• A female of childbearing potential is a sexually mature female who:
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Stage II-III colorectal cancer patients scheduled to receive oxaliplatin 510 mg/m^2 (cumulative dose) over 12 weeks as a component of adjuvant leucovorin calcium (calcium folinate), 5-fluorouracil and oxaliplatin (FOLFOX) treatment, in which patients are scheduled to receive oxaliplatin 85 mg/m^2 every 2 weeks for 12 weeks (i.e., 6 cycles), or adjuvant capecitabine and oxaliplatin (CAPOX) treatment, in which patients are scheduled to receive oxaliplatin 135 mg/m^2 every 3 weeks for 12 weeks (i.e., 4 cycles).
• No prior neurotoxic chemotherapy.
• No pre-existing clinical or pre-clinical peripheral neuropathy from any cause.
• No history of seizure disorder.
• No history of narrow-angle glaucoma.
• No symptoms of or history of schizophrenia, bipolar disease, suicidal thoughts and/or a major depression.
• No serious eating disorder such as bulimia or anorexia.
• No known diagnosis of ethanol (ETOH) addiction/dependence within the past 10 years.
• Concomitant medications:
  • No concomitant use of other adjuvant pharmacologic interventions (e.g., gabapentin, pregabalin, venlafaxine) with known or hypothesized efficacy for peripheral neuropathy. Must be discontinued at least 7 days prior to start of protocol treatment;
  • No anticipated or concurrent use of any antidepressant or serotonin-altering agent known to interact with duloxetine, due to concern regarding cumulative toxicity and potential drug interactions.
  • Use of a monoamine oxidase inhibitor (MAOI) or other antidepressants must be discontinued at least 14 days prior to start of protocol treatment;
  • No concomitant treatment with strong CYP1A2 and CYP2D6 inhibitors;
  • Chronic concomitant treatment with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants, phenothiazines, and Type 1C antiarrhythmics should be approached with caution. Concomitant administration of duloxetine and thioridazine should be avoided;
  • No use of warfarin or heparin products.
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential, a negative pregnancy test done ≤ 7 days prior to registration is required.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• In order to complete the mandatory patient-completed measure.
• Patients must be able to speak and read English.
• Calculated creatinine clearance > 30 mL/min.
• Aspartate aminotransferases (AST)/serum glutamic-oxaloacetic transaminase (SGOT) ≤ 3 x upper limit of normal (ULN).

• Patients ≥ 18 years of age.
• TGCT for which surgical resection is not an option (tumor biopsy to confirm diagnosis required if no histology/pathology available at screening).
• Symptomatic disease as defined as at least moderate pain per BPI Worst Pain or at least moderate stiffness per Worst Stiffness NRS item (defined as a score of 4 or more, with 10 describing the worst condition) within the screening period, prior to the first dose, and documented in the medical record.
• Participants should complete 14 consecutive days of questionnaires during the screening period and must meet minimum requirements as outlined in study protocol.
• Must have stable analgesic regimen, as judged by the investigator, for at least 2 weeks prior to first dose of study drug.
• Must have at least 1 measurable lesion according to RECIST Version 1.1, with a minimum tumor size of 2cm.
• Adequate organ and bone marrow function.
• If a female of childbearing potential, must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements.
• Must provide signed consent to participate in the study and is willing to comply with study-specific procedures.
• Willing and able to complete the patient-reported outcome (PRO) assessments on an electronic device.

• Previous use of systemic therapy targeting colony stimulating factor 1 (CSF1) or CSFR1 receptor (CSF1R); previous therapy with imatinib and nilotinib is allowed.
• Received therapy for TGCT, including investigational therapy within 14 days prior to the administration of study drug or within 28 days for therapies with a half-life longer than 3 days or an unknown half-life prior to the administration of study drug.
• Known metastatic TGCT or other active cancer that requires concurrent treatment (exceptions will be considered on a case-by-case basis).
• QT interval corrected by Fridericia's formula (QTcF) > 450 ms in males or > 470 ms in females or history of long QT syndrome.
• Concurrent treatment with any study-prohibited medications.
• Major surgery within 14 days of the first dose of study drug.
• Any clinically significant comorbidities.
• Active liver or biliary disease including evidence of fatty liver, nonalcoholic steatohepatitis (NASH), or cirrhosis.
• Malabsorption syndrome or other illness that could affect oral absorption.
• Known active human immunodeficiency virus (HIV), active or chronic hepatitis B, active or chronic hepatitis C, or known active mycobacterium tuberculosis infection.
• If female, the participant is pregnant or lactating.
• Known allergy or hypersensitivity to any component of the study drug.
• Contraindication to MRI.

• Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.
• Ki67 index ≥ 10 and ≤ 55%
• Patients ≥ 15 years of age and a body weight of > 40 kg at screening
• Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization:  [68Ga]-DOTA-TOC (e.g., Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging,  [68Ga]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging (e.g., NETSPOT®), Somatostatin Receptor scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® SPECT/CT),  SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging.
• The tumor uptake observed in the target lesions must be > normal liver uptake observed on planar imaging.
• Karnofsky Performance Score (KPS) ≥ 60.
• Presence of at least 1 measurable site of disease.
• Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities.

• Creatinine clearance < 40 mL/min calculated by the Cockroft Gault method.
• Hb concentration < 5.0 mmol/L (< 8.0 g/dL); WBC < 2 x 10E^9/L (2000/mm^3); platelets < 75 x 10E^9/L (75x10E3/mm^3).
• Total bilirubin > 3 x ULN.
• Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range.
• Pregnancy or lactation.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for 6 months after study drug discontinuation.
• Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
• Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization.
• Patients for whom, in the opinion of the investigator, other therapeutic options (e.g., chemo-, targeted therapy) are considered more appropriate than therapy offered in the study, based on patient and disease characteristics.
• Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies of GEP-NET administered for more than 1 month or within 12 weeks prior to randomization in the study.
• Any previous radioembolization, chemoembolization and radiofrequency ablation.
• Any surgery within 12 weeks prior to randomization in the study.
• Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to screening in the study. Patients with a history of brain metastases must have a head CT or MRI with contrast to document stable disease prior to randomization in the study.
• Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization via echocardiography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient’s measured cardiac ejection fraction in these patients must be >40% before randomization.
• QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome.
• Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%.
• Hyperkaleamia > 6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment.
• Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (e.g., octreotide long-acting), which cannot be interrupted for at least 6 weeks before the administration of Lutathera, unless the tumor uptake on target lesions observed by study-permitted somatostatin receptor imaging (SRI) modalities during continued long-acting SSA treatment is greater than the liver uptake observed by planar imaging.
• Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
• Prior external beam radiation therapy to more than 25% of the bone marrow.
• Current spontaneous urinary incontinence.
• Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
• Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
• Hypersensitivity to any somatostatin analogues, the IMPs active substance or to any of the excipients.
• Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days.

Eligibility last updated 2/28/22. Questions regarding updates should be directed to the study team contact.

• Have completed a Corcept-sponsored study of relacorilant in endogenous Cushing syndrome with at least 80% compliance with the dosing schedule.
• According to the Investigator's opinion, will benefit from continuing treatment with relacorilant.

• Premature discontinuation from a relacorilant parent study.
• Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism.
• Has poorly controlled hypertension.
• Has Stage ≥ 4 renal failure.

Eligibility last updated 2/8/22. Questions regarding updates should be directed to the study team contact.

Part A Main

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

Eligibility last updated 1/19/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 9/15/23. Questions regarding updates should be directed to the study team contact.

• Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.
• All women will, by definition, be considered menopausal due to surgical removal of both ovaries prior to trial enrollment.
• Patients must have newly diagnosed, stage II-IV low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinoma) of the ovary or peritoneum. Tumors must be assessed for nuclear p53 staining.
• Appropriate stage for study entry based on the following diagnostic workup: 
  • History/physical examination within 14 days prior to registration; 
  • Contrast-enhanced imaging of the chest, abdomen and pelvis within 28 days prior to registration. 
• Patients must have undergone an attempt at maximal upfront cytoreductive surgery, with either optimal (< 1 cm diameter residual disease/nodule) or suboptimal residual disease (> 1 cm diameter residual disease/nodule) status allowed. 
• Patients must have undergone a bilateral salpingo-oophorectomy. 
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to registration .
• Patients must be within ≤ 8 weeks of primary cytoreductive surgery prior to initial randomization.
• Patients must be able to take per oral (P.O.) medications. 
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (within 14 days prior to registration). 
• Platelets greater than or equal to 100,000 cells/mcl (within 14 days prior to registration).
• Creatinine less than or equal to 1.5 x upper limit of normal (ULN) (within 14 days prior to registration).
• Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible if there is no hydronephrosis and the estimated creatinine clearance (CCr) is >= 30 ml/min (within 14 days prior to registration).
• Bilirubin less than or equal to 1.5 x ULN (within 14 days prior to registration).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x ULN (within 14 days prior to registration).
• Alkaline phosphatase less than or equal to 2.5 x ULN (within 14 days prior to registration). 
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.

• Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol. 
• Patients may not have received neoadjuvant chemotherapy or radiotherapy for the treatment of this disease. 
• Patients may not have received previous hormonal therapy for the treatment of this disease. 
• Patients with known hypersensitivity to letrozole or hypersensitivity/intolerance to carboplatin/paclitaxel therapy. 
• Patients with severe cardiac disease. 
• Myocardial infarction or unstable angina within 6 months prior to registration. 
• New York Heart Association (NYHA) Class II or greater congestive heart failure. 
• Patients with known central nervous system metastases.
• Patients with active or uncontrolled systemic infection. 
• Patients with ≥ Grade 2 baseline neuropathy. 
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration.
• Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

• Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.
• All women will, by definition, be considered menopausal due to surgical removal of both ovaries prior to trial enrollment.
• Patients must have newly diagnosed, stage II-IV low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinoma) of the ovary or peritoneum. Tumors must be assessed for nuclear p53 staining.
• Appropriate stage for study entry based on the following diagnostic workup: 
  • History/physical examination within 14 days prior to registration; 
  • Contrast-enhanced imaging of the chest, abdomen and pelvis within 28 days prior to registration. 
• Patients must have undergone an attempt at maximal upfront cytoreductive surgery, with either optimal (< 1 cm diameter residual disease/nodule) or suboptimal residual disease (> 1 cm diameter residual disease/nodule) status allowed. 
• Patients must have undergone a bilateral salpingo-oophorectomy. 
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to registration .
• Patients must be within ≤ 8 weeks of primary cytoreductive surgery prior to initial randomization.
• Patients must be able to take per oral (P.O.) medications. 
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (within 14 days prior to registration). 
• Platelets greater than or equal to 100,000 cells/mcl (within 14 days prior to registration).
• Creatinine less than or equal to 1.5 x upper limit of normal (ULN) (within 14 days prior to registration).
• Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible if there is no hydronephrosis and the estimated creatinine clearance (CCr) is >= 30 ml/min (within 14 days prior to registration).
• Bilirubin less than or equal to 1.5 x ULN (within 14 days prior to registration).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x ULN (within 14 days prior to registration).
• Alkaline phosphatase less than or equal to 2.5 x ULN (within 14 days prior to registration). 
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.

• Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol. 
• Patients may not have received neoadjuvant chemotherapy or radiotherapy for the treatment of this disease. 
• Patients may not have received previous hormonal therapy for the treatment of this disease. 
• Patients with known hypersensitivity to letrozole or hypersensitivity/intolerance to carboplatin/paclitaxel therapy. 
• Patients with severe cardiac disease. 
• Myocardial infarction or unstable angina within 6 months prior to registration. 
• New York Heart Association (NYHA) Class II or greater congestive heart failure. 
• Patients with known central nervous system metastases.
• Patients with active or uncontrolled systemic infection. 
• Patients with ≥ Grade 2 baseline neuropathy. 
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration.
• Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

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

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

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

• Male or female, between 18 and 65 years of age (inclusive) at the time of Screening.
• Female subjects must:
  • not be pregnant, lactating, or breastfeeding;
  • be either postmenopausal (defined as amenorrhea for ≥ 12 months), surgically sterile (defined as having undergone hysterectomy and/or bilateral oophorectomy), or if of child-bearing potential (WOCBP) must agree to practice appropriate methods of birth control or remain abstinent during the study and for 30 days after the last dose of study drug;
  • Acceptable forms of contraception include any of the following:
  • oral contraceptives;
  • double barrier methods of non-hormonal contraception are permitted in this study:
  • female condom with spermicide (cream, spray, gel, suppository, contraceptive sponge, or polymer film)
  • diaphragm with spermicide (with or without a condom)
  • cervical cap with spermicide (with or without a condom)
  • male sexual partner who agrees to use a male condom in addition to female subject’s use of spermicide (cream, spray, gel, suppository, contraceptive
  • other explanation for the ALT elevations and the agreement of the medical monitor and sponsor.
  • Permanent discontinuation of prior tolvaptan treatment because of the abnormal liver chemistry test results.
  • If re-challenge with tolvaptan was performed, the ALT level should have increased to >2 x ULN upon re-challenge or the ALT level was increasing but tolvaptan was stopped for patient safety reasons before it reached > 2 x ULN after having previously normalized.
  • Appropriate control of hypertension including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless not considered appropriate for the subject) without the use of a diuretic in concert with KDIGO “Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease”.
  • Have read, understood, and provided written informed consent after the nature of the study has been fully explained and must be willing to comply with protocol requirements and study- related procedures.

• Known sensitivity or idiosyncratic reaction to any compound present in lixivaptan and related compounds.
• Hypovolemia or inability to perceive thirst.
• Subjects who are taking, have taken within the past 2 weeks, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, Seville oranges, or St. John's wort.
• Prior use of tolvaptan within the past 3 months or until a previously elevated ALT level has returned to ≤ 1 x ULN.
• Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin, nicotinamide, bardoxolone, venglustat, demeclocycline, or mammalian Target of Rapamycin (mTOR) kinase inhibitors (e.g., everolimus, sirolimus, etc.) to treat ADPKD within the past 3 months.
• Requirement for chronic diuretic use.
• Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] > 7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant renal disease, transplanted kidney, recent kidney surgery within the past 6 months (including cyst drainage or fenestration) or acute kidney injury within past 6 months.
• Clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia).
• New York Heart Association Functional Class 3 or 4 heart failure or other significant cardiac or electrocardiogram (ECG) findings that could pose a safety risk to the subject.
• Clinically significant liver disease or impairment or active chronic hepatitis at Screening.
• Elevated baseline levels of serum ALT or total bilirubin.
• History of drug or alcohol abuse in the past 2 years.

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

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

Eligibility last updated 7/1/22]. Questions regarding updates should be directed to the study team contact.

- Patients with atopic asthma (n= 20), based upon historic record of positive test for atopy (if available), or confirmed at screening by any positive test result from a panel of standard allergens including cat dander, dog dander, cockroach, dust mite, mold, and relevant local allergens, as determined through use of ImmunoCAP Specific IgE test, skin prick test, or radioallergosorbent test (RAST)

- Patients with non-atopic asthma (n=20), based upon historic record of negative test for atopy (if available), or confirmed at screening by negative test result across chosen atopy testing panel and no history or symptoms suggesting atopy

- No history of smoking or former smoker with smoking history of < 20 pack-years or equivalent history Smoking is defined as use of inhaled tobacco or cannabis products (e.g., cigarettes, cigars, electronic cigarettes, vaporizing devices, or pipes). A former smoker is defined as someone with smoking history who has not used inhaled tobacco or cannabis products within 6 months prior to screening.

