Eligibility last updated 8/3/23. Questions regarding updates should be directed to the study team contact.

• Males and females with a diagnosis of SBS-IF secondary to surgical resection of the small intestine, with Colon-in-Continuity (CIC) or stoma, who have completed parent trials TA799-007 or TA799-013.
• Able to give informed consent and agree to follow the details of participation as outlined in the protocol.

• Subject not capable of understanding or not willing to adhere to the trial visit schedules and other protocol requirements.
• Any other reason judged not eligible by the Investigator.
• Pregnancy or lactation.

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

Eligibility last updated 3/1/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 7/18/23. Questions regarding updates should be directed to the study team contact.

• Women with diagnosis of any type of breast cancer.
• Women with breast cancer on unilateral or bilateral side.
• Women with surgical intervention for treatment of breast cancer.

• Previous shoulder injury or known shoulder limitation on affected side.

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

Eligibility last updated 5/18/23. Questions regarding updates should be directed to the study team contact.

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.

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

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

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

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

• Adult patients ≥ 18 years of age.
• Must be able to provide informed consent.
• Physician diagnosis of axSpA, peripheral SpA or inflammatory bowel disease related arthritis.

• Individuals who do not comprehend English (i.e., participants must be able to read and sign a consent form without the assistance of an interpreter).
• Individuals who are unable to sign consent (e.g., mentally challenged, those declared legally incompetent).
• Individuals regarded as belonging to a vulnerable population (e.g., prisoners).
• Antibiotic exposure within two weeks of stool microbiome collection.
• Patients who have a history of malignancy, exception: documented history of cured non-metastatic squamous or basal cell skin carcinoma will be allowed.

Eligibility last updated 4/5/23. Questions regarding updates should be directed to the study team contact.

• ≥ 18 and ≤ 95 years old.
• Undergoing evaluation for endogenous Cushing Syndrome by various laboratory methods as a part of clinical evaluation at  the Endocrine clinics. 

Patients with baldness; however, 70-80% population of CS is represented by women.

• Patients exposed to exogenous glucocorticoids.

• Subject (or legal guardian where applicable) is willing and able to provide signed informed consent (or assent when applicable) and can follow protocol requirements.
• Have histologically- or cytologically-confirmed disease, which is relapsed/ refractory, and unresectable or metastatic disease, following at least 1 prior line of standard-of-care systemic therapy (systemic therapy may be administered with or without the use of surgery or radiation) and must not be candidates for therapies available that are known to confer clinical benefit:
  • Synovial sarcoma;
  • A SMARCB1-null tumor as determined by immunohistochemistry, fluorescent in situ hybridization, or other equivalent tests like gene mutation analysis.
• ≥ 18 years of age or ≥ 16 years old and weighs ≥ 50 kg:
  • Adolescent enrichment cohort: 16 to 17 years of age and weighs ≥ 40 kg.
• Subject able to safely swallow tablet or pill.
• Measurable disease as defined by RECIST v1.1, a lesion which is ≥ 10 mm in the longest diameter by computed tomography scan or ≥ 10 mm measurable by calipers on physical examination.
• Eastern Cooperative Oncology Group performance status ≤ 2:
  • Adolescent enrichment cohort: Lansky performance scale (LK scale): ≥ 60.
• Adequate organ function, defined as:
  • Bone marrow function: absolute neutrophil count ≥ 1.0 x 10^9 /L independent of growth factor support for ≤ 7 days prior to first dose of study drug for granulocyte colony-stimulating factor and ≤ 14 days prior to first dose of study drug for pegfilgrastim; hemoglobin ≥ 8 g/dL independent of transfusion support for ≤ 7 days prior to first dose of study drug; platelet count ≥ 75 x 10^9 /L independent of transfusion support for ≤ 3 days prior to first dose of study drug;
  • Coagulation: Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x the upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) < 1.5 x ULN (unless the subject is receiving anticoagulant therapy and INR and partial PT/aPTT are within therapeutic range of intended use of anticoagulants);
  • Liver function: total bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN for subjects with Gilbert’s syndrome), aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN; except for subjects who have tumor infiltration of the liver, where ALT and AST ≤ 5 x ULN;
  • Renal function: must have a creatinine clearance ≥ 60 mL/min (CockcroftGault equation);
  • Cardiac function: baseline corrected QT interval using Fredericia’s formula ≤ 470 ms (adolescents 12-17 years of age: ≤ 450 ms) and a left ventricular ejection fraction ≥ 50% evaluated via echocardiogram.
• Have available archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor not previously irradiated.
• A female subject may be eligible to participate if she is not pregnant or planning a pregnancy, not breastfeeding, and at least 1 of the following conditions applies:
  • A woman of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) defined as premenopausal 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 > 40 MIU/mL and estradiol < 40 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 1 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 postmenopausal status, the subject can resume use of HRT during the study without use of a contraceptive method;
  • A woman of childbearing potential, 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 after the last dose of study treatment, must:
    • Have 2 negative pregnancy tests verified by the investigator prior to the first dose of CFT8634;
    • Have serum pregnancy test within 14 days prior to Cycle 1 Day 1;
    • 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 2 reliable forms of contraception without interruption at least 30 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 after discontinuation of CFT8634.
• A male subject must have either had a prior vasectomy or agree to use a condom during the treatment period and for at least 90 days after the last dose of study treatment.
• Males must refrain from donating sperm while taking CFT8634 and for 90 days after discontinuation.
• Females must refrain from donating ova while taking CFT8634 and for 30 days after discontinuation.
• Subjects must refrain from donating blood during study treatment and for 30 days after discontinuation.

