  • Unresectable or metastatic disease (Stage 3b/4);
  • Refractory to standard therapies with no more than three prior lines of therapy in the metastatic setting.
• Cohort C: Basket Tumor Types (c-Met high-level amplifications):
  • Any tumor type regardless of histology, including osimertinib relapsed/refractory NSCLC, excluding NSCLC EXON 14 skip mutation, that meets inclusion criteria c-Met high-level amplification;
  • Unresectable or metastatic disease, refractory to or intolerant of standard therapies, or refused standard therapies, or if therapy was unavilable or unfeasible, with no more than three prior lines of therapy in the metastatic setting;
  • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
• Cohort D: Basket Tumor Types (c-Met fusions):
  • Any other tumor type histology that meets inclusion criteria c-Met fusions;
  • Unresectable or metastatic disease, refractory to or intolerant of standard therapies. or refused standard therapies, or if therapy unavailable or unfeasible, with no more than three prior lines of therapy in the metastatic setting;
  • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
• Abnormal c-Met dysregulation, by tissue and/or plasma, defined as the following from archival/local results or molecular pre-screening evaluations. 
• Phase 1 (100, 200, and 300 mg Cohorts):
  • c-Met overexpression by IHC 2+ ≥ 50% of tumor cells; or
  • c-Met amplification (c-Met/Cep-7 ratio ≥ 2.2 or GCN ≥ 6 gene copy); or
  • c-Met EXON 14 skip mutation per NGS or RT-PCR; or
  • c-Met fusions including the following, but not limited to: BAIAP2L1-MET; C8orf34- MET; CAPZA2-MET; DCTN1-MET; EPS15-MET; LRRFIP1-MET; MET-MET; OXR1- MET; PPFIBP1-MET; PTPRZ1-MET; TFG-MET; TPR-MET; TRIM4-MET; ZKSCAN1- MET; KIF5B-MET and any other known c-Met activating mutations.
• Phase 1 (400 mg Cohort) and Phase 2 RP2D:
  • c-Met high-level amplification (c-Met/Cep-7 ratio of ≥ 2.2 or GCN of ≥ 6 copy). A minimum of five subjects of the high-level amplification (c-Met/Cep-7 ratio of ≥ 5 or GCN ≥ 10 gene copy) for the Stage 1 of the Simon 2 stage design is required); or
  • c-Met EXON 14 skip mutation per NGS; or
  • c-Met fusions including the following, but not limited to: BAIAP2L1-MET; C8orf34- MET; CAPZA2-MET; DCTN1-MET; EPS15-MET; LRRFIP1-MET; MET-MET; OXR1- MET; PPFIBP1-MET; PTPRZ1-MET; TFG-MET; TPR-MET; TRIM4-MET; ZKSCAN1- MET; KIF5B-MET; or
  • other c-Met mutations in Dose Escalation (400 mg Cohort).
• Local/archival result of a positive c-Met dysregulation is required (except in Cohort A-1 in US). In Phase 2, Cohorts A-2 and D require provision of tumor tissue samples (archival or fresh tumor biopsy) either from the primary or a metastatic site. For Cohorts B and C, provision of tumor tissue (archival or fresh tumor biopsy) or blood (plasma) sample for entry is acceptable.
• In Phase 2, treated or untreated asymptomatic parenchymal CNS disease or leptomeningeal disease is allowed. 
• Measurable disease according to RECIST v1.1 (or relevant criteria per tumor type).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0–1.
  • Acceptable organ function, as evidenced by the following laboratory data during Screening period: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN;
  • Total serum bilirubin ≤ 1.5 x ULN;
  • For subjects with liver metastases: Total bilirubin ≤ 3.0 x ULN, AST/ ALT ≤ 5 x ULN;
  • Absolute neutrophil count (ANC) ≥ 1500 cells/mm^3 (1.5 x 10^9 /L); 
  • Platelet count ≥ 100,000 cells/mm^3 (100 x 10^9 /L);
  • Serum creatinine levels ≤ 1.5 ULN or Creatinine Clearance (CrCl) ≥ 60 mL/min as calculated by the Cockcroft-Gault method;
  • Hemoglobin ≥ 9 g/dL.
• For all prior anticancer treatment, including radiotherapy, chemotherapy, or targeted agents or hormonal therapy, a duration of 30 days or 5 half-lives of the agents used, whichever is shorter, must have elapsed, and any encountered toxicity must have resolved to levels meeting all the other eligibility criteria prior to the first dose of study treatment. Palliative radiotherapy to non-target lesions should be completed within 2 weeks prior to APL-101 administration.
• Adequate cardiac function (≤ NYHA class II) or normal cardiac function with left ventricular ejection fraction (LVEF) ≥ 50% at screening.
• Women of child-bearing potential (WOCBP) must have a negative serum or β-human chorionic gonadotropin (β-hCG) at screening or evidence of surgical sterility or evidence of postmenopausal status. Post-menopausal status is defined as any of the following: natural menopause with menses > 1 year ago; radiation or chemotherapy inducted oophorectomy with menses > 1 year ago and follicle stimulating hormone (FSH) level in the menopausal range.
• All subjects with reproductive potential must agree, and site must document as such, the use of effective contraceptive measures (e.g., oral contraceptives, intrauterine device, or double barrier method of condom and spermicide) during the study and for 7 months (WOCBP) or 4 months (men) following the last dose of study drug.
  • Notes: A postmenopausal woman will be defined as having no menses for 12 months without an alternative medical cause. Male sterility will be defined as only men sterilized surgically. For male subjects with a pregnant partner, a condom should be used for contraception. For male subjects with a non-pregnant female partner of child-bearing potential and woman of childbearing potential one of the following birth control methods with a failure rate of less than 1% per year when used consistently and correctly are recommended:
  • Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally;
  • Progesterone-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant;
  • Intrauterine device (IUD);
  • Intrauterine hormone-releasing system (IUS);
  • Bilateral tubal occlusion;
  • Vasectomized partner;
  • Sexual abstinence (considered a highly effective method only if defined as refraining from hetersexual intercourse during the entire period of risk associated with the study treatment. The reliabiity of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject).
• Birth control methods unacceptable for this clinical trial are:
  • Periodic abstinence (calendar, symptothermal, or post-ovulation methods);
  • Withdrawal (coitus interruptus);
  • Spermicide only;
  • Lactational amenorrhea method.
• Resolution of all acute chemotherapy, radiotherapy or surgery-related AEs to Grade ≤ 1, except for alopecia.
• No planned major surgery within 4 weeks of first dose of APL-101.
• Willing and able to participate in all required evaluations and procedures in this study including swallowing APL-101 in accordance administration schedule outlined.