Inclusion Criteria for Patients with UCC (Part A):

- Patients with UCC must meet the following criteria for study entry:

- Diagnosis of UCC 

- No history of smoking or former smoker with smoking history of < 20 pack-years or equivalent history

- Smoking is defined as use of inhaled tobacco or cannabis products (e.g., cigarettes, cigars, electronic cigarettes, vaporizing devices, or pipes).

- A former smoker is defined as someone with smoking history who has not used inhaled tobacco or cannabis products within 6 months prior to screening.

Inclusion Criteria for Patients with CRC COPD-CB or Patients with CRC COPD (Part B):

- Diagnosis of COPD GOLD I-II ± CB.

- Stable background treatment consisting of a bronchodilator medication and or stable
ICS therapy for ≥ 12 weeks prior to screening visit.

- Former smoker with ≥10 pack-years or equivalent history who has not used inhaled tobacco or cannabis products (e.g., cigarettes, cigars, electronic cigarettes, vaporizing devices, or pipes) within 6 months prior to screening

- Post-bronchodilator FEV1/ forced vital capacity (FVC) ratio ≤ 0.70 at screening.

- Chest X-ray or CT scan within 6 months prior to screening visit or during the screening period (prior to randomization [Study Visit 2]), that confirms the absence of clinically significant lung disease besides COPD.

Patients who meet any of the following criteria will be excluded from study entry:

-  Pregnant or breastfeeding, or intention of becoming pregnant during the study or within 28 days after the final dose of GDC-6599 Women of childbearing potential must have a negative serum pregnancy test result at screening and a negative urine pregnancy test within 1 day prior to initiation of study drug.

- History of diagnosed bleeding diathesis or easy bruising or bleeding (i.e., bruising or bleeding out of proportion to the degree of trauma).

- Post-bronchodilator FEV1/FVC ratio< 0.60 at screening (patients with CRC asthma and UCC only: Part A)

- Acute exacerbations of asthma or COPD within 8 weeks prior to screening

- Use of oral or systemic corticosteroids for the treatment of respiratory diseases, including cough, within 8 weeks prior to screening

- Continued, chronic use of oral or systemic corticosteroids for non-respiratory conditions is permitted, provided patient has been receiving a stable treatment regimen for at least 8 weeks prior to screening and, in the opinion of the investigator, is likely to remain on the stable treatment regimen through completion of the study.

- Use of anticoagulant or anti-platelet therapies within 2 weeks prior to screening

- Initiation of proton-pump inhibitor (PPI) therapy within 8 weeks prior to screening

- History of significant hepatic impairment, defined as Child-Pugh Class B or C, corresponding to a Child-Turcotte-Pugh Score ≥ 7

- History of aspiration pneumonia

- Respiratory infection (including upper respiratory infection), known COVID-19 infection, persistent symptoms of known prior COVID-19 infection, and/or known positive COVID-19 test within 8 weeks prior to screening and randomization COVID-19 testing is not required for participation in the study unless required by local regulations or institutional policies.

- Positive HIV antibody test at screening

- Positive hepatitis B surface antigen (HBsAg) at screening

- Positive hepatitis C virus (HCV) antibody test followed by a positive HCV RNA test at screening

- The HCV RNA test must be performed if a patient has a positive HCV antibody test at screening to determine if the patient has an HCV infection.

- Treatment with investigational therapy within 28 days or 5 drug-elimination half-lives (if known), whichever is longer, prior to initiation of study drug

- Treatment with any strong inhibitor or inducer of CYP3A within 28 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug

- Need for ongoing treatment with strong CYP3A inhibitor or inducer during the study

- Treatment with any vaccine within 7 days prior to initiation of study drug or a scheduled vaccination during study period (through follow-up/early termination visit)

- Treatment with angiotensin-converting enzyme (ACE) inhibitor within 8 weeks prior to screening

- Treatment with opioids (including codeine), pregabalin, gabapentin, amitriptyline, or nortriptyline for the treatment of cough within 2 weeks prior to screening

- Treatment with any of these medications for indications other than chronic cough is permitted, provided the patient is receiving a stable treatment regimen for at least 2 weeks prior to screening and, in the opinion of the investigator, is likely to remain on the stable treatment regimen through completion of the study.

- Treatment with dextromethorphan, guaifenesin, benzonatate, and any other overthe-counter or prescription medication containing an anti-tussive or expectorant for the treatment of cough within 2 weeks prior to screening

- History of serious adverse reaction or serious hypersensitivity to any drug or the study drug formulation excipients

- Malabsorption syndrome or other condition that would interfere with enteral absorption

- Planned major surgical intervention that may require general anesthetic and/or hospital stay during the study

- Serious infection requiring oral or IV antibiotics within 14 days prior to screening or randomization

- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study

- History of malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix or non-melanoma skin carcinoma

- Clinical laboratory value outside the reference range for the test laboratory at screening unless the value is deemed not clinically significant by the investigator. The Medical Monitor should be informed of the test result and the decision to include the patient in the study by investigator

- Any of the following clinical laboratory values at screening (even if not considered clinically significant):

– PT (INR) > upper limit of normal (ULN), PTT > ULN or platelet < lower limit of normal (LLN) – ALT or AST >ULN – Total bilirubin > ULN; patients with Gilbert syndrome may enroll provided total bilirubin ≤ 1.5× ULN and direct (conjugated) bilirubin is ≤ ULN

Eligibility last updated 12/29/23. Questions regarding updates should be directed to the study team contact.

• Participant must be at least 6 years of age, at the time of signing the informed consent/assent.
• Documented diagnosis of PH, confirmed by genotyping (historically available genotype information is acceptable for study eligibility).
• Participant successfully completed a Dicerna Pharmaceuticals, Inc. study of DCR-PHXC, or is the sibling of a participant who either successfully completed a Dicerna Pharmaceuticals, Inc. study of DCR-PHXC or completed 24 weeks of participation in Study DCR-PHXC-204:
  • For participants rolling over from a multidose study of DCR-PHXC, enrollment should occur within a window of 25 to 75 days from the last dose of study intervention. In order to minimize any gap in administration of DCR-PHXC, every effort should be made to enroll participants as soon as all assessments from the previous study have been completed. It should be noted if the participant was required to repeat the end-of-study (EOS) 24-hour Uox collection for violation of completeness criteria;
  • Siblings must:
  • be younger than 18 years of age;
  • meet all other eligibility criteria (including genotyping) iii. have two 24-hour Uox values ≥ 0.7 mmol (adjusted per 1.73 m^2 BSA) at Screening OR for siblings aged 0 to 5 years old, average spot Uox-to-creatinine ratio at Screening above 2 times the 95th percentile for age based on Matos et al, 1999:
  • 0.44 mol/mol in participants < 6 months;
  • 0.34 mol/mol in participants from 6 months to < 12 months;
  • 0.26 mol/mol in participants 12 months to < 2 years;
  • 0.20 mol/mol in participants from 2 to < 3 years; and
  • 016 mol/mol in participants from 3 to 5 years.
• Participants who perform 24-hour collections must have less than 20% variation between the two 24-hour urinary creatinine excretion values obtained in the screening period. Individuals who do not achieve < 20% variation between the 2 screening values may undergo a second round of urine collection. An extra 7 calendar days may be added to the screening window for participants to complete a second round of urine collection. Should potential participants again fail to achieve the within-20% variation, they will be excluded from participation.
• Estimated GFR at screening ≥ 30 mL/min normalized to 1.73 m^2 BSA, calculated using the CKD-EPI equation in participants aged ≥ 18 years (Levey & Stevens, 2010), or the 2012 multivariate equation by Schwartz in participants aged 6 to 17 years (Schwartz et al., 2012). In Japan, the equation by Uemura et al. will be used for participants aged 6 to 17 years and the equation by Matsuo et al. will be used in participants aged ≥ 18 years (Uemura et al., 2014; Matsuo et al., 2009).
  • Note: For participants rolling over from a 6-month multidose study of DCR-PHXC, the eGFR value from either the Day 150 or Day 180 (EOS) visit may be used for screening.
• Body weight ≥ 10.25 kg for participants rolling over from a previous study of DCR-PHXC OR body weight ≥ 12.75 kg for pediatric siblings.
• A male participant with a female partner of childbearing potential must agree to use contraception, during the treatment period and for at least 12 weeks after the last dose of study intervention and refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) during the treatment period and for at least 12 weeks after the last dose of study intervention.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Participant (and/or participant’s parent or legal guardian if participant is a minor [defined as patient < 18 years of age, or younger than the age of majority, according to local regulations]) is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol:
  • Adolescents (12 to < 18 years of age, or older than 12 years but younger than the age of majority, according to local regulations) must be able to provide written assent for participation;
  • For children younger than 12 years of age, assent will be based on local regulations.

