• Participants will be enrolled for this study from patients attending the Mayo Clinic Depression Center, Mayo Clinic Family Medicine clinics at Rochester and Kasson, MN;, Behavioral Health and Primary Care Clinic at Mayo Clinic Health System, Austin and Albert Lea, MN, with a diagnosis of major depression with a current moderate episode, with PHQ-9 scores 10-23.
• Participants will be required to be between 25 and 80 years old.
• Able to speak English.
• Able to provide written informed consent to participate in the study.
• Participants must have DSM-V diagnostic confirmation of major depressive disorder (MDD) (American Psychiatric Association 2013). 
• Participants will continue taking any prescribed medications from their clinical treatment team. 
• Participants with co-morbid secondary diagnoses of persistent depressive disorder and generalized anxiety disorders will be included in the study.
• Participants must consent to audio recording of random group sessions which will be disclosed at the final study session.
• Participants are willing to use the Mayo Clinic Patient Portal for communication purposes during the study.

• Participants with bipolar disorder, active psychosis, active suicidal ideations, and active substance abuse meeting criteria for substance use disorders except nicotine, obsessive compulsive disorder, active panic disorder with agoraphobia or other phobic disorder, active posttraumatic stress disorder, active severe personality disorders will be excluded.
• Participants with a severe major depressive episode- HAM-D scores ≥ 23.
• Pregnant women – because of time duration of the study.

• Participants will be enrolled for this study from patients attending the Mayo Clinic Depression Center, Mayo Clinic Family Medicine clinics at Rochester and Kasson, MN;, Behavioral Health and Primary Care Clinic at Mayo Clinic Health System, Austin and Albert Lea, MN, with a diagnosis of major depression with a current moderate episode, with PHQ-9 scores 10-23.
• Participants will be required to be between 25 and 80 years old.
• Able to speak English.
• Able to provide written informed consent to participate in the study.
• Participants must have DSM-V diagnostic confirmation of major depressive disorder (MDD) (American Psychiatric Association 2013). 
• Participants will continue taking any prescribed medications from their clinical treatment team. 
• Participants with co-morbid secondary diagnoses of persistent depressive disorder and generalized anxiety disorders will be included in the study.
• Participants must consent to audio recording of random group sessions which will be disclosed at the final study session.
• Participants are willing to use the Mayo Clinic Patient Portal for communication purposes during the study.

• Participants with bipolar disorder, active psychosis, active suicidal ideations, and active substance abuse meeting criteria for substance use disorders except nicotine, obsessive compulsive disorder, active panic disorder with agoraphobia or other phobic disorder, active posttraumatic stress disorder, active severe personality disorders will be excluded.
• Participants with a severe major depressive episode- HAM-D scores ≥ 23.
• Pregnant women – because of time duration of the study.

Enrollment criteria (n = 40):

Adult subjects undergoing MR imaging for radiation therapy planning will be recruited. No more than 40 subjects will be recruited to this study.

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

Eligibility last updated 2/28/23. Questions regarding updates should be directed to the study team contact.

• Written or oral pediatric assent from the subject if deemed capable of providing assent, and written informed consent from the subject’s parent(s) or legal guardian(s) for subjects < 18 years of age and for subjects ≥ 18 years of age who are not capable of providing consent in accordance with the governing Independent Ethics Committees (IEC)/Institutional Review Boards (IRB) and according to local laws and regulations. Subjects who are ≥ 18 years of age and capable of providing consent should sign an Informed Consent Form (ICF). Informed consent/assent may be done remotely, if allowed and remote consenting procedures are in place.
• Be a male or female 2 to 21 years of age, inclusive.
• Have a diagnosis of SCN8A-DEE supported by both clinical and genetic findings outlined as follows:
• Clinical findings
  •required:
  • Seizure onset prior to 18 months of age;
  • Developmental delay which may have occurred either prior to or with onset of seizures or after.
• Supportive (not required):
  • Multiple seizure types which include focal seizures (including focal to bilateral tonic-clonic), tonic-clonic seizures, epileptic/infantile spasms, tonic seizures;
  • History or ongoing motor abnormalities including hypotonia, dystonia, choreoathetosis, ataxia, spasticity, hyperekplexia;
  • Episodes of convulsive and nonconvulsive status epilepticus;
  • Beneficial response to sodium channel blockers such as phenytoin, valproate, carbamazepine, lacosamide, lamotrigine, rufinamide, and oxcarbazepine.
• Genetic findings (both required):
  • Pathological gain of function (GOF) mutation in SCN8A defined as either a previously identified GOF mutation or a presumed pathological GOF mutation. Presumed pathological GOF mutations must be either a missense mutation that is not seen in either parent (de novo) OR a mutation which leads to a hyperfunctioning channel in in vitro function tests. Presumed pathological GOF mutations must not be nonsense mutations or other mutations likely to lead to a truncated protein;
  • No other pathogenic mutation in an additional gene that is known to cause epilepsy and is more likely to cause the epilepsy experienced by the subject.  

Genetic findings required for SCN8A-DEE diagnosis may be based on genetic testing performed previously. The genetic mutation in the subject’s SCN8A gene (b[i]) and the absence of other pathogenic mutations that are more likely to cause the epilepsy experienced by the subject (b[ii]) must be confirmed at screening as part of the comprehensive epilepsy panel genotyping.

• Have SCN8A-DEE diagnosis confirmed by the DCP.
• In the 90 days before screening, have a history of on average at least 4 countable motor seizures (defined as GTCS, tonic, atonic or FOS with noticeable motor component) per month.
• Have on average at least 1 countable motor seizure (defined as GTCS, tonic, atonic or FOS with noticeable motor component) per week (4 per 28-day period) and not be seizure-free for more than 20 consecutive days per 28-day period during the baseline period.
• Have at least 4 weeks of reliably and consistently completed baseline seizure diary data.
• Being treated with at least 1 other ASM, but no more than 4 ASMs. Epidiolex®/Epidyolex® will be considered an ASM. The dose should be stable for at least 5 half-lives at screening. Vagus nerve stimulator (VNS) and ketogenic diet are not counted as ASMs.
• Have failed to achieve seizure freedom with at least 2 ASMs.
• The subject, if using a VNS, must have had the VNS placed at least 3 months prior to screening with stable settings for ≥ 30 days before screening; settings must remain stable throughout the duration of the study.
• The subject, if on a ketogenic diet, must have started the ketogenic diet at least 30 days prior to screening; diet must be stable, and continue through the duration of the study.
• Must be using a nocturnal alerting system or practice consistent with standards of care at the time of screening and continue to use this for the duration of the study. Acceptable nocturnal alerting systems or practices include but are not limited to:
  • Parent/caregiver sleeps in the same room as subject;
  • Video- and/or acoustic-based monitoring (e.g., use of baby monitor);
  • Device intended as a seizure alert system (e.g., bracelet devices).
• Must have an adequate rescue medication regimen per the investigator’s judgment in place at the time of screening and for the duration of the study.
• Female subjects of childbearing potential must agree to use contraception consistently from screening until the final study visit or 30 days after the last dose of study treatment, whichever is longer.

A female subject of childbearing potential is defined as a female capable of becoming pregnant, which includes subjects who have had their first menstrual cycle (ie, menarche) and are not surgically sterile (ie, bilateral oophorectomy, hysterectomy or bilateral tubal ligation for at least 3 months prior to screening). A male subject of childbearing potential is defined as a subject who has reached spermarche and has not been vasectomized for at least 3 months prior to screening.

• Highly effective methods of contraception are required for female subjects of childbearing potential:
  • Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS);
  • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (which may be oral, intravaginal, or transdermal) initiated and used in accordance with medical direction for at least 3 months prior to screening;
  • Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted initiated and used in accordance with medical direction for at least 3 months prior to screening;
  • Bilateral tubal ligation;
  • Total abstinence from sexual intercourse (periodic abstinence is not acceptable);
  • Sexual partner(s) who had been vasectomized at least 3 months prior to screening with medically confirmed successful procedure;

Male subjects must agree to use effective barrier contraception consistently from screening until 30 days after the last dose of study treatment. The acceptable method of contraception for male subjects is condom with spermicide (cream, spray, foam, gel, suppository, or polymer film).

• Have a body weight of at least 10 kg.
• Be able to carry out all the appropriate assessments and take the study treatment with the help of the parent/caregiver in the opinion of the investigator.
• Te subject’s parent/caregiver is able to accurately identify seizure types, especially countable motor seizures (defined as GTCS, tonic, atonic or FOS with noticeable motor component) and is able to complete seizure diary.