• Hypersensitivity to APL-101, excipients of the drug product, or other components of the study treatment regimen.
• Known actionable mutation/gene rearrangement of EGFR (except for Cohort C), ALK, ROS1, RET, NTRK, KRAS, and BRAF.
• Use or intended use of any other investigational product, including herbal medications, through Study Treatment Termination.
• Active uncontrolled systemic bacterial, viral, or fungal infection or clinically significant, active disease process, which in the opinion of the investigator makes the risk:benefit unfavorable for the participation of the trial. Screening for chronic conditions is not required.
• Life-threatening illness, significant organ system dysfunction or comorbid conditions, or other reasons that, in the investigator’s opinion, could compromise the subject’s safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of APL-101.
• Unstable angina or myocardial infarction within 1 year prior to first dose of APL-101, symptomatic or unstable arrhythmia requiring medical therapy, history of congenital prolonged QT syndrome, prolonged QT interval corrected by Fridericia formula (QTcF) at screening (> 450 msec based on the average of 3 measurements), or concurrent treatment with a medication that is a known risk for prolonging the QT interval.  Concomitant Therapy). Chronic controlled atrial fibrillation is not excluded.
• Historical seropositive results consistent with active infection for hepatitis C virus (HCV) or hepatitis B virus (HBV) with high viral loads not actively managed with antiviral therapy and human immunodeficiency virus (HIV) positive patients who are not clinically stable or on). If history is unclear, a test at Screening will be required.
• Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments.
• Unable to swallow orally administered medication whole.
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g., Crohn’s, ulcerative colitis, active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
• Women who are breastfeeding.
• Subjects with complications from prior radiation therapy will not be eligible until AEs return to baseline or ≤ Grade 1.
• History of another malignancy within 3 years prior to Cycle 1 Day 1. A subject with the following malignancies is eligible for this study if, in the opinion of the Investigator, they do not pose a significant risk to life expectancy:
  • Carcinoma of the skin without melanomatous features;
  • Curatively treated cervical carcinoma in situ;
  • Bladder tumors considered superficial such as noninvasive (TIa) and carcinoma in situ (TIs), thyroid papillary cancer with prior treatment, prostate cancer which has been surgically or medically treated and not likely to recur within 3 years.
• Subjects who are unable or unwilling to discontinue excluded mediciations for at least 5 half-lives prior to first dose of study drug.
• Subjects with active COVID-19 infection.