• Prior renal or hepatic transplantation; or planned transplantation within the study period;
• Currently receiving dialysis.
• Documented evidence of clinical manifestations of systemic oxalosis (including preexisting retinal, heart, or skin calcifications, or history of severe bone pain, pathological fractures, or bone deformations).
• Use of an RNAi drug (other than DCR-PHXC) within the last 6 months 5. History of one or more of the following reactions to an oligonucleotide-based therapy:
  • severe thrombocytopenia (platelet count ≤ 100,000/µL);
  • hepatotoxicity, defined as (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 3 × the upper limit of normal [ULN]) and (total bilirubin > 2 × ULN or International Normalized Ratio [INR] > 1.5);
  • severe flu-like symptoms leading to discontinuation of therapy;
  • localized skin reaction from the injection (graded severe) leading to discontinuation of therapy;
  • coagulopathy/clinically significant prolongation of clotting time.
• Participants receiving pyridoxine (vitamin B6) must have been at a stable dose for at least 4 weeks prior to Day 1 and must be willing to remain on the same stable dose throughout the study.
• Participation in any clinical study in which they received an investigational medicinal product (IMP) other than DCR-PHXC within 4 months before Screening:
  • For IMPs (other than DCR-PHXC) with the potential to reduce urine and/or plasma oxalate concentrations, these concentrations must have returned to historical baseline levels prior to Screening.
• Plasma oxalate > 30 µmol/L.
  • Note: For participants > 18 years of age rolling over from a 6-month multidose study of DCR-PHXC, the plasma oxalate value from either the Day 150 or Day 180 (EOS) visit may be used for screening. If the previous study is blinded at the time of entry in DCR-PHXC-301, plasma oxalate values will be reviewed by the unblinded Medical Monitor. For participants ≤ 18 years of age rolling over from a 6-month multidose study of DCR-PHXC, the plasma oxalate value from Screening in the previous study will be used.
• Known hypersensitivity to DCR-PHXC or any of its ingredients.
• Inability or unwillingness to comply with the specified study procedures, including collection of 24-hour urine samples, and the lifestyle considerations.

Eligibility last updated 5/4/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 to ≤ 74 years.
• Able and willing to voluntarily complete the informed consent process.
• Available for and agree to all study procedures, including feces, urine, and blood collection and adherence to diet control, follow-up visits, and compliance with all study procedures.
• Enteric hyperoxaluria secondary to Roux-en-Y bariatric surgery (at least 12 months post-surgery).
• Urinary oxalate ≥ 70 mg/24 hours (mean of at least 2 urine collections during Screening).
• Male subjects who are sexually abstinent or surgically sterilized (vasectomy), or those who are sexually active with a female partner(s) and agree to use an acceptable method of contraception (such as condom with spermicide) combined with an acceptable method of contraception for their non-pregnant female partner(s) (as defined in Inclusion Criterion #7) after informed consent, throughout the study, and for a minimum of 3 months after the last dose of IMP, and who do not intend to donate sperm in the period from Screening until 3 months following administration of the investigational medical product.
• Female subjects who meet 1 of the following:
  • Woman of childbearing potential (WOCBP) must have a negative pregnancy test (human chorionic gonadotropin) at Screening and at baseline prior to the start of IMP and must agree to use acceptable method(s) of contraception, combined with an acceptable method of contraception for their male partner(s) after informed consent, throughout the study and for a minimum of 3 months after the last dose of IMP. Acceptable methods of contraception include hormonal contraception, hormonal or non-hormonal intrauterine device, bilateral tubal occlusion, complete abstinence, vasectomized partner with documented azoospermia 3 months after procedure, diaphragm with spermicide, cervical cap with spermicide, vaginal sponge with spermicide, or male or female condom with or without spermicide.
  • Premenopausal woman with at least 1 of the following:
    • Documented hysterectomy;
    • Documented bilateral salpingectomy;
    • Documented bilateral oophorectomy;
    • Documented tubal ligation/occlusion;
    • Sexual abstinence is preferred or usual lifestyle of the subject.
  • Postmenopausal women (12 months or more amenorrhea verified by FSH assessment and over 45 years of age in the absence of other biological or physiological causes).

Inclusion Criteria
•Part 2:

• Age ≥ 18 to ≤ 74 years.
• Able and willing to voluntarily complete the informed consent process.
• Available for and agree to all study procedures, including feces, urine, and blood collection and adherence to diet control, follow-up visits, and compliance with all study procedures.
• Enteric hyperoxaluria secondary to history of malabsorption after bariatric surgery or surgical short-bowel syndrome.
• Urinary oxalate ≥ 45 mg/24 hours (mean of 2 samples during screening). (Tier 1 urinary oxalate must be ≥ 40 mg/24 hours to be eligible for Tier 2 screening).
• If taking probiotic supplements (enriched foods excluded), has been on stable, well-tolerated dose for at least 2 weeks prior to Day 1.
• Male subjects who are sexually abstinent or surgically sterilized (vasectomy), or those who are sexually active with a female partner(s) and agree to use an acceptable method of contraception (such as condom with spermicide) combined with a recommendation for use of an acceptable method of contraception for their non-pregnant female partner(s) after informed consent, throughout the study, and for a minimum of 3 months after the last dose of IMP, and who do not intend to donate sperm in the period from screening until 3 months following administration of the investigational medical product.
• Female subjects who meet 1 of the following:
  • WOCBP must have a negative pregnancy test (human chorionic gonadotropin) at screening and at baseline prior to the start of IMP and must agree to use acceptable method(s) of contraception, combined with a recommendation for use of an acceptable method of contraception for their male partner(s) after informed consent, throughout the study and for a minimum of 3 months after the last dose of IMP. Acceptable methods of contraception include hormonal contraception, hormonal or non-hormonal intrauterine device, bilateral tubal occlusion, complete abstinence, vasectomized partner with documented azoospermia 3 months after procedure, diaphragm with spermicide, cervical cap with spermicide, vaginal sponge with spermicide, or male or female condom with or without spermicide;
  • Premenopausal woman with at least 1 of the following:
  • Documented hysterectomy;
  • Documented bilateral salpingectomy;
  • Documented bilateral oophorectomy;
  • Documented tubal ligation/occlusion;
  • Sexual abstinence is preferred or usual lifestyle of the subject c. Postmenopausal women (12 months or more amenorrhea verified by FSH assessment and over 45 years of age in the absence of other biological or physiological causes).
• Screening laboratory evaluations (e.g., chemistry panel, complete blood count with differential, prothrombin time [PT]/activated partial thromboplastin time [aPTT], urinalysis) and electrocardiogram (ECG) must be within normal limits or judged to be not clinically significant by the investigator. A single repeat evaluation is acceptable.