• Has received major surgery within 3 weeks prior to the planned first dose of CFT8634:
  • Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment.
• Has received standard of care or investigational systemic anti-neoplastic therapy within 14 days or 5 half-lives, whichever is shorter, prior to the planned first dose of CFT8634.
• Has received radiation therapy within 14 days prior to the planned first dose of CFT8634.
• Prior treatment with a BRD9 degrader, unless approved following discussion with the Sponsor.
• Subjects with central nervous system (CNS) involvement (primary tumor or metastatic disease), except in the following circumstances:
  • Subjects with previously treated brain metastases may be permitted to participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of study treatment and any neurologic symptoms have stabilized), have no evidence of new or enlarging brain metastases, and, if they are taking corticosteroids, they are on stable or tapering doses for at least 7 days prior to first dose of study treatment. Antiseizure therapy is permitted provided the medication is not otherwise excluded and seizures have been controlled for at least 4 weeks since the last antiseizure medication adjustment;
  • Subjects with asymptomatic brain metastases found on screening magnetic resonance imaging (MRI) may be permitted to be entered into the study without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant.
• Subject has any evidence of a CNS bleed including intratumoral hemorrhage.
• Known bleeding diathesis.
• Impaired cardiac function or clinically significant cardiac disease including any of the following:
  • Congestive heart failure requiring treatment, with at least a New York Heart Association Class II;
  • Uncontrolled arterial hypertension;
  • Clinically significant arrythmias (subjects well-controlled on medication may be considered eligible following discussion and documented approval of the Sponsor) d. Unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of study treatment.
• Presence of inflammatory vascular disease or microangiopathy (e.g., thrombotic microangiopathies, hemolytic uremic syndrome [HUS], atypical HUS).
• Known malignancy, other than study indication, that is progressing or has required treatment within the past 3 years.
  • Subjects 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.
• Received live, attenuated vaccine within 4 weeks of first dose of study treatment.
• Known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
• Subjects with a history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or at risk for HBV/HCV infection must have a negative HBV/HCV test to be considered eligible for this study.
• Had a venous thrombosis within 2 weeks prior to first dose of study drug.
  • Note: Subjects with a history of a deep vein thrombosis > 2 weeks prior to the first dose of study drug who are stable on anticoagulation therapy may be eligible for this study.
• Uncontrolled active systemic infection or any life-threatening illness, medical condition, or organ system dysfunction that could compromise the subject’s safety or put the study outcomes at undue risk.
• Subjects with gastrointestinal absorption issues (e.g., malabsorption syndrome or other illness that could affect oral absorption).
• Concurrent administration of strong cytochrome P450 (CYP) 3A4 inhibitors and inducers, and multidrug resistance mutation 1 inhibitors.
  • Note: If a subject can be switched to a similar agent that is not a strong CYP3A modulator or is a weak CYP3A modulator they may be permitted to enroll in the study.
• Proton pump inhibitor (PPI) drugs must be discontinued at least 7 days prior to the first dose of study drug and H2 blockers should be discontinued at least 24 hours prior to the start of study drug. Other antacid medication, like calcium containing medications, may be administered at least 6 hours from study treatment.
• Presence of grade > 2 toxicity (Common Terminology Criteria for Adverse Events v5.0) due to prior cancer therapy (subjects with alopecia may be enrolled).
• 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 (female) or 90 days (male) after the last dose of study treatment/discontinuation.
• Previously identified hypersensitivity to components of the study treatment or excipients.