• Have previously been enrolled in this study and received blinded treatment.
• Have participated in an interventional clinical trial <30 days prior to screening.
• Have symptoms that would be more consistent with another epilepsy disorder such as Dravet syndrome (e.g., fever-induced episodes of status epilepticus, frequent myoclonic seizures, worsening on sodium channel blockers).
• Are currently receiving cannabinoids or medical marijuana except Epidiolex/Epidyolex, unless approved by the Sponsor.
• Are currently taking systemic steroids (excluding inhaled medication for asthma treatments) such as adrenocorticotropin hormone (ACTH), high dose prednisolone for epileptic spasms.
• If subject has received these medications in the past, must be off these medications for at least 3 months prior to the screening visit and these drugs may not be initiated during the duration of the study. Intermittent steroids to treat nonepilepsy related diseases (such as allergies or dermatological conditions) are not exclusionary.
• Are taking strong CYP3A4 inhibitor (e.g., ketoconazole, erythromycin, ritonavir) or inducer (e.g., rifabutin, rifampin, St. John's Wort) other than concurrent ASMs.
• Have a history of severe drug allergy or hypersensitivity to NBI-921352 or its excipients.
• Have a previous exposure to NBI-921352.
• Have any other disorder for which the treatment takes priority over treatment of SCN8A-DEE or is likely to interfere with study treatment or impair treatment compliance.
• Have a history of moderate or severe head trauma or other neurological disorders or systemic medical diseases that are, in the investigator’s opinion, likely to affect nervous system functioning.
• Have a clinically significant medical condition or chronic disease (including history of neurological, hepatic, renal, cardiovascular, gastrointestinal, significant malabsorption, hematologic, pulmonary, psychiatric, or endocrine disease) that in the opinion of the investigator would preclude the subject from participating in and completing the study or that could confound interpretation of study outcome.
• Are taking or have received disallowed concomitant medication or it is anticipated that the subject will require treatment with at least one of the disallowed concomitant medications during the study.
• Have clinically significant abnormal vital signs at the screening visit as determined by the investigator.
• Have one or more clinical laboratory test values outside the reference range, based on blood samples taken at the screening visit, that are of potential risk to the subject’s safety as determined by the investigator, or have at the screening visit:
  • A serum creatine value > 1.5 times the upper limit of the reference range;
  • A total bilirubin value > 1.5 times the upper limit of the reference range;
  • A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value > 2.5 times the upper limit of the reference range. For subjects on valproate, ALT or AST values up to 3 times the upper limit of the reference range are acceptable, if these values have remained stable over the past 3 months based on investigator judgement.
• Have, at the screening visit, an ECG finding of a corrected QT interval using Fridericia’s formula (QTcF) > 450 msec or presence of any significant cardiac abnormality.
• The subject or subject’s parent/caregiver, in the investigator’s opinion, is unlikely to comply with the protocol, including the requirement to travel to the study sites for study visits, or is unsuitable for any reason.
• Have attempted suicide within the last year or are at significant risk of suicide (either in the opinion of the investigator or defined as a “yes” to suicidal ideation questions 4 or 5 or “yes” to suicidal behavior on the C-SSRS within the past 12-months).
• Females who are pregnant or currently breastfeeding.
• Have a history of a positive hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B surface antigen (HBsAg), or human immunodeficiency virus antibody (HIV-Ab) test results at screening. Subject with positive hepatitis C antibody (HCV-Ab) and confirmatory positive polymerase chain reaction (PCR) reflex test results at screening will be allowed to participate in the study provided that the subject is asymptomatic as assessed by the investigator and does not have exclusionary liver function test abnormalities (ALT, AST, and total bilirubin).
• Have ingested grapefruit juice or grapefruit products within a 7-day period before Day -1.

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

Eligibility last updated 11/7/22. Questions regarding updates should be directed to the study team contact.

• Male or females aged 18 to 75 years, inclusive at the time of informed consent.
• Confirmed diagnosis of pulmonary sarcoidosis for at least 6 months (cutaneous and ocular involvement permitted), defined by the following criteria:
  • Documented histologically proven diagnosis of sarcoidosis by tissue biopsy (any organ);
  • Documented evidence of parenchymal lung involvement by historical radiological evidence (eg, computed tomography [CT], magnetic resonance imaging [MRI], fluorodeoxyglucose positron emission tomography [18F-FDG]/CT or chest X-ray; or on screening high-resolution CT).
• Evidence of symptomatic pulmonary sarcoidosis, as demonstrated by the following criteria:
  • Modified medical research council (MRC) dyspnea scale grade of at least 1 (and remain stable between screening and baseline);
  • KSQ-Lung score ≤ 70.
• Patients must be receiving treatment with OCS (prednisone or equivalent) and fulfill the following criteria:
  • Treatment of ≥ 3 months;
  • Starting dose between ≥ 7.5 and ≤ 25 mg/day;
  • Stable dose for ≥ 4 weeks prior to Day 1;
  • Willing to attempt OCS taper to 0 mg/day.
• Body weight ≥ 40 kg and < 160 kg.
• If female of childbearing potential, must:
  • Not be pregnant or lactating, and have a negative pregnancy test at Screening (serum) and at Day 1 (urine) prior to first study drug infusion;
  • Be willing to use acceptable contraception from Screening until 8 weeks after the last study drug administration;
  • Note: To be considered of non-childbearing potential, the patient must be either surgically sterile or postmenopausal (confirmed by amenorrhea duration of at least 12 months with no alternative medical cause.
• Provide written informed consent.
• Agree to comply with all study procedures and requirements.  

• Current disease presentation consistent with Lofgren’s syndrome (i.e., presence of the triad of erythema nodosum, bilateral hilar lymphadenopathy on chest X-ray, and joint pain).
• Treatment with > 1 oral immunosuppressant therapy (e.g., methotrexate, leflunomide).
• Treatment (within 4 months of Day 1) with biological immunomodulators, such as TNF-α inhibitors (eg, infliximab, adalimumab) or antifibrotics (pirfenidone, nintedanib) or interleukin inhibitors (e.g., canakinumab, ustekinumab).
• Likelihood of significant pulmonary fibrosis as shown by any 1 or more of the following:
  • High resolution CT fibrosis > 20% at Screening;
  • FVC % predicted < 50%;
  • KSQ-Lung score < 30.
• Clinically significant bronchiectasis or cavitary sarcoidosis with mycetoma at Screening or during the previous 12 months.
• Clinically significant pulmonary hypertension requiring treatment with vasodilators.
• Patients with cardiac sarcoidosis (inclusive of but not limited to active inflammation with low ejection fraction, presence of arrhythmias), neurosarcoidosis, or renal sarcoidosis.
• Clinically significant cutaneous and ocular sarcoidosis.
• History of Addisonian symptoms that precluded previous OCS taper attempts.
• History of severe allergic or anaphylactic reactions to therapeutic proteins or known sensitivity to efzofitimod or its inactive components (L-histidine, sodium chloride, sucrose, L-methionine, and polysorbate-20).
• In the opinion of the Investigator and Medical Monitor, current evidence of clinically significant cardiovascular, hepatic, neurological, renal, hematological, lymphatic, metabolic, or gastrointestinal disease, or any condition that requires other treatment or surgery, that may preclude the assessment of efficacy, confound the assessment of safety, or compromise patients compliance with study procedures.
• Active or history of malignancy within the last 5 years, except for  in situ carcinoma of the cervix, breast or stomach; or effectively managed stage 1 prostate carcinoma. 
• An exception is also made for history of other malignancies considered by the investigator to be cured, have no recurrence within 5 years of screening, and not requiring ongoing therapy.
• Major surgery or hospitalization within 3 months prior to Day 1 or anticipated surgery during the study.
• Participation in another clinical study of an investigational agent or device within 3 months (small molecules and device), 6 months (biologics), or 5 half-lives (if known) of the agent, whichever is longer.
• Is an active, heavy smoker of tobacco/nicotine-containing products (defined as > 20 cigarettes/day or e-cigarette equivalent).
• Active substance abuse (drugs, alcohol, or cannabis) or history of substance abuse within 12 months prior to Screening.
• Clinically significant abnormalities in the Screening physical examination, vital signs, ECG, or clinical laboratory test results that, in the opinion of the Investigator and Medical Monitor, preclude the patient’s participation in the clinical study.
• History of (anti-Jo-1) anti-synthetase syndrome or Jo-1 positive at baseline.

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

Eligibility last updated 8/25/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• BMI ≥ 35.
• Dyspnea MRC class II or greater.
• Diagnosis of lung disease.
• Signed informed consent.

• BMI < 35.
• Pregnancy.
• Recent respiratory illness (within the last 6 weeks).
• Recent exacerbation of chronic lung disease (within the last 6 weeks).
• Already participating in a structured diet and/or exercise program.
• Medical contraindication to weight loss (cancer).
• Medical contraindication to unsupervised exercise (unstable angina).
• People with implanted defibrillators or pacemakers (Although the electrical current that is sent through the body during the body composition scan is extremely low, it is not recommended for patients with implanted defibrillators or pacemakers)
• People with implanted defibrillators or pacemakers (although the electrical current that is sent through the body during the body composition scan is extremely low, it is not recommended for patients with implanted defibrillators or pacemakers).

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

Eligibility last updated 12/9/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 12/20/22. Questions regarding updates should be directed to the study team contact.

• STEP 1 REGISTRATION
• Tumor tissue must be available for submission for central pathology review
• Documentation from the enrolling site confirming the presence of IDH mutation and 1p/19q status; the provided information must document assays performed in clinical laboratory improvement amendments (CLIA)-approved laboratories
• Appropriate stage for study entry based on the following diagnostic workup:
  • History/physical examination within 60 days prior to registration
  • Imaging of the brain within 60 days prior to registration
• Only English speaking patients are eligible to participate as the cognitive and quality of life assessments are available only in English
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• Karnofsky performance status of >= 70 within 60 days prior to registration
• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
• Platelets >= 100,000 cells/mm^3
• Hemoglobin >= 10.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable)
• Bilirubin =< 1.5 upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
• CD4 lymphocyte count is highly encouraged
• Women of childbearing age must have a negative serum pregnancy test within 14 days prior to registration
• Post-operative magnetic resonance (MR) imaging must be obtained for radiation therapy planning; enrolling sites are highly encouraged to obtain thin-slice volumetric fluid attenuated inversion recovery (FLAIR) and T1 post contrast sequences for planning purposes
• STEP 2 REGISTRATION
• The following baseline neurocognitive assessments must be completed and uploaded within 27 calendar days prior to step 2 registration: HVLT-R, TMT, and COWA
  • NOTE: Completed baseline neurocognitive assessments can be uploaded at the time of step 1 registration
• The following baseline patient reported outcome assessments must be completed and uploaded within 27 calendar days prior to Step 2 registration: MDASI-BT, LASA QOL, WPAI
• Financial clearance for proton therapy treatment within 30 days following step 1 registration
• Centrally reviewed histologically proven diagnosis of supratentorial, Word Health Organization (WHO) grade II or III astrocytoma, oligodendroglioma or oligoastrocytoma; tissue must be submitted x calendar days after step 1 registration
• Documentation must be uploaded within 15 business days and will be verified by the translational/pathology study co-chairs within 5 business days after receiving the upload; the documentation should demonstrate 1) evaluation of known IDH1 and IDH2 mutational hotspots (sequencing is encouraged) evaluation of chromosomes 1p and 19q copy number utilizing either fluorescence in situ hybridization (FISH) or other suitable assay