• Acute or chronic medical (including COVID-19 infection), surgical, psychiatric, or social condition or laboratory abnormality that may increase subject risk associated with study participation, compromise adherence to study procedures and requirements, or may confound interpretation of study safety or PD results and, in the judgment of the investigator, would make the subject inappropriate for enrollment.
• Acute renal failure or estimated glomerular filtration rate <45 mL/min/1.73 m2.
• Unable or unwilling to discontinue vitamin C supplementation for the study duration
• Diagnosis of primary hyperoxaluria or any other cause of hyperoxaluria.
• Pregnant (self or partner), or lactating.
• Taking any type of systemic (e.g., oral or intravenous) antibiotic within less than 5 times the halflife of the antibiotic prior to Day 1.
  • Exception: topical antibiotics are allowed.
• Major surgery (an operation upon an organ within the cranium, chest, abdomen, or pelvic cavity) or inpatient hospital stay within the past 3 months prior to screening.
• Currently taking or plans to take any type of systemic (e.g., oral or intravenous) antibiotic within 30 days prior to Day 1 through the final safety assessment.
  • Exception: topical antibiotics are allowed.
• Major surgery (an operation upon an organ within the cranium, chest, abdomen, or pelvic cavity) or inpatient hospital stay within the past 3 months prior to Screening.
• Planned surgery, hospitalizations, dental work, or interventional studies between Screening and last anticipated visit.
• Intolerance of or allergic reaction to EcN or any of the ingredients in SYNB8802 or placebo formulations.
• Dependence on alcohol or drugs of abuse.
• History of or current immunodeficiency disorder including autoimmune disorders and HIV antibody positivity.
• Hepatitis B surface antigen positivity (subjects with hepatitis B surface antibody positivity and hepatitis B core antibody positivity are not excluded, provided that the hepatitis B surface antigen is negative).
• Hepatitis C antibody positivity, unless a hepatitis C virus ribonucleic acid test is performed, and the result is negative.
• Administration or ingestion of an investigational drug within 30 days or 5 half-lives, whichever is longer, prior to Screening Visit; or current enrollment in an investigational study.
• History of bacteremia within 30 days prior to the anticipated first dose of IMP.
• History of inflammatory bowel disease.

Eligibility last updated 2/1/22. Questions regarding updates should be directed to the study team contact.

Cases

• Women 14 years or older who are undergoing surgical evaluation for potential primary peritoneal, fallopian tube, or epithelial ovarian cancer  
• Women who have previously participated in the research study and are returning to MCR for secondary debulking surgery for these diseases will be re-consented for permission to use excess tissue from the second surgery.
• Women who are not considering surgery but who schedule consultations through medical oncology for ovarian, primary peritoneal, or fallopian tube cancer

Community Controls

• Women age 14 and older residing in the six state areas of MN, IA, WI, SD, ND and IL.
  • No prior bilateral oophorectomy
  • No prior diagnosis of ovarian, primary peritoneal, or fallopian tube cancer

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

Eligibility last updated 8/9/23. Questions regarding updates should be directed to the study team contact.

• Men and Women ≥ 18 years of age.
• The patient has severe symptomatic mitral regurgitation meet criteria for the commercially available MitraClip.
• The patient also has documented paroxysmal, persistent, or permanent atrial fibrillation AND The patient meets the WATCHMAN labeling guidelines.
• The patient is eligible for short-term oral anticoagulation therapy with Warfarin or a direct oral anticoagulant.
• The patient or legal representative is able to understand and willing to provide written informed consent to participate in the trial.
• The patient is able and willing to return for required follow-up visit.

• Mitral valve anatomy not deemed suitable for TMVr.
• Moderate to severe mitral stenosis (mean gradient >10 mmHg or MVA <1.5 cm^2).
• Contraindication for short-term anticoagulation.
• The patient has intra-cardiac thrombus as visualized by TEE within 1 week prior to Watchman procedure.
• Prior occlusion of LAA.
• Implanted mechanical mitral valve.
• The patient requires long-term warfarin therapy due to:
  • Secondary to conditions such as prior arterial embolism or other indications such as pulmonary embolism or deep vein thrombosis within the previous 6 months;
  • The patient is in a hypercoagulable state;
  • Exclude the patient if per medical record documentation the patient meets any of the following criteria:
    • Thrombosis occurring at under 40 years age;
    • Idiopathic or recurrent VTE (venous thromboembolism;
    • Thrombosis at an unusual site (cerebral veins, hepatic veins, renal veins, IVC, mesenteric veins);
    • Family history of VTE or of inherited prothrombotic disorder, recurrence/extension of thrombosis while adequately anti-coagulated.
• The patient is actively enrolled in another trial of a cardiovascular device or an investigational drug (post-market study and registries are acceptable).
• The patient is pregnant, or pregnancy is planned during the course of the investigation if patient is of child bearing potential.
• Any clinically significant medical condition or presence of any laboratory abnormality performed prior to randomization that is considered by the investigator to be clinically important and could interfere with the conduct of the study or not meeting procedure guidelines for WATCHMAN or TMVr with MitraClip.
• The patient has a life expectancy of less than one year.

Key

• Diagnosed with 1 of the following diagnoses according to the 2016 World Health Organization (WHO) classification for systemic mastocytosis (SM):
  • Indolent systemic mastocytosis (ISM);
  • Smoldering systemic  mastocytosis (SSM).
• Moderate-to-severe symptoms based on a disease-specific PRO and after establishing a stable regimen of at least 2 antimediator therapies over a 14-day eligibility period.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2.
• For patients receiving corticosteroids, the dose must be ≤ 10 mg/day of prednisone or
• equivalent.

Key

• Diagnosed with any of the following WHO SM classifications: bone marrow mastocytosis, advanced systemic  mastocytosis including SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia; or mast cell sarcoma.
• Diagnosed with mastocytosis of the skin without systemic involvement.
• Received prior treatment with any targeted KIT inhibitor.
• Received prior cytoreductive therapy or investigational agent for < 14 days or 5 half-lives of the drug and for cladribine, interferon alpha, pegylated interferon, or antibody therapy < 28 days or 5 half-lives of the drug (whichever is longer), before starting screening assessments.
• Received radiotherapy or psoralen and ultraviolet A therapy <14 days before starting screening assessments
• Received any hematopoietic growth factor support  < 14 days before starting screening assessments.
• History of clinically significant bleeding event within 30 days before the first dose of study drug or need for therapeutic anticoagulation on study.
• Need for treatment of corticosteroids at > 10 mg/day of prednisone or equivalent.

Eligibility last updated 3/2/23. Questions regarding updates should be directed to the study team contact.

• Signed Informed Consent Form.
• Age 18 to 75 years at time of signing Informed Consent Form.
• Ability to comply with the study protocol, in the investigator's judgment.
• Diagnosis of pMN according to renal biopsy prior to or during screening.
  • Diagnosis should be based on light and immunofluorescence microscopy, and if possible, electron microscopy.
• UPCR ≥ 5 g from 24-hour urine collection despite best supportive care for ≥ 3 months prior to screening or UPCR ≥ 4 g despite best supportive care ≥ 6 months prior to screening.
  • Best supportive care comprises renin-angiotensin system blockade with ACE inhibitor and/or ARB at maximally tolerated approved dose.
• Systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg at screening
• eGFR ≥ 40 mL/min/1.73m^2 or qualified endogenous creatinine clearance ≥ 40 mL/min based on 24-hour urine collection during screening. eGFR is calculated using the CKD-EPI equation (Levey, et al. 2009).
• Patients who previously responded to CNIs (CsA or tacrolimus), rituximab, or alkylating agents with either a CR or PR and subsequently relapsed are eligible but require discontinuation of CNIs or alkylating agents for ≥ 6 months and rituximab for ≥ 9 months prior to screening.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraception during the treatment period and for 18 months after the final dose of obinutuzumab and for 28 days after the final dose of tacrolimus.
  • A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.
  • The following are examples of adequate contraceptive methods: bilateral tubal ligation; male sterilization; hormonal contraceptives; hormone-releasing intrauterine devices; copper intrauterine devices; male or female condom with or without spermicide; and cap, diaphragm, or sponge with spermicide.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
• For men receiving tacrolimus:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, as defined below:
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
  • With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 28 days after the final dose of tacrolimus to avoid exposing the embryo.
  • For patients enrolled in the extended China enrollment phase at NMPA-recognized sites: current resident of mainland China and of Chinese ancestry.