Eligibility last updated 9/9/21. Questions regarding updates should be directed to the study team contact.

Key

• Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• ECOG Performance Status of ≤ 2 within 28 days prior to registration
• Archival tissue must be available and identified during screening and shipped prior to Day -21. If archival tissue is not available and the subject is not undergoing a standard of care biopsy, the subject must undergo a research biopsy to obtain fresh tissue prior to start of treatment.
• Carcinoma of unknown primary after the following diagnostic procedures have been performed if clinically indicated and are unrevealing of the primary site:
  • Complete history and clinically appropriate physical
  • CT scan of chest, abdomen, and pelvis
  • Directed evaluation of symptomatic areas
  • Mammogram in women
  • Colonoscopy in patients with liver metastasis or an elevated CEA
  • Direct pathologic comparison with prior tumor specimens, where possible, even if prior tumor is early-stage or clinically remote from current disease
• Histologic confirmation of metastatic adenocarcinoma, poorly differentiated non-small cell carcinoma, or poorly differentiated squamous carcinoma. NOTE: Pathology consultation at Mayo Clinic is recommended if clinically indicated. One scenario is where unknown primary is the most likely diagnosis but immunostains show relatively site-specific marker staining (e.g., CD45, TTF1, chromogranin, GATA3, PAX8, PSA, melanocytic markers). Information provided for pathology consultation should include recent H&P and imaging reports.
• If available, submission of genomic sequencing or expression profiling results is mandatory.
• At least one measurable lesion (per RECIST 1.1) outside the planned RT fields.
• Stable or progressive disease after, or was unable to tolerate, at least one line of prior anticancer therapy for this disease. NOTE: For patients with stable disease, it is strongly encouraged to confirm the presence of active disease (eg, demonstrating FDG avidity via PET or repeat biopsy).
• Radiation oncology consultation at enrolling site ≤ 56 days prior to registration to confirm at least two metastatic lesions which are targetable by RT at doses and schedule prescribed in this study and which reside in non-overlapping RT fields.
• Absolute Neutrophil Count (ANC) ≥ 900 K/mm3
• Hemoglobin (Hgb) ≥ 8.5 g/dL without transfusion or EPO dependency (≤ 7 days prior to assessment)
• Platelets ≥ 90,000 / mcL
• Creatinine OR Calculated creatinine clearance: ≤ 1.5 X upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
• Bilirubin Total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN OR total bilirubin ≤2 X ULN if liver metastases are present
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
• Albumin > 2.5 g/dL
• Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to registration. NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: breast milk cannot be stored for future use while the mother is being treated on study
• Females of childbearing potential and males must be willing to abstain from heterosexual activity (abstinence) or use effective methods of contraception as described in Section 5.5 from the time of informed consent until 120 days after treatment discontinuation. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
• Willingness to return to the enrolling institution for follow up
• Willingness to provide tissue and blood samples for correlative research purposes

• Prior radiation to an area of the body which, if included in the current radiation field, poses an unacceptably high risk of toxicity in the opinion of the investigator. NOTE: A prior field that overlaps with the current field, by itself, does not exclude the patient.
• Any of the following
  • Melanoma. NOTE: Positive tumor staining for S-100 or HMB45 alone does not exclude patients.
  • If immunostains are performed, and any of the below tests are positive:
    • Hematologic CD45+ (others such as CD2, CD20, CD30, CD43 also suggest hematologic origin)
    • Lung or thyroid origin (Thyroid Transcription Factor [TTF-1]). NOTE: Patients with biopsy proven TTF-1 positive tumor who do not have clinical evidence for either lung or thyroid cancer (e.g. a dominant lung mass) are still eligible.
• Progressed on 4 or more lines of prior chemotherapy for this cancer. NOTE: Bisphosphonates and neoadjuvant/adjuvant anticancer therapies (including locally directed therapies) do not count as a line of therapy with regard to this exclusion criteria.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. NOTE: Inhaled steroids or steroid injections for joint disease are allowed.
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Prior severe allergic reactions to a monoclonal antibody or hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Other active malignancy which requires current treatment and which in the opinion of the site investigator is likely to interfere with evaluation of disease assessment. NOTE: Continuation of hormonal therapies is allowed.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Major surgery ≤ 4 weeks from registration. NOTE: Diagnostic laparoscopy (without other intervention) and/or biopsies (needle aspirate, core biopsy, open biopsy, etc…) are not considered major surgery
• Uncontrolled intercurrent illness which in the opinion of the investigator poses unacceptably high risk when combined with study treatment, including but not limited to the following:
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Severely impaired lung function
  • Known history of active TB (Bacillus Tuberculosis)
  • Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (NOTE: Optimal glycemic control should be achieved before starting trial therapy.)
  • Significant underlying liver disease such as cirrhosis or severe hepatic impairment
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• For patients in whom planned RT fields will include the heart, any of the following heart conditions, if in the opinion of the investigator they pose unacceptably high risk when combined with study treatment:
  • Prior symptomatic congestive heart failure
  • Documented myocardial infarction ≤6 months prior to registration (pretreatment ECG evidence of infarct only will not exclude patients)
  • Prior significant ventricular arrhythmia requiring medication
  • Prior 2nd or 3rd degree heart block or other types of clinically significant conduction delay ≤ 6 months prior to registration
  • Clinically significant pericardial disease (including pericardial effusion, pericarditis) or cardiac valvular disease ≤12 months prior to registration