• Definitive clinical or radiologic evidence of metastatic disease; if applicable
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity or cervix are permissible)
• Prior cranial radiotherapy or radiotherapy to the head and neck where potential field overlaps would exist
• Prior chemotherapy or radiotherapy for any brain tumor
• Histologic diagnosis of glioblastoma (WHO grade IV) or pilocytic astrocytoma (WHO grade I)
• Definitive evidence of multifocal disease
• Planned use of cytotoxic chemotherapy during radiation (only adjuvant temozolomide therapy will be used on this protocol)
• Patients with infra-tentorial tumors are not eligible
• Prior history of neurologic or psychiatric disease believed to impact cognitive function
• The use of memantine during or following radiation is NOT allowed
• Severe, active co-morbidity defined as follows:
  • Unstable angina or congestive heart failure requiring hospitalization within 6 months prior to enrollment
  • Transmural myocardial infarction within the last 6 months prior to step 2 registration; evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 28 days prior to step 2 registration (Note: EKG to be performed only if clinical suspicion of cardiac issue)
  • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
  • Serious and inadequately controlled arrhythmia at step 2 registration
  • Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
  • Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter; acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol
  • Any other severe immunocompromised condition
  • Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
  • End-stage renal disease (i.e., on dialysis or dialysis has been recommended)
  • Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy
• Inability to undergo MRI with and without contrast (e.g. claustrophobia, non-MRI compatible implant or foreign body, gadolinium allergy or renal dysfunction preventing the patient from receiving gadolinium- institutional guidelines should be used to determine if patients are at risk for renal dysfunction); note that patients with severe claustrophobia are permitted on this study if they are willing and able to undergo MRI with adequate sedation or anesthesia

• Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements. 
• Age > 18 years at time of study entry. 
• Willingness and ability to comply with study and follow-up procedures. 
• Histological confirmation of diagnosis of low-grade serous carcinoma of ovary, fallopian tube or peritoneum; original diagnosis of de novo low-grade serous carcinoma or original diagnosis of serous borderline tumor with subsequent diagnosis of low-grade serous carcinoma:
  • In order to prevent inclusion of patients with high-grade serous carcinoma, diagnosis of low-grade serous carcinoma will be verified as part of screening review by a gynecologic pathologist. Tissue for confirmation can be from primary tumor or recurrence.
• Patient must have recurrent, measurable disease by RECIST v1.1. 
• There are no restrictions on number of prior therapies. 
• Patient cannot have previously received a prior cyclin dependent kinase inhibitor (CDKi). Patients who were treated with letrozole or another aromatase inhibitor for other indications must have not taken the drug for 6 months prior to initiating letrozole for this trial and may not have progressed on treatment.
• Patients must not have remaining ovarian function to be included. In women who have at least one retained ovary, menopause must be confirmed with laboratory confirmation. Women who have ovarian function are eligible but must be placed on hormonal suppression. Menopause must be confirmed with laboratory confirmation, to include an estradiol level as this is assessed within 8 weeks of patient having been on tamoxifen. 
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
• Resolution of all acute toxic effects of prior therapy or surgical procedures to National Cancer Institute (NCI) CTCAE Grade ≤ 1. 
• Patient has adequate bone marrow and organ function as defined by the following laboratory values at screening:
  • Absolute neutrophil count ≥ 1.5 × 10^9/L;
  • Platelets ≥ 100 × 10^9/L;
  • Hemoglobin ≥ 9.0 g/dL;
  • Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication;
  • INR ≤ 1.5;
  • Serum creatinine < 1.5 mg/dL or creatinine clearance ≥ 50 mL/min;
  • In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN. If the patient has liver metastases, ALT and AST < 5 x ULN;
  • Total bilirubin < ULN or total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN in patients with well-documented Gilbert's Syndrome.
• Patient with available standard 12-lead ECG with the following parameters at screening: 
  • QTcF interval at screening < 450msec (using Fridericia's correction);
  • Resting heart rate 50-90 bpm.
• Must be able to swallow ribociclib and letrozole capsules/tablets.
• Patients receiving tamoxifen or toremifine must have washout period of 5 half-lives prior to randomization.

• Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole. 
• Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. Patients with known brain metastases are excluded.
• Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
  • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment;
  • Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Patient has a known history of HIV infection (testing not mandatory).
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.). 
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:
  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening;
  • History of documented congestive heart failure (New York Heart Association functional classification III-IV);
  • Documented cardiomyopathy;
  • Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO);
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block);
  • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: 
    • Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia;
    • Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 halflives or 7 days prior to starting study drug) or replaced by safe alternative medication;
    • Inability to determine the QT interval on screening (QTcF, using Fridericia’s correction);
    • Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening;
• Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug:
  • Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges;
  • That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5;
  • Herbal preparations/medications, dietary supplements.
• Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational product (whichever is longer) or participation in any other type of medical research judged not to be scientifically or medically compatible with this study. If the patient is
  enrolled or planned to be enrolled in another study that does not involve an investigational drug, the agreement of Novartis study medical lead is required to establish eligibility.
• Patient is currently receiving warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed. Direct-Acting Oral Anticoagulants (DOACS) are permitted. 
• Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
• Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥25% of the bone marrow (Ellis, 1961) was irradiated.
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery).
• Patient with a Child-Pugh score B or C.
• Patients who are pregnant or breastfeeding. 
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for 3 weeks after study drug discontinuation. Highly effective contraception methods include:
  • Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
    contraception;
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
• Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers, and drugs that are known to prolong the QT interval unless the prohibited concomitant medication can be replaced by other drugs of less potential to inhibit or induce CYP3A4 or prolong QT interval
• Patients whose tumors contain both low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC).
• Patients with history of haemopoietic stem cell or bone marrow transplant.

• Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• Subject is willing to undergo core needle or incisional/ excisional biopsy unless sufficient tissue is available from diagnostic tumor/ lymph node biopsy (from within 6 months prior to ICF signature) for translational research purposes.
• Subject has histologically confirmed (per local evaluation) diagnosis of de novo, previously untreated, a-BCL according to 2016 WHO classification including:
  • DLBCL, NOS (including GCB and ABC types);
  • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements;
  • Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
  • Primary cutaneous DLBCL-leg type;
  • EBV+ DLBCL, NOS;
  • Grade 3b FL.
• Chemo- and immunotherapy-naïve FL transformed to a-BCL. Patient must not have received any previous therapy for the FL component.
• Subject is considered an appropriate candidate (per investigator assessment) for induction therapy with 6 cycles of R-CHOP-21 or polatuzumab-R-CHP immunochemotherapy.
• Subject has IPI score 0 to 5 in Part 1 and IPI 2 to 5 in Part 2. For the CELMoD and polatuzumab-R-CHP cohort, the subject must also have IPI score 0 to 5 in Part 2A and IPI 2 to 5 in Part 2B.
• Subjects must have measurable disease defined by at least one FDG-avid lesion for FDG-avid subtype and one bi-dimensionally measurable (> 1.5 cm in longest diameter) disease by computed tomography (CT) or magnetic resonance imaging (MRI), as defined by the Lugano classification (Cheson, 2014).
• Subject has an ECOG performance status of 0, 1, or 2.
• Subjects must have the following laboratory values:
  • ANC ≥ 1.5 × 10^9 /L or ≥ 1.0 × 10^9 /L in case of documented bone marrow involvement (> 50% or tumor cells), without growth factor support for 7 days (14 days if peg-G-CSF);
  • Hemoglobin (Hb) ≥ 8 g/dL;
  • Platelets (PLT) ≥ 75 × 10^9 /L or ≥ 50 × 10^9 /L in case of documented bone marrow involvement (> 50% or tumor cells), without transfusion for 7 days;
  • AST/SGOT and alanine aminotransferase )ALT)/ serum glutamate pyruvic transaminase (SGPT) ≤ 2.5 × ULN. In the case of documented liver involvement by lymphoma, ALT/SGPT and AST/SGOT must be ≤ 5.0 × ULN;
  • Serum total bilirubin ≤ 2.0 mg/dL (34 μmol/L) except in cases of Gilbert’s syndrome, then ≤ 5.0 mg/dL (86 μmol/L);
  • Subjects receiving polatuzumab vedotin must have serum total bilirubin ≤ 1.5 × ULN (26 μmol/L) (corresponding to mild degree as per National Cancer Institute Organ Dysfunction Working Group [NCI ODWG] criteria) except in cases of Gilbert’s syndrome, then ≤ 3.0 mg/dL (51 μmol/L);
  • Estimated serum creatinine clearance (CrCl) of ≥ 50 mL/min using the modification of diet in renal disease (MDRD) formula.
• All subjects must:
  • Have an understanding that the study drug could have a potential teratogenic risk.
  • Agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment;
  • Agree not to share study medication with another person;
  • Agree to follow all requirements defined in the Pregnancy Prevention Program (see APPENDIX D) for CC-220 or CC-99282 Pregnancy Prevention Plan for Subjects in Clinical trials.
• Females must agree to abstain from breastfeeding during study participation and for at least 28 days after last dose of CC-220 or CC-99282 discontinuation and according to the approved rituximab product/prescribing information.
• Females of childbearing potential (FCBP^)* must:
  • Have two 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 after end of study therapy. 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 two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting IP, during the study treatment (including dose interruptions), and for at least 28 days after the last dose of CC-220 or CC-99282 and for 12 months after the last dose of rituximab or polatuzumab vedotin, whichever is longer. Contraception requirements are detailed in APPENDIX D.
• Male subjects must:
  • Practice true abstinence* (which must be reviewed on a monthly basis and source documented) or agree to use a condom (APPENDIX D) during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions and for at least 28 days after the last dose of CC-220, or CC-99282, 6 months after the last dose of polatuzumab vedotin, or 90 days for rituximab, whichever is longer, even if he has undergone a successful vasectomy.
  • Must agree to refrain from donating sperm while on study treatment, during dose interruptions, and for at least 28 days following last dose of CC-220, CC-99282 6 months after the last dose of polatuzumab vedotin, or 90 days following last dose for rituximab, whichever is longer.
  • ^A FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) 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).
  • *True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