• Patients with a secondary cause of MN (e.g., hepatitis B, SLE, medications, malignancies).
• Uncontrolled blood pressure, in the opinion of the investigator, during 3 months prior to screening.
• Evidence of ≥  50% reduction in proteinuria during the previous 6 months prior to randomization.
• Receipt of renal replacement therapy (e.g., renal transplantation, chronic dialysis).
• Type 1 or 2 diabetes mellitus (to exclude proteinuria secondary to diabetic nephropathy).
• Patients who have recent history of steroid-induced diabetes but no evidence on renal biopsy for diabetic nephropathy performed within 6 months of entry into the study are eligible.
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab or 28 days after the final dose of tacrolimus.
• Women of childbearing potential, including those who have had a tubal ligation, must have a negative pregnancy test result within 1 day prior to each obinutuzumab infusion.
• History of resistance (no response) to CNIs or B-cell depleting antibodies.
• Patients with non-response to rituximab due to development of human anti-chimeric antibodies will be eligible.
• Receipt of previous therapies as follows:
  • Treatment with MMF or oral, intramuscular, or intravenous corticosteroids within 1 month prior to screening;
  • Any B-cell depleting therapy such as rituximab, ocrelizumab, or ofatumumab within 9 months prior to screening;
  • Treatment with cyclophosphamide or CNI within 6 months prior to screening;
  • Treatment with any biologic therapy (other than B-cell depleting agents) such as belimumab, ustekinumab, or anifrolumab (investigational) within 6 months prior to screening;
  • Treatment with an inhibitor of Janus-associated kinase, Bruton’s tyrosine kinase, or tyrosine kinase 2, including but not limited to tofacitinib, baricitinib, upadacitinib, filgotinib (investigational), ibrutinib, or fenebrutinib (investigational) within 3 months prior to screening;
  • Treatment with any investigational agent within 28 days of screening or 5 drug-elimination half-lives of the investigational drug, whichever is longer;
  • Receipt of a live vaccine within 28 days prior to screening or during screening.
• Thrombocytopenia, anemia, and/or coagulopathy with high risk for clinically significant bleeding or organ dysfunction or requiring plasmapheresis, IVIg, or acute blood product transfusions.
• Significant or uncontrolled medical disease which, in the investigator’s opinion, would preclude patient participation.
• Known HIV infection. 
• Tuberculosis (TB) infection:
  •  Testing for latent TB will be performed at screening if required by local regulations or in accordance with local clinical practice;
  •  Latent TB after completion of appropriate treatment is not exclusionary.
• Known active infection of any kind, excluding fungal infection of the nail beds.
• Any major episode of infection requiring hospitalization or treatment either with IV anti-infective treatments during the 2 months prior to or during screening or with oral anti-infective treatments during the 2 weeks prior to or during screening.
• History of serious recurrent or chronic infection.
• History of progressive multifocal leukoencephalopathy (PML).
• History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ, except non-melanomatous carcinomas of the skin that have been treated or excised and have resolved.
• Major surgery requiring hospitalization within the 4 weeks prior to screening.
• Current active alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening.
• Intolerance or contraindication to study therapies, including:
  • Evidence of intolerance or toxicity associated with tacrolimus prior to screening;
  • History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion;
  • Intolerance or contraindication to oral or IV corticosteroids and premedications;
  • Intolerance or hypersensitivity to tacrolimus and its excipients;
  • Lack of peripheral venous access. 
• Laboratory parameters:
  • AST or ALT 2.5 > the upper limit of normal (ULN);
  • Amylase or lipase > 2 x ULN;
  • Neutrophils < 1.5 x 10^3 /µL;
  • CD19+ B cells < 5/µL;
  • Positive for hepatitis B surface antigen (HBsAg) at screening.
  • Patients who are HBsAg negative and hepatitis B core antibody positive with no detectable hepatitis B virus (HBV) DNA will be allowed into the study but will require regular HBV DNA monitoring;
  • Positive hepatitis C virus (HCV) antibody at screening.
  • Patients with positive hepatitis C antibody test result with no detectable HCV RNA for at least 12 months after completion of antiviral therapy are eligible but will require regular HCV RNA monitoring;
  • Hemoglobin < 9 g/dL;
  • Platelet count < 75,000/µL;
  • Positive serum human chorionic gonadotropin measured at screening.

Eligibility last updated 12/2/21. Questions regarding updates should be directed to the study team contact.

• Informed consent/assent:
  • For adult participants (≥ 18 years of age), ability to comprehend and willingness to sign an ICF;
  • For adolescent participants (≥ 12 to < 18 years of age), written informed consent of the parent(s) or legal guardian and written assent from the adolescent participant.
    • Note: Adolescents who during the course of the study become legal adults will be asked for their consent to participate in the study.
• Female and male adults and adolescents ≥ 12 years of age.
• Clinical diagnosis of FOP (based on findings of congenital malformation of the great toes, episodic soft-tissue swelling, and/or progressive HO).
• Participant-reported FOP disease activity within 1 year of the screening visit. This is defined as pain, swelling, and other signs and symptoms associated with FOP flare-ups or wosening of joint function or radiographic progression of HO (increase in site or number of HO lesions) with or without an association with flare-up episodes.
• Ability to swallow and retain orally administered tablets, either whole or crushed and dispersed in foods or liquids.
• Willingness to avoid pregnancy or fathering children based on the criteria below.
  • Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 90 days after the last dose of study drug and must refrain from donating sperm during this period. Permitted methods in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.
  • Female participants of childbearing potential must have a negative pregnancy test at screening (serum) and before the first dose on Day 1 (urine). Female participants of childbearing potential must agree to take appropriate precautions to avoid pregnancy from screening through 190 days after the last dose of study drug and must refrain from donating oocytes during this period. Permitted methods in preventing pregnancy should be communicated to the participants and their understanding confirmed.
  • Women without childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age) are eligible.
• Willing and able to undergo low-dose WBCT (excluding the head) imaging without requiring intubation.
• Willing and able to comply with study procedures and requirements and attend all study visits as defined in this Protocol.

• Pregnant or breast-feeding.
• CAJIS score ≥ 24.
• FOP disease severity that in the investigator's opinion precludes participation (e.g., ankyloses of most or all joints, symptomatic thoracic insufficiency syndrome, or recurrent respiratory infections).
• History of uncontrolled or unstable cardiovascular, respiratory, renal, gastrointestinal, endocrine, hematopoietic, psychiatric, and/or neurological disease within 6 months of screening.
• Any clinically significant medical condition other than FOP that would, in the investigator's judgment, interfere with full participation in the study, pose a significant risk to the participant, or interfere with interpretation of study data.
• Presence of a clinically significant finding on echocardiogram (as assessed by the investigator).
• Presence of an abnormal finding on ECG at screening that in the investigator's opinion is clinically significant and/or the following ECG parameters: QTcF interval > 450 milliseconds, QRS interval > 120 milliseconds, PR interval > 220 milliseconds, ECG evidence of Brugada syndrome, atrial fibrillation or atrial flutter, or Mobitz II or higher grade atrioventricular block.
• Current treatment with a potent/strong inhibitor or inducer of CYP3A4 within 5 half-lives before the first dose of study treatment or expected to receive such treatment during the study.
  • Note: Topical ketoconazole is allowed.
• Use of the following medications:
  • Imatinib 30 days prior to baseline (Day 1 visit);
  • Any medication that might interfere with HO formation in the 90 days before baseline (Day 1 visit);
  • Bisphosphonates within 1 year of screening.
• Participation in an investigational drug study for the treatment of FOP or any other indication within 30 days or 5 half-lives (whichever is longer) before baseline (Day 1 visit).
• Planning to receive a live vaccine during the course of the study or within 6 weeks after the last dose of study drug.
• Known or suspected allergy to INCB000928 or any component of the study drug.
• Known history of clinically significant drug or alcohol abuse as defined by the investigator in the l year before baseline (Day 1 visit).
• Chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.
• HIV, HBV, or HCV infection.