NOTE: As part of history and physical, all patients must be assessed for signs or symptoms of cardiac disease, or for prior history of cardiac disease. These conditions include but are not limited to diseases related to cardiac valves, pericardium, myocardium, atrioventricular delays or arrhythmias. It is strongly recommended that signs or symptoms of potentially clinically significant disease be evaluated with comprehensive cardiac echo.

• For patients in whom planned RT fields during the study will include the chest, any of the following, if in the opinion of the site investigator they pose unacceptably high risk when combined with study treatment:
  • Prior fistula within thorax, including bronchoalveolar or esophageal.
  • Respiratory condition that required oxygen supplementation ≤ 3 months prior to registration
  • Clinically significant pulmonary hypertension ≤ 12 months prior to registration
  • Pneumonia requiring treatment ≤ 1 month prior to registration
  • Pulmonary embolism requiring treatment ≤ 6 months prior to registration
  • Pleural effusion requiring drainage ≤ 12 months prior to registration
• Has known history of or any evidence of active, non-infectious pneumonitis
• Currently uncontrolled hyper/hypothyroidism or hyper/hypocortism if in the opinion of the investigator they pose unacceptably high risk when combined with study treatment
• Received live vaccine ≤ 30 days prior to registration. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

• Eligible subjects will be those who provided prior consent under protocols 2128-05, 2118-05, 1465-04, and 489-04.

• Not in one of the above studies or deceased since prior contact.

Part 1 Dose Escalation:

• Histological or cytological diagnosis of solid tumor or Hodgkin’s Lymphoma who have relapsed or progressed and who are ineligible for all therapies with demonstrated clinical benefit.
  • Note: there is no limit to the number of prior treatment regimens; or
• Relapsed/refractory CD20 positive, B-cell NHL who have progressed following at least 2 prior systemic therapies. For aggressive histologies, frontline treatment must have included an alkylating agent; or
• Relapsed/refractory classical Hodgkin’s Lymphoma who have progressed following at least 2 prior systemic therapies and have progressed on checkpoint inhibitors (for Part 1B only);
• In Part 1A (45 mg/kg dose cohort only), Part 1B or Part 1C, archival tumor tissue and fresh post-treatment tumor biopsy obtained that allows preparation of the number of slides required in the separate study-specific specimen preparation instructions. Samples will be collected, processed and stored according to a separate laboratory manual.

Part 2 Dose Expansion for Combination Therapy with Rituximab:

• Relapsed/refractory DLBCL including histologically confirmed de novo (NOS) or transformed DLBCL (including transformation from follicular lymphoma of any grade, gastric MALT lymphoma and non-gastric MALT lymphoma) expressing CD20 by IHC (immunohistochemistry) or flow cytometry, primary mediastinal large B‐cell lymphoma, or T‐cell rich large B cell lymphoma, which are relapsed after at least 2 prior lines of systemic therapy including at least one rituximab-containing regimen or refractory disease to rituximab without better available choices.
• Confirmed marginal zone or follicular lymphoma (Grade 1-3a) expressing CD20+ by IHC or flow cytometry, relapsed after at least 2 prior line of systemic therapy including at least one rituximab-chemotherapy combination regimen or refractory to rituximab-containing regimen without better available choices; for indolent NHL histology, progression following prior treatment with an alkylating agent is allowed but not required.
  • NOTE: Refractory disease is defined as progression within 6 months of last dose of therapy. Relapsed disease is defined as disease recurrence or PD following a response after more than 6 months after last dose. Patients who received CAR-T therapy are allowed but cannot have progressive disease within 3 months of CAR-T therapy.
  • At least one measurable lesion as defined by Lugano criteria (version 2014).
  • Available fresh metastatic biopsy sample prior to study entry and one mandatory on-treatment tumor biopsy in US clinical sites, unless there is difficulty obtaining the sample (e.g., hard to reach tumors or biopsies requiring surgical intervention). Waiver of biopsy samples must be discussed with the medical monitor. Tumor biopsy samples collected should allow for sample preparation as detailed in the separate study-specific specimen preparation instructions. Mandatory archival pre-treatment or optional ontreatment FFPE tumor tissue that allow for sample preparation as detailed in the separate study-specific specimen preparation instructions will be collected from subjects enrolled at sites in China in the NHL cohort of Part 2.