• Subject has any significant medical condition, active infection (including SARS-CoV-2 suspected or confirmed), laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
  • A patient who is excluded for SARS-CoV-2 infection could be rescreened;
  • In the case of prior SARS-CoV-2 infection, 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 receiving investigational treatment;
  • Additionally, a patient who is currently in another interventional trial for COVID-19 may not participate in the clinical trial until the protocol-specific washout period is achieved;
  • Testing to exclude asymptomatic SARS-CoV-2 prior to enrollment should follow local standard practice.
• 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.
• Subject has any other subtype of lymphoma.
• Subject has documented or suspected CNS involvement by lymphoma.
• Subject has persistent diarrhea or malabsorption ≥ Grade 2 (NCI CTCAE v5.0), despite medical management.
• Subject has peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0).
• Subjects with a history of progressive multifocal leukoencephalopathy.
• Subject is on chronic systemic immunosuppressive therapy or corticosteroids (e.g., prednisone or equivalent not to exceed 10 mg per day within the last 14 days); stable use of inhaled or topical corticosteroids is allowed.
• Subject has impaired cardiac function or clinically significant cardiac disease, including any of the following:
  • Left ventricular ejection fraction (LVEF) < 45% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO);
  • Heart failure (New York Heart Association Class III or IV);
  • Clinically significant abnormal electrocardiogram (ECG) finding at screening;
  • Unstable angina or myocardial infarction ≤ 6 months prior to starting;
  • Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation or cardiac conduction abnormalities not mitigated by a pacemaker.
• Subject had major surgery ≤ 2 weeks prior to starting CC-220 or CC-99282; subject must have recovered from any clinically significant effects of recent surgery.
• Subject has any condition causing inability to swallow tablets.
• Subject has known seropositivity for or active viral infection with human immunodeficiency virus (HIV).
• Subject has known chronic active hepatitis B (hepatitis B virus surface antigen [HBsAg] positive and/or hepatitis B core antibody [anti-HBc] positive with viral DNA positive) or C (positive serology requiring treatment and/or with evidence of liver damage) infection.
• Subject has history of other malignancy, unless being free of the disease for ≥ 3 years; exceptions to the ≥ 3-year time limit include history of the following:
  • Localized nonmelanoma skin cancer;
  • Carcinoma in situ of the cervix;
  • Carcinoma in situ of the breast;
  • Incidental histologic finding of prostate cancer (T1a or T1b as per Tumor Node Metastasis [TNM] staging system) or prostate cancer that has been treated with curative intent.
•  Subject has current treatment with strong CYP3A4/5 modulators.
• Subject has hypersensitivity to the active substance or to murine proteins, or to any of the other excipients of rituximab or polatuzumab vedotin.
• Subject has known hypersensitivity to any component of CHOP/CHP regimen.
• Subject has known allergy to thalidomide, pomalidomide, or lenalidomide.
• Subject received live attenuated vaccines or live COVID-19 vaccines within 30 days prior to initiation of study treatment.

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

Eligibility last updated 12/13/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Cognitively Impaired (EOAD and EO-nonAD) Cohorts Only:

• Meets NIA-AA criteria for MCI due to AD or probable AD dementia.
• Have a global CDR score ≤ 1.0.
• Have capacity to provide informed consent (IC) or has a legal authorized representative or guardian who provides IC.
• Age between 40-64 years (inclusive) at the time of consent .
• Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI .
• Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure.
• Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan.
• Fluent in English.

Inclusion Criteria
•Cognitively Normal (CN) Cohort Only:

• Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living.
• Have a global CDR score = 0.
• Have capacity to provide informed consent.
• Have a Mini-Mental State Exam score between 26-30 (inclusive). Exceptions may be made for participant with less than 8 years of education at the discretion of the Site PI.
• Age between 40-64 years (inclusive) at the time of consent.
• Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI.
• Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure.
• Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan.
• Fluent in English.

Exclusion Criteria
•All (EOAD, EO-nonAD and CN) Cohorts:

• Meets core clinical criteria for non-AD dementia.
• Two or more first degree relatives with a history of early-onset dementia suggestive of autosomal dominant transmission, unless known pathogenic mutations in APP, PSEN1, PSEN2 have been excluded.
• Known mutation in an ADAD gene (APP, PSEN1, PSEN2) or other autosomal dominant genes associated with other neurodegenerative disorders.
• Contraindications to 3T MRI (e.g., claustrophobia, pacemaker, select aneurismal clip, artificial heart valve, select ear implants, select stents incompatible with 3T MRI, metal fragments or foreign objects in the eyes, skin or body, etc.).
• Lifetime medical history of a brain disorder other than the disorder causing dementia except for headache (exceptions are allowed at the discretion of the Site PI
  •e.g., seizure disorder thought to be due to EOAD).
•  MRI scan with evidence of infection or focal lesions, cortical strokes, multiple lacunes (single lacune is allowable unless it meets criteria for strategic lacune affecting cognition).
• Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the Site PI).
• Medical radiation exposure will be assessed by the study physician. If the candidate participant has had more than one nuclear medicine study in the prior 12 months, study inclusion will require approval from the PET Core.
• Investigational agents are prohibited 30 days prior to entry.
• Previous enrollment in a therapeutic trial targeting amyloid or tau.
• Participation in other clinical studies with neuropsychological measures, with the exception of participants who are co-enrolled in the NACC Uniform Data Set (UDS) protocol (Note: This criterion is intended to reduce repeat measures effects during neuropsychological testing. Exceptions are allowed at the discretion of the Site PI).
• Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria).
• Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar disorder with or without psychotic features.
• Current history (in previous 6 months) of moderate or severe substance abuse (nicotine or caffeine is allowed).
• Suicidal behaviors in the past 12 months or active suicidal ideations.
• Residing in a 24-hour care skilled nursing facility (at the time of screening).
• History of torsades de pointes or taking medications known to prolong the QT interval.
• Corrected QT (QTc) interval ≥ 458 msec in males or ≥ 474 msec in females.
• For optional lumbar puncture procedure only:
  • Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be not clinically significant by the Site PI:
    • Platelet count <100,000/µl; 
    • INR>1.2;
    • Abnormal PT or PTT at screening.
  • Contraindications to the procedure, including but not limited to severe degenerative joint disease, deformity of the spine, history of a bleeding disorder. 
  • Suspected elevated intracranial pressure, Arnold Chiari malformation or mass lesion d. Use of the anticoagulant medications such as but not limited to warfarin, rivaroxaban, dabigatran.
• Deemed ineligible by the Site PI for any other reason.

• Undergone an overnight polysomnogram that was used to diagnose REM Sleep Behavior Disorder.
• 18 years of age or older.
• Capable of providing informed consent using the current IRB approved consent document.

• Known diagnosis of PD, dementia of any type, or MSA,
• RBD associated with narcolepsy or suspected due to another neurological etiology (i.e. non-idiopathic RBD),
• For Lumbar puncture only: Anticoagulant medication or bleeding disorder,
• For Lumbar puncture only: Prior lumbar surgery or procedure that precludes LP.

• Willing and able to provide written informed consent.
• Males or females, ≥ 18 years of age.
• Receiving a human leukocyte antigen (HLA) matched allogeneic peripheral BMT from a family or unrelated donor, HLA-mismatched related or unrelated donor, or haploidentical donor.
• Diagnosed with 1 of the following underlying diseases:
  • Refractory anemia;
  • Refractory anemia with ringed sideroblasts;
  • Refractory cytopenia with multilineage dysplasia;
  • Refractory cytopenia with multilineage dysplasia and ringed sideroblasts;
  • Refractory anemia with excess blasts
    •1 (5-10% blasts);
  • Refractory anemia with excess blasts
    •2 (10-20% blasts);
  • Myelodysplastic syndrome, unclassified;
  • Myelodysplastic syndrome associated with isolated del (5q);
  • Chronic myelomonocytic leukemia;
  • Lymphoma (including Hodgkin's) with chemosensitive disease (i.e., response to chemotherapy) and receiving a related donor transplant;
  • Aplastic anemia;
  • Primary or secondary myelofibrosis.
• Acute myeloid leukemia (AML), with or without a history of myelodysplastic syndrome, in first or second complete remission.
• Acute lymphoblastic leukemia, in first or second complete remission.
• Acute undifferentiated leukemia in first or second remission.
• Acute biphenotypic leukemia in first or second complete remission.
• Chronic myelogenous leukemia in either chronic or accelerated phase.
• One of the following myelodysplastic syndrome(s) defined by the following:
  • Receiving myeloablative or reduced-intensity conditioning regimens.
• Adequate renal and hepatic function, within 6 weeks of initiation of conditioning, as measured by:
  • Hepatic (within 72 hours of Day 0): alanine aminotransferase;
  • Renal (within 72 hours of Day 0): Serum creatinine within normal range for age or if serum creatinine above ULN range for age, a creatinine clearance [CrCl]) ≥60 mL/min.;
  • Baseline blood samples drawn for serum Platelia galactomannan enzyme immunoassay (GM EIA) and β-D glucan levels within 14 days before randomization, with results available prior to randomization;
  • Baseline Toxoplasma serologies available within 6 weeks prior to randomization;
  • Baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency testing with no evidence of G6PD deficiency performed within 6 weeks prior to randomization.
• Female subjects of child-bearing potential < 2 years post-menopausal must agree to and comply with using 1 barrier method (e.g., female condom with spermicide) plus one other highly effective method of birth control (e.g., oral contraceptive, implant, injectable, indwelling intrauterine device, vasectomized partner), or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, agree to use barrier contraception (condom with spermicide), and also agree not to donate sperm while participating in the study and for 120 days from the last IV dose of study drug.