Note: Successfully treated HCV is allowed.

• Participants with laboratory values at screening defined in Table 7.

Eligibility last updated 2/7/22. Questions regarding updates should be directed to the study team contact.

• 2 to 21 years of age.
• Have a visually significant cataract or need IOL replacement surgery.
• Compromised capsular bag prohibiting implantation of standard posterior IOL.
• Subject or parent/guardian must be able to comply with visit schedule and study requirements.
• Subject's legal representative must be able to sign the Informed Consent.

• Under 2 years of age.
• Unable to meet Postoperative evaluation requirements.
• No useful vision or vision potential in fellow eye.
• Mentally retarded patients.
• History of corneal disease.
• Abnormality of the iris or ocular structure.
• ACD less than 3.2 mm.
• Uncontrolled glaucoma.
• IOP > 25 mmHg.
• Chronic or recurrent uveitis.
• Preexisting macular pathology that may complicate the ability to assess the benefit of this lens.
• Retinal detachment or family history.
• Retinal disease that may limit visual potential.
• Optic nerve disease that may limit visual potential.
• Diabetes mellitus.
• Pregnant, lactating or plan to become pregnant.

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

Eligibility last updated 6/19/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 11/23/22. Questions regarding updates should be directed to the study team contact.

• At least 18 years of age, at the time of signing the informed consent. 
• Signs and symptoms of CDI including diarrhea such that in the Investigator's opinion CDI antimicrobial therapy is required. Diarrhea is defined as a change in bowel habits, with ≥ 3 Unformed Bowel Movements (UBMs) (5, 6 or 7 on the Bristol Stool Chart) in the 24 hours prior to randomization. 
• The presence of either toxin A and/or B of C. difficile in the stool determined by a positive free toxin test, produced within 72 hours prior to randomization. 
• Male or Female
  •Male must agree to use contraception as detailed in the protocol during the treatment period and for at least 5 days after study treatment and refrain from donating sperm during this period.
• Female patient is eligible to participate if she is not pregnant, not breastfeeding, and either:
• Not a woman of childbearing potential (WOCBP). A WOCBP who agrees to follow the contraceptive guidance per protocol during the treatment period and for at least 5 days after study treatment. 
• Documented signed informed consent and any authorizations required by local law (e.g., Protected Health Information [PHI]).

• More than one prior episode of CDI in the previous 3 months or more than 3 episodes in the past 12 months.
• A history of chronic diarrheal disease including inflammatory bowel disease (Crohn's disease or ulcerative colitis). 
• Positive diagnostic test for other gastro intestinal (GI) pathogens within 2 weeks of randomization. 
• Major gastrointestinal (GI) surgery (e.g., significant bowel resection) within 3 months of randomization (except appendectomy). Presence of a colostomy or ileostomy or likely requirement of an ostomy during the study. 
• Life threatening or fulminant CDI with evidence of hypotension, septic shock, peritoneal signs or absence of bowel sounds, or toxic megacolon. 
• Current history of significantly compromised immune system:
  • HIV positive with a CD4<200 cells/mm3 within 6 months of randomization;
  • Severe neutropenia with neutrophil count < 500 cells/mL;
  • Concurrent immunosuppressive therapy for recent (within previous 6 months) or anticipated solid organ transplant or bone marrow transplant;
  • Concurrent chemotherapy, radiotherapy or biologic for active malignancy. Or active malignancy with ablative chemotherapy within the past 3 months or anticipated during the study;
  • More than one day (24 hours) of dosing of antimicrobial treatment active against CDI for the current episode of CDI prior to randomization;
  • Prior or current use of anti-toxin antibodies including bezlotoxumab;
  • Unable to discontinue products used to affect bowel movement or disease progression;
  • Involved in a clinical trial and received an IMP for indications other than CDI within 1 month or five half-lives (whichever is longer) or within 3 months if the IMP was for CDI;
  • Received an investigational vaccine against C.difficile;
  • Patients that the Investigator feels are inappropriate for the study for any other reason; e.g., have any conditions that would make the patient unsuitable for inclusion, patients not likely to complete the study for whatever reason, known hypersensitivity or intolerance to study IMPs, patients unwilling or unable to comply with protocol requirements.

• Be willing and able to provide signed informed consent for the trial.
• Age ≥ 18 years at the time of signed consent.
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
• Have histologically-confirmed NHL or MM that is relapsed/refractory disease and must not be candidates for regimens known to provide clinical benefit to be eligible for the study.

MM:

• Subject must have a documented diagnosis of MM and measurable disease at enrollment. Measurable disease is defined as:
  • M-protein ≥ 0.5  sPEP; or
  • ≥ 200mg/24-hour urine collection by uPEP; or
  • Serum FLC levels > 100 mg/L involved light chain and an abnormal kappa/lambda (κ/λ) ratio in subjects without measurable serum or urine M-protein; or
  • For subjects with immunoglobulin class A (IgA), myeloma whose disease can only be reliably measured by quantitative immunoglobulin measurement, a serum IgA level ≥ 0.50 g/dL.
• In addition, prior treatments for subjects must have the following:
  • Received at least 3 prior anti-myeloma regimens including at least 2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody (induction with or  without a bone marrow transplant with or without maintenance therapy is considered one regimen);
  • Refractory disease defined as disease that is nonresponsive to therapy (failure to achieve minimal response or development of progressive disease) or disease progression within 60 days from the last dose of their last myeloma therapy.
  • Note: If the most recent prior therapy was BCMA CAR-T, there is no time dependency from the last infusion until documented progression.

NHL:

• Subjects must have documented diagnosis of NHL and measurable disease (consistent with Lugano classification) defined by:
  • Either fluorodeoxyglucose (FDG)-avidity on positron emission tomography (PET)-computed tomography (CT) using the 5-point scale or measurable disease defined as at least one lesion that can be accurately measured in at least two dimensions with contrast enhanced CT scan. Minimum measurement must be ≥ 15 mm in the longest diameter. This baseline scan would occur within 6 weeks of their projected C1D1 visit.
• NHL subjects must have received the following regarding prior therapy:
  • Peripheral T-cell Lymphoma: At least one prior line containing alkylator-based chemotherapy;
  • Note: For subjects with ALCL, the subject must also have received CD30 antibody therapy.
  • Mantle Cell Lymphoma: ≥ 2 lines of therapy, including CD20 antibody and alkylator chemotherapy, and a BTK inhibitor;
  • Follicular Lymphoma: ≥ 2 lines of therapy, including CD20 antibody therapy and alkylator  chemotherapy;
  • Diffuse Large B-cell Lymphoma: ≥ 2 lines of therapy, including prior CD20 antibody therapy, and has received prior autologous bone marrow transplant (or is ineligible for bone marrow transplant);
  • Other NHL: Subjects must have been treated with all standard of care therapies available to the subject which, in the assessment of the investigator, may be beneficial to the subject.
• In Phase 2, only subjects with the following indications will be eligible for the appropriate expansion arm:
  • Relapsed/refractory MM (as defined in Phase 1 of the study);
  • Relapsed/refractory MCL (defined as above). Subjects must have received at least ≥ 2 prior treatment regimens containing an anti-CD20 antibody and alkylator chemotherapy and a regimen containing a BTK inhibitor;
  • Relapsed/refractory T-cell NHL including: PTCL, PTCL-NOS, AITL and ALCL with relapsed refractory disease following 1 prior line of therapy containing alkylator-based chemotherapy will be included. Subjects with ALCL must have had prior exposure to anti CD30 antibody as part of their prior treatment regimen.
• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (lymph node for NHL subjects, bone marrow aspirate and biopsy for MM subjects) not previously irradiated.
• Subjects need to have adequate organ function defined as follows to include:
  • Absolute neutrophil count (ANC) ≥ 1.0 x 10^9 /L independent of growth factor support for at least 7 days prior to first dose for G-CSF, and for at least 14 days prior to first dose if using pegfilgrastim;
  • Platelets ≥ 75,000 cells/µL independent of transfusion support for at least 7 days prior to first dose;
  • Hemoglobin ≥ 8.0 g/dL independent of transfusion support for at least 7 days prior to first dose;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN); except for subjects who have tumor infiltration of the liver, where ALT or AST ≤ 5 x ULN;
  • Total bilirubin ≤ 1.5 x ULN (unless due to Gilbert’s syndrome);
  • CrCl ≥ 40 mL/min (Cockcroft-Gault equation, or per institutional standard, or measured);
  • Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and activated partial thromboplastin time (aPTT) < 1.5 x ULN (unless the subject is receiving anticoagulant therapy and INR and PTT/aPTT is within therapeutic range of intended use of anticoagulants).
• Note: Subjects receiving therapy for a thromboembolic event that occurred ≥ 3 months prior to enrollment are eligible for participation on the study if they are stable on a regimen of anticoagulation with a warfarin, low-molecular weight heparin or any other approved therapeutic anticoagulation.
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
  • A woman of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] > 40 MIU/mL and estradiol <4 0 pg/mL [< 147 pmol/L] must be obtained);
  • Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods specified if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment.
  • Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods specified if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment.
  • For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw, with the exact interval dependent on the type and dosage of HRT. Following confirmation of their post-menopausal status, the subject can resume use of HRT during the study without use of a contraceptive method.
  • A woman of childbearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study treatment and for 30 days for females and 30 days for males after the last dose of study treatment, must;
  • Have two negative pregnancy tests verified by the investigator prior to the first dose of CFT7455.
  • Serum pregnancy test within 10 to 14 days prior to C1D1;
  • Serum/urine pregnancy test within 24 hours prior to first dose.
  • Agree to having ongoing pregnancy tests during the study and after discontinuation of the study;
  • Highly effective contraception methods include:
  • Female sterilization, total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment;
  • For male partners of female subjects: Male sterilization (at least 6 months prior to screening);
  • Use of highly effective contraception methods as indicated (abstinence) without interruption at least 14 days prior to first dose, during the conduct of the study including periods of dose interruptions of the study treatment, and for 30 days for females and 30 days for male after discontinuation of CFT7455.
  • Note: Women are considered postmenopausal and not of childbearing potential if they have had 12 months of natural amenorrhea with an appropriate clinical profile or have had either surgical bilateral oophorectomy or tubal ligation at least 6 weeks prior to the first dose of study treatment.
• A male participant must have either had a prior vasectomy or agree to use a condom during the treatment period and for at least 30 days after the last dose of study treatment.
• Males must refrain from donating sperm while on CFT7455 and for 30 days after discontinuation.
• Females must refrain from donating ova while on CFT7455 and for 30 days after discontinuation.
• Subjects must refrain from donating blood during study treatment and for 30 days after discontinuation.

• Presence of myeloma or lymphoma in the central nervous system (CNS).
• Has received prior radiotherapy within 2 weeks of start of study treatment.
• Subjects with active pneumonitis.
• Subjects with any of the following:
  • Non-secretory or oligosecretory multiple myeloma;
  • Plasma cell leukemia;
  • Systemic light chain amyloidosis;
  • Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes (POEMS) Syndrome;
  • Lymphoblastic lymphoma;
  • Mycosis fungoides;
  • Sezary syndrome;
  • Primary cutaneous T-cell lymphomas;
  • B-cell or T-cell prolymphocytic leukemia;
  • Chronic lymphocytic lymphoma/small cell lymphoma;
  • Richter’s transformation;
  • Burkitt lymphoma.
• Have received prior CC92480 as the most recent therapy.
• Subjects with a peripheral neuropathy ≥ Grade 2.
• Impaired cardiac function or clinically significant cardiac disease, including any of the following:
  • Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA ≥ Grade 2), uncontrolled hypertension, or clinically significant arrhythmia;
  • Corrected QT (QTcF) >480 msec for males and females using Fridericia’s correction on screening ECG;
  • Acute myocardial infarction or unstable angina pectoris within 6 months prior to study entry.
• VTE occurring within 3 months of the first dose in Cycle 1 onto the study or a subject who is unable or unwilling to undergo protocol required venous thromboembolism prophylaxis.
• Known malignancy other than study indication that is progressing or has required treatment within the past 3 years.
  • Note 1: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
  • Note 2: Clinically significant and unequivocal myelodysplastic syndrome (MDS) is excluded.
• Major surgery within 2 weeks of the first dose of study treatment.
• Presence of ≥Grade 2 toxicity (CTCAE v5.0) due to prior cancer therapy.
• Initiation of hematopoietic colony-stimulating growth factors (e.g., G-CSF, GMCSF, MCSF) ≤ 1 week prior to start of study treatment. An erythroid stimulating agent is allowed if it was initiated at least 2 weeks prior to the first dose of study treatment.
• Received live, attenuated vaccine within 4 weeks of first dose.
• Known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
• Any Subject with a known history or risk of Hepatitis B must be tested for HBV. Subjects will be excluded if there is a reactive Hepatitis B surface antigen (HBS-Ag) or Hepatitis B core antibody (anti-HBc total).
• Any Subject with a known history or risk of Hepatitis C must be tested for HCV. Subjects with positive test for hepatitis C (HCV) infection are excluded regardless of viral load. If hepatitis C antibody test is positive, a confirmatory test should be performed. If the test is negative, subject is eligible for this trial.
• Uncontrolled active systemic infection or any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
• Concurrent administration of strong CYP3A modulators (inducers or inhibitors).
  • Note: If a subject can be switched to a similar agent which is not a strong CYP3A modulator or is a weak CYP3A modulator they may be permitted to enroll in the study.
• Is currently participating in, or has participated in, a study of an investigational agent, or has used an investigational treatment within ≤ 5 half-lives or within 4 weeks (whichever is shorter) prior to the first dose of study treatment.
• Inability or difficulty swallowing capsules, or tablets (as available), malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound results of the study, interfere with the subject’s participation for full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has a known psychiatric or substance abuse disorder that would interfere with cooperating with requirements of the study.
• Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 30 days after the last dose of study treatment.
• Previously identified hypersensitivity to components of the study treatment or excipients.
• Study enrollment has been closed for one or all respective cohorts or the study has been terminated by the Sponsor.

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

Eligibility last updated 8/23/23. 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).

• Aged ≥ 55 years.
• Able and willing to give consent to study participation.
• Presence of unilateral or bilateral GA, secondary to AMD.

• History or evidence of choroidal neovascularisation (for example, wet AMD) in both eyes.  Subjects with CNV in only one eye may be included after approval from Gyroscope.
• Currently receiving active treatment for CNV in either eye.
• Presence of severe non-proliferative diabetic retinopathy or worse in either eye.
• Have received any investigational product for the treatment of GA within the past 6 months, or 5 half-lives (whichever is longer) other than nutritional supplements such as the age-related eye disease study formula.
• Received gene/cell therapy at any time previously.
• Have any other significant ocular or non-ocular medical or psychiatric condition which,in the opinion of the Investigator, may either put the Subject at risk or may influence the results of the study.

Eligibility last updated 10/22/21. Questions regarding updates should be directed to the study team contact.