Part 2 Dose Expansion for Combination Therapy with Pembrolizumab:

• Locally advanced or metastatic NSCLC that expresses PD-L1 (Tumor Proportion Score (TPS) ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum containing chemotherapy and checkpoint therapy.
• Patients with NSCLC must have progressed on treatment with one prior PD1/L1 inhibitor administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies.
• Patients who have had more than 1 prior PD-(L)1 inhibitor may be considered after discussion with the Medical Monitor. PD-1/L1 inhibitor treatment progression is defined by meeting all of the following criteria:
  • has received at least 2 doses of the PD-1/L1 inhibitor (must be an approved PD-1/L1 inhibitor);
  • has been on a continuous regimen of the PD-1/L1 inhibitor for at least 4 months without disease progression;
  • has demonstrated radiographic disease progression after PD-1/L1.
• Epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer with any high-grade serous component and immune-oncology (IO) treatment naive subjects with metastases progressed on or after platinum-containing therapy and are not eligible for further platinum-containing treatment. Patients must meet the following criteria:
  • platinum-refractory, platinum-resistant disease defined by progression of disease on a platinum-containing regimen or recurrence of disease within 180 days of receiving the last dose of platinum-based treatment;
  • must not have progressed during the first 3 months of first line platinum-based therapy or must not have progressed within 3 months after completing first line platinum-based therapy;
  • must not have evidence of bowel obstruction requiring hospitalization and decompression within the past 30 days;
  • must not have ascites that requires therapeutic paracentesis in the last 30 days;
  • must not have tumors with low malignant potential (ie. borderline tumors) or mucinous tumors.
  • Prior lines of therapy to include:
    • Patients must have had 1 to 3 prior lines of therapy including at least one bevacizumab-containing regimen or ineligible for all other available therapies; Or
    • Patients must be in the 4th or 5th line of treatment, irrespective of bevacizumab or who are ineligible for all therapies with demonstrated clinical benefit; Or
    • Patients with known BRCA-positive associated cancer or mutation, prior therapy must include PARP inhibitors (unless contraindicated)
  • At least one measurable lesion as defined by RECIST 1.1 solid tumors.
  • Available fresh metastatic biopsy sample prior to study entry and one mandatory on-treatment tumor biopsy, unless there is difficulty obtaining the sample (e.g., hard to reach tumors or biopsies requiring surgical intervention). Waiver of biopsy samples must be discussed with the medical monitor. Tumor biopsy samples collected should allow for sample preparation as detailed in the separate study-specific specimen preparation instructions.

All Subjects:

• Males or females, of any race, age ≥ 18 years;
• Be willing and able to provide written informed consent for the trial.
• Eastern Cooperative Oncology Group Performance Status 0 or 1.
• Subjects able to follow the requirements of the study protocol and complete the trial.
• Women of childbearing potential must:
  • Agree to use at least 2 effective contraceptive methods (1 highly effective method in combination with a barrier method; oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner), one of which must be barrier, from signing the ICF, throughout the study, and for up to 8 weeks following the last dose of TJ011133;
  • If using treatment with rituximab, women of childbearing potential should continue to use effective contraceptive methods for 12 months following treatment with rituximab;
  • If using treatment with pembrolizumab, women of childbearing potential should continue to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment;
  • Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at Screening; and have a negative serum or urine pregnancy test (Investigator’s discretion) within 72 hours prior to Cycle 1 Day -1 of study treatment (note that the screening serum pregnancy test can be used as the test prior to Day -1 study treatment if it is performed within the prior 72 hours);
  • Avoid conceiving for 8 weeks after the last dose of TJ011133;
  • Avoid donation of ova from signing the ICF until 8 weeks after the last dose of TJ011133 (12 months after the last dose of rituximab);
  • Agree to ongoing urine pregnancy testing, if clinically indicated, during the course of the study.
• Males must agree to use a condom (a latex condom is recommended) during sexual contact with a pregnant female or a female of childbearing potential and will avoid donation of sperm or having a female partner conceive from the time of signing the ICF, while participating in the study, during dose interruptions, and for at least 90 days after the last dose of study treatment, even if he has undergone a successful vasectomy.
• Subject with a QT interval corrected for heart rate using Fridericia's formula (QTcF) and/or QT interval corrected for heart rate using Bazett's formula of ≤ 450 msec for males, ≤ 470 msec for females.
• No systemic anti-cancer therapy within 4 weeks of starting study treatment or at least 5 half-lives (whichever is shorter) before study drug administration, and all AEs have either resolved or stabilized.
  • Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• A 28-day washout period after the completion of programmed death-1 (PD-1)/PD-L1 therapy.
• Adequate bone marrow function in subjects with solid tumors, including the following:
  • Part 1
  • Absolute neutrophil count ≥ 1500/μL (≥ 1.5 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 100 × 10^3μL (≥ 100 ×10^9 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of the first study drug administration;
  • Part 2
  • Absolute neutrophil count ≥ 1500/μL (≥ 1.5 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 75 × 10^3μL (≥ 75 × 109 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 8 g/dL without transfusion within 2 weeks of the first study drug administration.
  • Adequate bone marrow function in subjects with NHL, including:
  • Part 1
  • Absolute neutrophil count ≥1000/μL (≥ 1.0 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 100 × 10^3μL (≥ 100 × 10^9 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of the first study drug administration;
  • Part 2
  • Absolute neutrophil count ≥1000/μL (≥ 1.0 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 50 × 10^3μL (≥ 50 ×10^9 /L) without transfusion within 2 weeks of the first study drug administration. For sites in China, Platelet ≥ 75 × 10^3μL (≥ 50 ×10^9 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 8 g/dL without transfusion within 2 weeks of the first study drug administration. For sites in China, Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of the first study drug administration.
• Adequate renal function and serum creatine ≤ 1.5 × ULN or estimated serum creatinine clearance of ≥60 mL/min using the Cockcroft-Gault equation.
• Adequate liver function, including:
  • Total serum bilirubin ≤ 1.5 × ULN (≤ 3.0 × ULN if the subject has documented Gilbert syndrome);
  • AST and ALT ≤ 2.5 × ULN; ≤ 5.0 × ULN (if there is liver tumor present).
• Normal parameters within the following (unless the subject is receiving anticoagulant therapy):
  • Prothrombin Time ≤ 1.5 ULN, or 11 to 15 seconds in the absence of a normal range;
  • Partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 × ULN;
  • International normalized ratio ≤1.5 × ULN.
• Resolved acute effects of any prior therapy to baseline severity or Grade ≤ 1 NCI CTCAE version 5.0 except for AEs not constituting a safety risk by Investigator judgment

• Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable; i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Subjects with Burkitt’s lymphoma, lymphoblastic lymphoma, Richter's transformation, primary effusion lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma.
• Subjects with mantle cell lymphoma with blastoid and TP53 alterations (applies to Part 1 only, all types of mantle cell lymphoma are excluded in Part 2).
• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
  • Left ventricular ejection fraction 25% of the bone marrow (non-lymphoma subjects only), or any subject who has received prior radiotherapy within 2 weeks of the start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease. For NSCLC subjects, radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment is not allowed (Parts 1B and Part 2 in combination with pembrolizumab only).
• Prior treatment with CD47 or SIRPα inhibitors;
• A woman of childbearing potential who has a positive urine pregnancy test (e.g., within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Pregnant or nursing females or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 8 weeks for TJ011133, 120 days for pembrolizumab and 12 months for rituximab after the last dose of study treatment.
• Has a diagnosis of immunodeficiency (known active human immunodeficiency virus, hepatitis B virus/hepatitis C virus infection) or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
• Blood product transfusions within 14 days of Cycle 1 Day 1.
• Prior autologous stem cell transplant ≤3 months prior to starting TJ011133.
• Prior allogeneic stem cell transplant with either standard or reduced intensity conditioning.
• Has received chimeric antigen receptor (CAR) or chimeric antigen receptor T-cell (CAR-T) therapy within 90 days of starting TJ011133 OR has received prior CAR or CAR-T therapy and progressed within 90 days of infusion.
• Has received any experimental antibodies or a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Received any vaccine within 7 days of planned start of study therapy. Exceptions may apply with SARS-CoV-2 (COVID-19) vaccine, I-Mab Biopharma will provide up-to-date guidance based on evolving current practices.
• History of AIHA or autoimmune thrombocytopenia.
• Any bleeding history within 6 months of planned start of study therapy.
• Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep venous thrombosis, or pulmonary embolism.
• Any other significant medical condition, laboratory abnormality, or psychiatric illness that places the subject at unacceptable risk or that would prevent the subject from complying with the study.
• Second malignancy within the last 3 years (Part 2 dose expansion cohort only) with the exception of cutaneous squamous cell carcinoma or cutaneous basal cell carcinoma or cervical carcinoma in situ.
• Active graft versus host disease (GVHD) or ongoing immunosuppression for GVHD.
• Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening.
• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab or rituximab and/or any of its excipients;
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Not recovered (i.e., to ≤ Grade 1 or to baseline) from AEs emerging from previous treatments (except alopecia or neuropathy).
• Incomplete recovery from AEs and/or major surgery (must be ≤ Grade 1).
• History of a ≥ Grade 3 irAE with prior immunotherapy with the exception of non-clinically significant laboratory abnormalities.
• Unwilling or unable to comply with study procedures (including follow-up procedures).