• Diagnosis of AML not in morphological remission.
• Diagnosis of chemotherapy-resistant lymphoma.
• Suspected or diagnosed invasive fungal disease (IFD) within 4 weeks of screening.
• Diagnosed symptomatic heart failure with left ventricular ejection fraction (LVEF) at rest ≤ 40%, LVEF > 40% but fails to improve with exercise, or shortening fraction ≤ 26%.
• Personal or family history of Long QT interval on ECG (QT) syndrome or a prolonged QT interval corrected (QTc) interval (> 470 msec in males and > 480 msec in females); or concurrent administration of terfenadine, cisapride, astemizole, erythromycin, pimozide, or quinidine.
• Diagnosed reduced lung function with either diffusion capacity (corrected for hemoglobin), forced expiratory volume 1, forced vital capacity ≤ 45% of predicted value, or O2 saturation ≤ 85% on room air.
• Suspected or documented PCP within 2 years of screening.
• Positive baseline serum Platelia GM EIA (≥ 0.5) and/or β-D glucan assay (≥ 80 pg/mL).
• Receipt of previous allogeneic BMT.
• Planned receipt of cord blood for transplantation.
• Planned peripheral blood or marrow autograft.
• Underlying diagnosis of multiple myeloma.
• Grade 2 or higher ataxia, tremor, motor neuropathy, or sensory neuropathy, per NCI CTCAE version 5.0.
• History of severe ataxia, neuropathy or tremors; or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson's disease or Huntington's disease).
• Planned or ongoing therapy at screening with a known neurotoxic medication for a complete list of prohibited neurotoxic medications).
• Known hypersensitivity to Rezafungin for Injection, any echinocandin, fluconazole, posaconazole, other azole antifungal, or to any of their excipients.
• Known hypersensitivity or inability to receive TMP/SMX or any of its excipients.
• Recent use of an investigational medicinal product within 28 days of the first dose of prophylactic study drug or presence of an investigational device at the time of screening.
• Known infection with HIV.
• Pregnant or lactating females.
• The Principal Investigator (PI) determines that the subject should not participate in the study.
• Considered unlikely to follow up for 90 days after receipt of the BMT due to logistic concerns (i.e., location relative to transplant center).

Eligibility last updated 10/5/21. Questions regarding updates should be directed to the study team contact.

• Male and female subjects ≥ 18 years old.
• Diagnosis of dcSSc according to the 2013 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria.
• Must have disease duration (defined as interval from first non-Raynaud disease manifestation) of ≤ 5 years.
• Must have mRSS of ≥ 15 but ≤ 35.
• Active disease defined as any of the following within the 6 months prior to screening:
  • Increase in mRSS by ≥ 3 units;
  • Increase in mRSS by ≥ 2 units with involvement of 1 new body area;
  • Involvement of 2 new body areas;
  • Symptoms indicative of skin activity such as severe cutaneous itching or burning.
• Subjects receiving concomitant immunosuppression must be on a stable dose for at least 3 months prior to screening.
• Adequate organ and bone marrow functions evaluated during the 28 days prior to enrollment as follows:
  • Absolute neutrophil count ≥ 1.5 × 10^9 /L;
  • Platelet count ≥ 100 × 10^9 /L;
  • Total bilirubin ≤ 1.0 × upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal limits; and
  • Serum creatinine ≤ 1.5 × ULN. 
• Female subjects of childbearing potential have a negative pregnancy test at screening. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression:
  • Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug;
  • Sexually active women of childbearing potential enrolled in the study must agree to use two forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug. Effective birth control includes:
    • IUD plus one barrier method;
    • on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; or
    • 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm), or a vasectomized partner.
• For male patients who are sexually active and who are partners of premenopausal women: agreement to use 2 forms of contraception as in criterion above during the treatment period and for at least 3 months after the last dose of study drug.
• Male subjects must not donate sperm for 3 months after last dose of study drug.
• Able to provide written informed consent prior to the performance of any study-specific procedures.

• Subject has corrected QT interval using Fredericia’s formula (QTcF) > 450 ms.
• Ongoing use or current use of concomitant medication known to have the potential for QTc prolongation.
• Female subject who is pregnant or breastfeeding.
• Participated in another study with an investigational drug within 28 days of study entry (for studies involving biologics, within three half-lives of the biologic).
• History or other evidence of severe illness or any other conditions that would make the subject, in the opinion of the Investigator, unsuitable for the study.
• Chronic heart failure with New York Heart Association Classes II, III, or IV.
• Acute or chronic liver disease (e.g., cirrhosis).
• Positive human immunodeficiency virus (HIV) test.
• Active hepatitis C virus (HCV), hepatitis B virus (HBV), or positive whole blood tuberculin test
• Diagnosed with any malignancy within 3 years of enrollment, with the exception of basal cell or completely resected squamous cell carcinoma of the skin, resected in situ cervical malignancy, resected breast ductal carcinoma in situ, or low-risk prostate cancer after curative resection
• Has had previous exposure to belumosudil or known allergy/sensitivity to belumosudil, or any other ROCK2 inhibitor.
• Scleroderma renal crisis within 4 months prior to enrollment.
• FVC ≤ 50% Predicted.

• Provide written informed consent from subjects, an impartial witness (for a subject who is physically unable to sign the informed consent form, but able to provide his/her consent by some other means [e.g., speaking, nodding, blinking]), or the subject’s legally authorized representative (LAR) (for a subject who lacks capacity to consent for him/herself [e.g., a subject without mental capacity to consent]), prior to beginning any study procedures.
• Cervical spinal cord injury who meet either of the following criteria:
  • AIS A with ISNCSCI neurological level of injury between C4 and C7 (for C4, the subject must have at least 1 point of motor activity within the ZPP inclusive of C5 to T1);
  • AIS B or C with ISNCSCI neurological level of injury between C4 and C7, and UEMS ≤ 28.
• Male and female subjects, age between 18 and 70 years at time of consent.
• Body mass index (BMI) < 40 kg/m^2.
• Acute traumatic spinal cord injury subjects who can receive MT-3921 as soon as possible after the injury, at least within 48 hours from the time of the injury.
• Willing and able to participate in all aspects of the study, including completion of subjective evaluations, attendance at scheduled clinic visits, and compliance with all protocol requirements as evidenced by providing informed consent.
• Both female and male subjects of childbearing potential must agree to use of contraception or abstinence during the study.

• Any concomitant injury that, in the judgement of the Investigator, interferes with the performance, interpretation or validity of neurological examinations (including fractures requiring casts), such as but not limited to multiple spinal cord lesions, brachial/lumbar plexus injury, cauda equina injury or traumatic brain injury defined by a Glasgow Coma Scale (GCS) <14 at time of examination.
• Poly-traumatic Injury as defined by Injury Severity Score (ISS) values > 25 at time of Screening.
• Penetrating spinal cord injuries.
• Complete transection of the spinal cord or spinal cord contusion size > 3 cm determined by MRI.
• Subjects who are highly anticipated to be dependent on long-term mechanical ventilation (e.g., beyond 10-14 days), which would interfere with study procedures including neurological exams.
• Any other significant pre-existing medical conditions prior to spinal cord injury or current conditions that, in the judgement of the Investigator, may increase the risks associated with study participation, and would preclude successful participation in the study.
• Subjects with history of active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV), except for adequately treated hepatitis B (HBV) and hepatitis C virus (HCV) with documentation of sustained virologic response defined as undetectable HCV RNA at least 12 weeks after the end of treatment.
• History of anaphylaxis or significant allergy to any food and medications.
• History or presence of malignancy within the last 3 years prior to screening, except subjects who have been treated successfully with no recurrence for >1 year of basal cell or squamous cell carcinoma of the skin or in-situ cervical cancer.
• Subjects with hereditary fructose intolerance.
• Psychoactive substance use disorder at any time during the 3 months preceding study entry (as defined by Diagnostic and Statistical Manual of Mental Disorders [DSM-5]).
• Participation in any clinical trial of a new chemical entity within 12 weeks prior to Screening.
• Pregnant or nursing women.

Inclusion Criteria
•General: 

• The subject (or, when applicable, the subject’s legally acceptable representative) signs an informed consent form indicating that the subject has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.
• The subject is an outpatient of either sex, at least 40 years old, at the time of consent.
• Subjects must, in the opinion of the investigator, be able to participate in all scheduled evaluations, likely to be compliant, and likely to complete all required tests, including neuroimaging brain scans and lumbar punctures.
• The subject has a body mass index (BMI) ≥ 18 and ≤ 35 kg/m^2 at screening.

Inclusion Criteria
•Diagnostic:

• The subject has a diagnosis of possible or probable MSA using the modified Gilman et al, 2008 diagnostic criteria (Gilman et al. 2008).
• The subject’s onset of first MSA symptoms (including parkinsonism, cerebellar symptoms, orthostatic or urinary symptoms) occurred ≤ 4 years before screening, as assessed by the investigator.
• The subject’s anticipated life expectancy is ≥ 3 years, per investigator judgment.
• The subject has an UMSARS Part I score of ≤ 21 (excluding Item #11, sexual function), and additionally has:
  • Severity score ≤ 2 on the swallowing item (#2);
  • Severity score ≤ 2 on the ambulation item (#7);
  • Severity score ≤ 2 on the falling item (#8).
• The subject has an UMSARS Part IV disability score ≤ 3.
• Subject has a MoCA ≥ 18. Additionally, subject has sufficiently intact cognition to complete study assessments and follow study instructions, per investigator's judgment.
• A male subject who is nonsterilized and sexually active with a female partner of childbearing potential is eligible to participate if he agrees to use a barrier method of contraception (i.e., condom with or without spermicide) from the signing of informed consent throughout the study and for 90 days plus 5 half-lives (total of 190 days) after the last dose.
• Female subjects are eligible to participate if:
  • they are not pregnant or nursing; and
  • they are of nonchildbearing potential or agree to use highly effective contraception from the signing of informed consent throughout the study and for 30 days plus 5 half-lives (total of 130 days) after the last dose of study drug.

Exclusion Criteria
•Medical History:

• The subject has serious or unstable clinically significant illness including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic or autoimmune (e.g., multiple sclerosis), hematologic, or other major disease, which, in the judgment of the investigator, is poorly controlled or otherwise likely to deteriorate, compromises the subject’s safety or ability to complete the study, or compromises the interpretation of the study results.
• The subject has other medical problems (neurological, visual, orthopedic, psychiatric) that, in the opinion of the investigator, may significantly interfere with completion of the study or interpretation of study endpoints.
• The subject has a disorder that is likely to interfere with drug disposition and elimination.
• In the opinion of the investigator, the subject has a diagnosis of depression or other psychiatric disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), AND this disorder is poorly controlled AND of sufficient severity to interfere with completion of the study or interpretation of the endpoints.
• The subject is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the subject has attempted suicide within the past year before screening. Subjects who have positive answers on Item 4 or 5 on the C-SSRS (based on the past year) before randomization are excluded.
• The subject has a history of alcohol or substance use disorder (except tobacco use disorder), as defined by the DSM-5, within 1 year before screening or between screening and randomization, or, in the opinion of the investigator, the subject’s current or past use of substances may interfere with performance on the assessments.
• The subject has a positive finding on an alcohol or illicit drug screen. A positive result for cannabis or prescription medications does not require exclusion.
• The subject has undergone surgery for the treatment of MSA (e.g., pallidotomy, deep brain stimulation, fetal tissue transplantation).
• The subject has a history of epilepsy or seizures, except self-limited febrile childhood seizures.
• The subject has any contraindication to lumbar puncture including but not limited to thrombocytopenia or other coagulation disorders (including subjects who are receiving anticoagulants and cannot safely stop them), the absence of cutaneous or soft-tissue infection overlying or adjacent to the site of lumbar puncture, previous spinal surgery that could complicate access to the subarachnoid space, or conditions associated with raised intracranial pressure such as a closed head injury within 3 months or benign intracranial hypertension, or any spinal abnormality or other aspects (e.g., tattoos in the midline lumbar area) or other clinical findings (papilledema seen with ophthalmoscopy) that may complicate or contraindicate lumbar puncture, as judged by the investigator. Subjects who are using low-dose aspirin, low molecular weight heparin, coumadin, or other anticoagulants may still participate if use of these medications can be safely suspended before lumbar puncture, per investigator judgment and local medical practices.

Exclusion Criteria
•Diagnostic Assessments:

• Any clinically significant abnormality as determined by investigator at screening or between screening and randomization in physical examination findings, vital signs, ECGs, or clinical laboratory test results that may compromise the subject’s safety or ability to complete the study or compromise the interpretation of the study results.
• Presence of any of the following contraindications to MRI:
  • claustrophobia that would contraindicate brain MRI or the presence of a pacemaker;
  • cardiac defibrillator; spinal cord or vagus nerve stimulator;
  • aneurysm clip;
  • artificial heart valve; recently placed (within 1 year) coronary or carotid stent; ear implant;
  • CSF shunt; other implanted medical device (e.g., insulin pump); or
  • metal fragments or foreign objects in the eyes, skin, or body.
• Ophthalmic abnormalities. The following are considered exclusionary:
  • Ophthalmic abnormalities and conditions that, in the judgment of the investigator and/or ophthalmologist, would affect subject safety and/or impair the ability to perform a quality ophthalmological evaluation;
  • Congenital or acquired ophthalmic conditions (primary or secondary) that are considered poorly controlled within the last 12 months before screening, with or without treatment, or otherwise expected to lead to significant deterioration in visual acuity in the next 12 months after randomization;
  • Any ocular opacities that may prevent quality fundus assessment;
  • Neovascular or exudative (wet) form of age-related macular degeneration.
• The subject has any of the following at the screening visit:
  • estimated glomerular filtration rate (determined with the Chronic Kidney Disease Epidemiology Collaboration equation) < 50 mL/min; QT interval with Fridericia correction method > 450 ms for male subjects and > 470 ms for female subjects;
  • a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value > 1.5 × the upper limit of normal (ULN).
• Clinically significant vital sign abnormalities at screening, defined as:
  • Systolic blood pressure ≥ 160 mm Hg;
  • Diastolic blood pressure ≥ 90 mm Hg (blood pressure assessed with the subject at rest in the seated position; may be repeated up to 3 times), or;
  • Pulse rate 100 beats per minute (subject at rest in the seated position).
• The subject has a positive hepatitis B surface antigen test result, known or suspected active hepatitis C infection, or known history of HIV infection:
  • Note: Subjects with positive hepatitis C virus (HCV) serology results may be enrolled if results from a quantitative polymerase chain reaction for HCV RNA is negative, to exclude active hepatitis C infection, and if the investigator agrees that the subject can safely participate in the study.
• The subject has a brain MRI that shows clinically significant evidence of malignant, ischemic, demyelinating, structural, or degenerative brain disease (other than MSA) that may confound diagnosis or subject safety during the study, or the subject has findings that compromise the safety of lumbar puncture per investigator judgment.
• The subject has a current blood clotting or bleeding disorder, including clinically significant abnormal findings in laboratory tests of coagulation.

Exclusion Criteria
•Other:

• The subject has poor venous access such that IV drug delivery or PK/safety blood sampling would be difficult.
• The subject has participated in another study investigating active or passive immunization against αSYN for PD or MSA, or has had immunoglobulin G therapy, within 6 months before screening.
• The subject’s participation in a previous study of a disease-modifying therapy (with proven receipt of active treatment) will compromise the interpretability of the data from the present study, per consultation with medical monitor or designee. For example, subjects who participated in a study of gene therapy and antisense oligonucleotides (or other disease-modifying treatment) and received active treatment would be excluded.
• The subject has received any investigational compound that, in the opinion of the investigator or sponsor, may not have completely washed out before the screening visit or may affect the safety or efficacy evaluations.
• The subject has a positive pregnancy test result at screening.
• The subject is an immediate family member, is a study site employee, or is in a dependent relationship (e.g., as a spouse, parent, child, or sibling) with a study site employee who is involved in the conduct of this study.
• The subject has donated 400 mL or more of his or her blood volume within 90 days before the start of the screening visit.  

Eligibility last updated 8/10/22. Questions regarding updates should be directed to the study team contact.

• Confirmed diagnosis of Crohn's disease (CD) for at least 3 months prior to Baseline.
• Crohn's disease activity index (CDAI) score 220
  •450 at Baseline.
• Confirmed diagnosis of moderate to severe Crohn's Disease as assessed by stool frequency (SF), abdominal pain (AP) score, and Simple Endoscopic score for CD (SES-CD).
• Demonstrated intolerance or inadequate response to one or more anti-tumor necrosis factor (TNF) therapies.

• Current diagnosis of ulcerative colitis or indeterminate colitis.
• Receipt of CD approved biologic agents prior to Baseline (as detailed in protocol), or any investigational biologic or other agent or procedure prior to Baseline (as detailed in protocol).
• Prior exposure to p19 and/or p40 inhibitors (e.g., risankizumab and ustekinumab).
• Currently know complications of CD (strictures, short bowel, etc).

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

Eligibility last updated 7/28/22. Questions regarding updates should be directed to the study team contact.

• Males and females, age ≥ 18 years.
• Patients with tumors of the head and neck, thorax, abdomen, pelvis, and extremities.
• Histological confirmation of oncologic diagnosis.
• Completed oncologic imaging (per discretion of treating physician).
• ECOG Performance Status 0-3.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Provide informed written consent.