Eligibility last updated 1/19/22. Questions regarding updates should be directed to the study team contact.

• Is a known carrier of a heterozygous loss-of-function GRN mutation causative of FTD with a global CDR® plus NACC FTLD score of 0 to 2; and
  • A CDR® plus NACC FTLD-SB score ≤ 0.5 with an elevated level of serum NfL; or
  • A CDR® plus NACC FTLD-SB score of > 0.5 with 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD (Rascovsky 2011), or a diagnosis of PPA (Gorno-Tempini 2011).
• Age 25 to 85 years, inclusive, at Screening.
• At Screening, women must be nonpregnant and nonlactating, and one of the following conditions must apply:
  • Not a woman of childbearing potential (WOCBP) (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1-year postmenopausal [amenorrhea duration of 12 consecutive months with no identified cause other than menopause]);
  • Is a WOCBP and agrees to use an acceptable contraceptive method from Screening until 10 weeks after the last dose of study treatment. Acceptable contraception is defined as using hormonal contraceptives (e.g., combined oral contraceptive pill) or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. In addition, total abstinence, if in accordance with the lifestyle of the participant, is acceptable;
  • A WOCBP must have a serum pregnancy test conducted at screening. Additional requirements for pregnancy testing during and after study intervention are described in the Schedules of Assessments.
• Men must agree to use acceptable contraception and not donate sperm from Day 0 until 10 weeks after the last dose of study treatment. Acceptable contraception for the male participant when having sexual intercourse with a WOCBP who is not currently pregnant is defined as using a condom. In addition, WOCBP partners must use hormonal contraceptives (e.g., combined oral contraceptive pill) or an intrauterine device.
• Agrees not to donate blood or blood products for transfusion for the duration of the study and for 1 year after the final dose of study treatment.
• Willing to and can comply with the study protocol requirements, in the opinion of the investigator.
• Willing and able to give informed consent. If the patient is not competent, a legally authorized representative must provide informed consent on their behalf, and the patient must provide assent, in accordance with local regulations, guidelines, and institutional review board (IRB) or independent ethics committee (IEC).
• Patient has the availability of a person (“study partner”) who has frequent and sufficient contact with the patient (at least 5 hours per week of in-person contact) and who can provide accurate information to the study site regarding the patient's behavior, cognitive, and functional abilities, as well as their health, throughout the study. Requirements for the study partner include:
  • Willing and able to provide informed consent to participate in the study as a study partner;
  • The study partner must have sufficient cognitive capacity to accurately report upon the participant’s behavior, cognitive, and functional abilities, in the opinion of the investigator;
  • The study partner should be in sufficiently good general health to have a high likelihood of maintaining the same level of interaction with the participant and participation in study procedures throughout the study duration;
  • The same study partner should participate throughout the duration of Part 1 of the study. If a change in study partner is necessary, the medical monitor must be contacted;
  • Study partner agrees to provide information at investigational site visits that require partner input for COA completion;
  • Study partner agrees to accompany the participant at COA visits, as follows:
    • At-risk participants (CDR® plus NACC FTLD-SB score ≤ 0.5) require the study partner at the COA visits only;
    • . − Symptomatic participants (CDR® plus NACC FTLD-SB score > 0.5) require the study partner at each visit;
    • At-risk participants who become symptomatic (CDR® plus NACC FTLDSB > ) during the study treatment period require the study partner at each visit moving forward through Study Completion. Inclusion criteria applicable to those participants participating in the optional Winterlight Labs Speech Assessment (WLA) only:
    • Has available and willing study partner to administer the WLA;
    • Has WiFi access in their residence or WiFi access in a private area where the testing can take place;
    • Participants and study partners must be proficient in English, Spanish, French, or German in the investigator’s opinion.