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant women;
  • Nursing women;
  • Women of childbearing potential who are unwilling to employ adequate contraception.
• 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.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.  NOTE:  Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Patients (men or women) must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis by physical exam or radiologic study.
• Invasive primary tumor or metastatic tissue confirmation of HER2-positive status, defined as presence of one or more of the following criteria:
  • Over-expression by immunohistochemistry (IHC) with score of 3+ (in > 30% of invasive tumor cells) AND/OR HER2 gene amplification (average of > 6 HER2 gene copies per nucleus or a FISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.0), according to guidelines and in keeping with past eligibility for ratio of ≥ 2.0 rather than the ratio of > 2.2 required by new guidelines:
    • http://www.asco.org/quality-guidelines/recommendations-human-epidermal-growth-factor-receptor-2-testing-breast-cancer
  • Note: Patients with a negative or equivocal overall result (FISH ratio of < 2.0 or ≤ 6.0 HER2 gene copies per nucleus) and IHC staining scores of 0, 1+, 2+ are not eligible for enrollment.
• No increase in corticosteroid dose in the week prior to baseline brain imaging.
• Age ≥ 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Patients must have normal organ and marrow function as described below:
  • Absolute neutrophil count > 1,000/uL;
  • Platelets > 100,000/uL;
  • Total bilirubin ≤ 1.5 X upper limit of normal (ULN) ;
  • AST(SGOT)/ALT(SGPT) ≤3 X institutional ULN without liver metastases, or ≤ 5X institutional ULN with liver metastases;
  • Creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 50 mL/min.
• Left ventricular ejection fraction ≥ 50%, as determined by RVG (MUGA) or echocardiogram within 60 days prior to initiation of protocol therapy.
• Prior therapy (see specifics by each cohort below):
  • Prior trastuzumab is allowed for all cohorts;
  • Prior capecitabine is NOT allowed for participants enrolled to Cohorts 3A/3B ONLY;
  • Prior lapatinib is allowed for Cohorts 1, 2, and 3B, but NOT Cohort 3A;
  • Prior T-DM1 is NOT allowed for Cohorts 4A and 4B but is required for Cohort 4C. Dose reductions on prior T-DM1 for Cohort 4C do not preclude enrollment on Cohort 4C. Patients on 4C may have progressed on prior T-DM1 in the CNS or non-CNS sites and had to have tolerated therapy without significant toxicity that would preclude retreatment;
  • No prior therapy with neratinib is allowed on any cohort;
  • There is no limit to the number of previous lines of therapy (including chemotherapy, trastuzumab, and endocrine therapies). At least 2 weeks washout period post chemotherapy, any prior protocol therapy, lapatinib, other targeted or biologic or immunotherapy, or radiation therapy is required prior to study entry;
  • No washout is required for hormonal therapy, but concurrent hormonal therapy is not allowed for patients on study. The only exception to this is longstanding ovarian suppression in pre-menopausal patients, if this has been started ≥ 6 months prior to study enrollment. Other hormonal therapies are not allowed while patients are on study.
• The effects of neratinib, capecitabine, and T-DM1 on the developing human fetus are not known. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• HIV-positive individuals on combination antiretroviral therapy are eligible for enrollment and will be monitored closely for potential pharmacokinetic interactions with neratinib.
• Concomitant medications listed in Appendix J should be avoided (when possible) while on study.
• Ability to understand and willingness to sign a written informed consent document.
• For Cohorts 1, 3A/3B, 4B and 4C patients must have new or progressive measurable CNS lesions, as assessed by the patient’s treating physician. This includes patients who have progressed after at least one line of standard local treatment for CNS disease (WBRT, SRS, or surgical resection as below).
• In Cohort 2, eligible patients will include those who have CNS disease that is amenable for surgery (typically < 3 brain metastases and with planned resection by neurosurgery). These patients may include those who have received or not received previous treatment(s) for their CNS.
• Further eligibility details for patients with progressive disease (Cohorts 1, 3A/3B, 4A, 4B, 4C):
  • Patients must have measurable CNS disease, defined as at least one parenchymal brain lesion that can be accurately measured in at least one dimension with longest dimension ≥10 mm by local radiology review. Note: measurable non-CNS disease is NOT required for study participation;
  • It is anticipated that some patients may have multiple progressive CNS lesions, one or several of which are treated with SRS or surgery with residual untreated lesions remaining. Such patients are eligible for enrollment on this study providing that at least one residual (i.e., non-SRS-treated or non-resected) lesion is measurable (≥10 mm). The location of the measurable lesion should be documented in the patient chart and case report form;
  • Patients who have had prior cranial surgery are eligible, provided that there is evidence of measurable residual or progressive lesions, and at least 2 weeks have passed since surgery. If a patient has surgical resection followed by WBRT, then there must be evidence of progressive CNS disease after the completion of WBRT;
  • Except for those in Cohort 4A where prior local CNS therapy is not allowed, patients who have had prior WBRT and/or SRS and then whose prior treated lesions have progressed thereafter are also eligible for all other cohorts. In this case, lesions which have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression.
• Further eligibility details for patients with operable disease (Cohort 2):
  • It is anticipated that that patients who have intracranial disease amenable to surgery will have measurable CNS disease prior to study entry and to resection. However, this is not an eligibility requirement. Measurable disease is also not required to continue on protocol subsequent to surgical resection;
  • For patients who undergo surgery, postoperative whole brain radiation therapy will not be allowed while patients are on study (concurrent neratinib and radiation therapy has not been studied and toxicity of this is unknown). Patients will require discontinuation of neratinib if WBRT will be administered. However, if the treated provider feels that targeted radiosurgery (SRS, gamma knife, etc.) would be of benefit postoperatively, patients may proceed with this and then begin neratinib AFTER radiation completes.
• Further eligibility details for patients on Cohort 4A: All patients on Cohort 4A will not have received prior radiation or surgery to their brain. Prior systemic therapy aimed to treat disease in the brain is allowed (i.e., prior systemic standard therapy or protocol systemic therapy for brain mets).
  • Note: Laboratory tests required for eligibility must be completed within 4 weeks prior to study entry. Baseline measurements in the CNS must be documented from tests up to 21 days prior to planned start of protocol therapy unless not covered by insurance. If insurance coverage is an issue, a case by case approval of testing beyond this window may be approved by the overall study PI. Other non-laboratory tests must be performed as indicated.

• Participants who have had chemotherapy or radiotherapy (including investigational agents) within 2 weeks prior to entering the study or those who have not recovered adequately from adverse events due to agents administered more than 4 weeks earlier (excluding alopecia). Washout from trastuzumab or hormonal therapy is not required.
• Participants who are currently receiving any other investigational agents.
• History of severe allergic reactions or intolerability attributed to compounds of similar chemical or biologic composition to neratinib (all cohorts), capecitabine for Cohorts 3A/3B, and T-DM1 for Cohorts 4A-4C.
• Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin, carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or primidone.
• Patients who are receiving any cancer-directed concurrent therapy, such as concurrent chemotherapy, radiotherapy, or hormonal therapy while on study. Concurrent treatment with bisphosphonates and denosumab is allowed for bony metastases but should be started before the first dose of neratinib.
• Any prior treatment with capecitabine for patients enrolled to Cohorts 3A/3B, prior lapatinib for participants on Cohort 3A, and T-DM1 for Cohorts 4A-4B.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• For Cohorts 4A, 4B, and 4C: Patients with myocardial infarction or cardiomyopathy onset within the last 6 months are excluded.
• Active hepatitis B or hepatitis C with abnormal liver function tests (Cohorts 4A-4C):
  • Positive Hepatitis B (Hepatitis B surface antigen and antibody) and/or Hepatitis C (Hepatitis C antibody test) as indicated by serologies conducted ≤ 3 months prior to registration if liver function tests are outside of the normal institutional range.
  • Note: Patients with positive Hepatitis B or C serologies without known active disease are eligible if they meet all laboratory requirements.  Patients with laboratory evidence of vaccination to Hepatitis B (e.g., positive antibodies) are also eligible.
• Active liver disease from autoimmune disorders or sclerosing cholangitis.
• Lung disease from etiology other than metastatic breast cancer resulting in dyspnea at rest (4A-4C).
• More than two seizures over the last 4 weeks prior to study entry.
• Patients with known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body. However, Head CT with contrast is allowed in place of MRI at baseline and throughout the study if MRI is contraindicated and a participant’s CNS lesions are clearly measurable on the head CT.
• Those with leptomeningeal metastases as the only site of CNS disease.
• Significant malabsorption syndrome or inability to tolerate oral medications.
• Any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea.
• Inability to comply with study and/or follow-up procedures.
• Pregnant women are excluded from this study because neratinib (and other agents on study) is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with neratinib, breastfeeding should be discontinued if the mother is treated with neratinib. Negative urine pregnancy test is required for women of childbearing potential within 4 weeks of planned treatment start.
• Individuals with a history of a different active malignancy are ineligible.

• Signed informed consent.
• Age ≥ 18 years with life expectancy > 12 weeks.
• Histologically proven, newly diagnosed supratentorial glioblastoma based on the World Health Organization (WHO) classification (2016); prior diagnosis of lower grade astrocytoma that has been upgraded to histologically confirmed glioblastoma is eligible if chemotherapy and radiotherapy treatment-naïve.
• Randomization must occur within 5 weeks of resection (subjects undergoing biopsy only are excluded).
• Craniotomy site must be adequately healed, free of drainage or cellulitis and the underlying cranioplasty must appear intact prior to start of study treatment.
• Available and willing to submit sufficient and of adequate quality tumor tissue representative of glioblastoma to perform MGMT promoter methylation status testing.
• Karnofsky performance status (KPS) ≥ 60.
• Stable or decreasing corticosteroids within 5 days prior to study treatment start.
• Willing to forego the use of Tumor Treating Fields therapy (Optune®).
• Adequate organ function within 14 days prior to randomization:
• Bone marrow:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L;
  • Platelets count ≥ 100 x 10^9/L;
  • Hemoglobin ≥ 10 g/dL (eligibility level for hemoglobin may be met by transfusion).
• Renal:
  • Serum creatinine < 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min as calculated using the method standard for the institution.
• Hepatic:
  • Total serum bilirubin ≤ 2 x ULN unless the patient has documented Gilbert syndrome;  
  • Aspartate and alanine transaminase (AST/SGOT and ALT/SGPT) ≤ 2.5 x ULN; ≤ 5.0 x ULN if there is liver involvement secondary to tumor;
  • Alkaline phosphatase (ALP) ≤ 2.5 x ULN; ≤ 5 x ULN in case of bone metastasis.
• Negative serum pregnancy test (for females of childbearing potential) within 14 days prior to randomization.
• Male and female subjects of reproductive potential must agree to use an effective method of contraception (e.g., oral contraceptives, intrauterine device, barrier method) throughout the study and for at least 3 months after the last dose of study treatment.
• Men are considered of reproductive potential unless they have undergone a vasectomy and confirmed sterile by a post-vasectomy semen analysis .
• Women are considered of reproductive potential unless they have undergone hysterectomy and/or surgical sterilization (at least 6 weeks following a bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusive procedure that has been confirmed in accordance with the device's label), have medically confirmed ovarian failure, or achieved postmenopausal status (defined as cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women.
• Willing and able to comply with protocol.

• Unable to swallow tablets or capsules.
• Pregnant or breastfeeding.
• Prior chemotherapy (including carmustine-containing wafers (Gliadel®), immunotherapy (including vaccine therapy)) or investigation agent for GBM or GS (previous 5-aminolevulinic acid [ALA]-mediated photodynamic therapy [PDT] administered prior to surgery to aid in optimal surgical resection is permitted).
• Prior radiotherapy to the brain.
• Unable to discontinue use of EIAEDs, if previously taking EIAEDs, must have been discontinued ≥ 2 weeks prior to randomization.
• Use of a strong inducer or moderate or strong inhibitor of CYP3A4 within 7 days prior to randomization or expected requirement for use on study therapy.
• Use of any medication that can prolong the QT/QTc interval within 7 days prior to randomization or expected requirement for use on study therapy.
• Active bacterial, fungal or viral infection requiring systemic treatment.
• Personal or immediate family history of long QT syndrome, QTc interval > 450 msec (males) or > 470 msec (females) at screening (recommended that QTc be calculated using Fridericia correction formula, QTcF), or a history of unexplained syncope.
• Any contraindication to temozolomide listed in the local product label.
• Another malignancy except adequately treated non-melanoma skin cancer; subjects who have had another malignancy in the past, but have been disease-free for more than 5 years, and subjects who have had a localized malignancy treated with curative intent and disease free for more than 2 years are eligible.
• Participation in other studies involving investigational drug(s) within 30 days prior to randomization.
• Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for participation in this study.

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

Eligibility last updated 2/21/23. Questions regarding updates should be directed to the study team contact.

All Subjects

• Presence of thoracic aortic pathology deemed to warrant surgical repair which requires proximal graft placement in Zone 0-2:
  • Aneurysms:
    • Fusiform aneurysm (≥ 55 mm); or
    • Fusiform aneurysm (> 2 times native aortic diameter); or
    • Saccular aneurysm (no diameter criteria).
  • Non-aneurysms
    • Intramural hematoma (no diameter criteria); or
    • Penetrating aortic ulcer (no diameter criteria); or
    • Traumatic aortic transection (no diameter criteria); or
    • Other isolated lesion with non-diseased proximal and distal landing zone, or Type B aortic dissection requiring treatment for rupture or impending rupture, malperfusion syndrome, rapid expansion, uncontrollable pain, aneurysmal dilatation or prophylactic reasons; or
    • Residual aortic dissection following surgical repair of Type A aortic dissection requiring treatment. TBE implant must be at least 14 days after the surgical repair procedure.
• Age ≥ 18 years at time of informed consent signature.
• Subject is capable of complying with protocol requirements, including follow-up.
• Informed Consent Form (ICF) is signed by Subject or legal representative.
• Must have appropriate proximal aortic landing zone, defined as:
  • Requires placement of the proximal extent of the Aortic Component in Zone 0-2 for exclusion of the lesion.
  • Acceptable proximal landing zone outer curvature length for the required device.
  • Landing zone inner diameters between 16-48 mm in Zone 1-2 Subjects and 24-48 mm in Zone 0 Subjects.
  • Landing zone includes either the brachiocephalic, left common carotid or left subclavian native ostium.
    • If the landing zone includes brachiocephalic it cannot be heavily calcified or heavily thrombosed;
    • If the landing zone includes either the left common carotid or left subclavian it cannot be heavily calcified, heavily thrombosed or aneurysmal.
  • Dissection Patients: Primary entry tear must be distal to the target branch vessel and proximal extent of the proximal landing zone must not be dissected.
  • For patients with prior replacement of the ascending aorta and/or aortic arch by a surgical graft, there must be at least 2 cm of landing zone proximal to the most distal anastomosis site.
• Must have appropriate target branch vessel landing zone, defined as:
  • Length of ≥ 3 cm proximal to first major branch vessel if using Aortic Component with 8 mm portal diameter; or
  • Length of ≥ 2.5 cm proximal to first major branch vessel if using Aortic Component with 12 mm portal diameter (required for Zone 0 Subjects);
  • Target branch vessel inner diameters of 6-15 mm if using Aortic Component with 8 mm portal diameter; or
  • Inner diameters of 11-18 mm if using Aortic Component with 12 mm portal diameter (required for Zone 0 Subjects);
  • Target branch vessel landing zone must be in native aorta that cannot be severely tortuous (i.e., vessel tortuosity that results in a 180 degree turn within the treated target branch vessel length), aneurysmal, dissected, heavily calcified, or heavily thrombosed.
• For patients with aneurysm/isolated lesion, must have appropriate distal aortic landing zone, defined as:
  • Outer curvature length must be ≥ 2 cm proximal to the celiac artery;
  • Aortic inner diameters between 16-48 mm (diameter should be between 16-42 mm if using distal CTAG Device extension);
  • Landing zone cannot be aneurysmal, heavily calcified, or heavily thrombosed;
  • Landing zone in native aorta or previously implanted Conformable GORE® TAG® Device.

Zone 0/1 Subjects Only

• Subject does not have a mechanical aortic valve.
• Subject is considered a high risk candidate for conventional open surgical repair at the discretion of the Investigator.

All Subjects

• Concomitant disease of the ascending aorta or  aneurysm of the abdominal aorta requiring repair.
• Previous endovascular repair of the ascending aorta.
• Previous endovascular repair of the DTA with a non-Gore device.
• Surgery within 30 days prior to enrollment with the exception of:
  • Surgery for Ascending Aortic Dissection and/or placement of vascular conduit for access;
  • Surgery to treat any other presenting injuries in Traumatic Transection subjects only.
• Infected aorta.
• Life expectancy < 2 years.
• Myocardial infarction within 6 weeks prior to treatment.
• Stroke within 6 weeks prior to treatment, stroke defined as rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin.
• Patient has an active systemic infection (e.g. infection requiring treatment with parenteral anti-infective medication) that may place the patient at increased risk of endovascular infection. Patients with a chronic infection (such as HIV, Hepatitis C, etc.) that is well controlled under their current treatment regimen may be eligible.
• Pregnant female at time of informed consent signature.
• Degenerative connective tissue disease; e.g., Marfan’s or Ehler-Danlos Syndrome.
• Participation in another drug or medical device study within one year of study enrollment.
• Known history of drug abuse within one year of treatment.
• Presence of protruding and/or irregular thrombus and/or atheroma in the aortic arch or ascending aorta.
• Tortuous or stenotic iliac and/or femoral arteries preventing introducer sheath insertion and the inability to use a conduit for vascular access.
• Planned coverage of celiac artery.
• Patient has known sensitivities or allergies to the device materials.
• Patient has known hypersensitivity or contraindication to anticoagulants or contrast media, which is not amenable to pre-treatment.
• Previous instance of Heparin Induced Thrombocytopenia type 2 (HIT-2) or known hypersensitivity to heparin.
• Patient with a history of a hypercoagulability disorder and/or hypercoagulability state.
• Diameter taper outside of the device sizing range between proximal and distal landing zones of aorta and the inability to use additional devices of different diameters to compensate for the taper.
• Mycotic aneurysm.
• Persistent refractory shock (systolic blood pressure < 90 mm Hg).
• Patient has body habitus or other medical condition which prevents adequate visualization of the aorta.
• Renal failure defined as patients with an estimated Glomerular Filtration Rate (eGFR) < 30 (ml/min/1.73 m2) or currently requiring dialysis.

Zone 0/1 Subjects Only

• Patient at high risk for a neurological event; e.g., stroke.

Zone 0/1 Subjects Only:  

PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have been diagnosed with CLL and have > 5000 B-cells per uL of peripheral blood at any point during the course of their disease.
• This blood submission is mandatory prior to registration/randomization to perform FISH centrally that will be used for stratification. It should be obtained as soon after preregistration as possible.

REGISTRATION ELIGIBILITY CRITERIA (STEP 1) 

• Patients must be diagnosed with CLL in accordance with 2018 IWCLL criteria [28] that includes all of the following:
  • ≥ 5 x10^9 B lymphocytes (5000/μL) in the peripheral blood measured by flow cytometry at any point in the course of the disease;
  • On local morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes;
  • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in >10% of cells must lack t(11;14) translocation by interphase cytogenetics.
• Patients must be intermediate or high-risk Rai stage CLL.
  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus any of the following: enlarged lymph nodes, hepatomegaly, or splenomegaly'
  • High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia.
• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which includes at least one of the following criteria:
  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia);
  • Massive (≥ 6 cm below the costal margin), progressive or symptomatic splenomegaly;
  • Massive nodes (≥ 10 cm) or progressive or symptomatic lymphadenopathy;
  • Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of ≥ 50% over a 2 month period;
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy;
  • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine);
  • Constitutional symptoms, which include any of the following:
    • Unintentional weight loss of 10% or more within 6 months;
    • Significant fatigue;
    • Fevers >100.5 degrees F for 2 weeks or more without evidence of infection;
    • Night sweats ≥1 month without evidence of infection.
• Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids).
• Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration.
• Age ≥ 65 years.
• ECOG performance status 0-2.
• Required initial laboratory values.
• Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 except if due to bone marrow involvement.
• Platelet Count (untransfused) ≥ 30,000/mm^3.
• Calc. Creatinine Clearance ≥ 40 mL/min (by Cockcroft-Gault).
• Bilirubin ≤ 1.5 x upper limit of normal (ULN) except if due to liver involvement, hemolysis, or Gilbert’s disease.
• AST / ALT ≤ 2.5 x upper limit of normal (ULN) except if due to liver involvement.
• Patients must not have any history of Richter’s transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%).
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
  • Please note: IVIG can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load.
• Patients with Class III or Class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible.
• Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible.
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to registration on the study.
• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days prior to registration on the study. 
• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed.
• Patients must discontinue the drug 14 days prior to registration on the study.
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily.
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics.
• Central FISH blood results are mandatory prior to registration/randomization for it will be used for stratification.
• Patients must be able to swallow capsules and not have the following conditions:  disease significantly affecting gastrointestinal absorption, resection of the stomach or small bowel, partial or complete bowel obstruction.
• Patients must not have a known allergy to mannitol.
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions).
• Patients may not have had major surgery within 10 days prior to registration, or minor surgery within 7 days prior to registration. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician.
• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase for prophylaxis/treatment of TLS.

RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)

• Completion of treatment through Cycle 14 Day 28, and remain on ibrutinib therapy.
• Receipt of central BM MRD results.
• Response assessment completed per Section 5.0 with CR determination.

Eligibility last updated 1/17/22. Questions regarding updates should be directed to the study team contact.