• Dementia due to a condition other than FTD including, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, Huntington disease, or vascular dementia.
• Known mutation causative of neurodegenerative disorder(s) other than heterozygous loss-of-function GRN mutations causative of FTD.
• Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins.
• Signs or symptoms of progressive supranuclear palsy or bulbar dysfunction, such as postural instability, eye problems, and swallowing difficulties.
• History of moderate or severe substance use disorder within the past 2 years, with the exception of nicotine, as defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria (American Psychiatric Association 2013).
• Currently has or has had an acute illness that requires or required systemic antibiotics within 30 days prior to first study treatment administration.
• Clinically significant vitamin B12 or folate deficiency (if treated, must be on a stable regimen for at least 3 months prior to first study treatment administration).
• Untreated hypothyroidism (if treated, thyroid supplementation dose must be stable for at least 3 months with a normal thyroid-stimulating hormone level prior to study treatment administration).
• Insufficiently controlled diabetes mellitus (e.g., hemoglobin A1C ≥ 8%).
• Any surgery (major or emergent) or hospitalization within 30 days prior to first study treatment administration.
• History of cancer within the last 5 years with the exception of basal cell or squamous cell carcinoma.
• Positive for hepatitis B surface antigen, human immunodeficiency virus-1 or -2 antibodies or antigen, or history of spirochetal infection of the CNS (e.g., syphilis, borreliosis, or Lyme disease). Participants with a positive hepatitis C virus antibody will be allowed if hepatitis C RNA is negative.
• Significant kidney disease as indicated by either of the following:
  • Estimated glomerular filtration rate (eGFR) 95 mm Hg or systolic BP > 150 mm Hg) at screening.
• History or presence of an abnormal ECG that is clinically significant, including complete left bundle branch block, second- or third-degree atrioventricular block, or evidence of acute or subacute myocardial infarction or ischemia.
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy) or clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia).
  • Note: Participants with premature ventricular contractions are eligible to participate.
• For participants who consent to lumbar puncture, participant has contraindication to lumbar dural puncture, including coagulopathy, concomitant anticoagulation medication (except for a platelet inhibitor such as aspirin), thrombocytopenia, or other factor(s) that precludes safe lumbar puncture.
• History or presence of clinically evident vascular disease potentially affecting the brain (e.g., clinically significant carotid or vertebral artery stenosis or plaque; cerebral hemorrhage or infarct greater than 1 cm3; 3 or more lacunar infarcts in any location; cerebral contusion; encephalomalacia; intracranial aneurysm; arteriovenous malformation; subdural hematoma); hydrocephalus; space-occupying lesions (e.g., abscess or brain tumor such as meningioma) that have the potential to affect cognitive function; or intracranial tumor that is clinically relevant (e.g., glioma, cerebral metastasis).
• History of a clinically significant, persistent neurologic deficit, structural brain damage, or CNS trauma.
• Resides in a skilled nursing facility, convalescent home, or long-term care facility at screening; or requires continuous nursing care (i.e., > 3 months).
• Unable to tolerate MRI procedures (e.g., due to anxiety or claustrophobia) or has a contraindication to MRI, including, but not limited to, the presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body that are not compatible with an MRI scan; or any other clinical history or examination finding that would pose a potential hazard in combination with MRI.
• Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise their ability to comply with the protocol-required testing or procedures, or compromise the participant’s well-being, safety, or clinical interpretability.

Eligibility last updated 1/4/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•For All Participants:

• Have completed the Week 24 visit of the feeder study.

Inclusion Criteria
•For Participants Assigned to the Open-label Treatment Cohort:

• Do not require immediate surgical intervention and is not planning corrective surgery/irradiation or medical therapy for TED during the course of the study.
• Did not permanently discontinue batoclimab.

Exclusion Criteria
•For All Participants:

• In the Investigator's judgement, the benefits of entry in the study do not outweigh the risk.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 9/30/22. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 9/7/22. Questions regarding updates should be directed to the study team contact.