Eligibility last updated 6//28/22. Questions regarding updates should be directed to the study team contact.

• Individuals identified to carry one or both mutations.
• Patients with diagnosed IgG4 disease or related disease.
• Healthy control individuals of different ages and both genders.

• History of chemotherapy for malignancies.
• Acute infectious disease.
• Pregnancy.

Eligibility last updated 7/27/22. Questions regarding updates should be directed to the study team contact.

• Participant must be ≥ 18 years at the time of screening.
• Histologically- or cytologically-documented NSCLC and have been treated with concurrent CRT for locally advanced, unresectable (Stage III) disease.
• Provision of a tumour tissue sample obtained prior to CRT.
• Documented tumour PD-L1 status ≥ 1% by central lab.
• Documented EGFR and ALK wild-type status (local or central).
• Participants must have not progressed following definitive, platinum-based, concurrent chemoradiation therapy. Screening imaging should include brain imaging (MRI is the preferred modality however high-quality CT with IV contrast is acceptable).
• Participants must have received at least 2 cycles of platinum--based chemotherapy concurrent with radiation therapy, which must be completed within 1 to 42 days prior to the first dose of study intervention in the study (1 cycle is defined as 21 or 28 days). For weekly chemotherapy regimens (i.e., carboplatin/paclitaxel), 4 weekly doses administered concurrently with radiation therapy are considered equivalent to 2 cycles.
• For participants who are recovering from toxicities associated with prior treatment, the first dose of study intervention may be delayed by up to 42 days from the end of chemoradiation therapy. Sites are encouraged to complete screening and initiate study treatment as soon as possible after completion of cCRT.
• Participants must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 66 Gy) as part of the chemoradiation therapy, to be randomised. Radiation therapy should be administered by intensity modulated RT (preferred) or 3D-conforming technique.
• WHO performance status of 0 or 1 at randomization.
• Adequate organ and marrow function.

• History of another primary malignancy except for malignancy treated with curative intent with no known active disease > 5 years before the first dose of study intervention and of low potential risk for recurrence, basal cell carcinoma of the skin, squamous cell carcinoma of the skin or lentigo maligna that has undergone potentially curative therapy, adequately treated carcinoma in situ or Ta tumourstreated with curative intent and without evidence of disease.
• Mixed small cell and non-small cell lung cancer histology.
• Participants who receive sequential (not inclusive of induction) chemoradiation therapy for locally advanced (Stage III) unresectable NSCLC.
• Participants with locally advanced (Stage III) unresectable NSCLC who have progressed during platinum-based cCRT.
• Any unresolved toxicity CTCAE >Grade 2 from the prior chemoradiation therapy (excluding alopecia).
• Participants with ≥grade 2 pneumonitis from prior chemoradiation therapy.
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis, ILD, pleural effusion, or pulmonary fibrosis diagnosed in the past 6 months prior to randomization.
• Active or prior documented autoimmune or inflammatory disorders (with exceptions).
• Active EBV infection, or known or suspected chronic active EBV infection at screening.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
• Negative pregnancy test (serum) for WOCBP:
  • Female participants must be 1 year post menopausal, surgically sterile, or using 1 highly effective form of birth control;
  • Male participants who intend to be sexually active with a WOCBP must be surgically sterile or using an acceptable method of contraception.

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

Eligibility last updated 9/21/23. Questions regarding updates should be directed to the study team contact.

• Participants who are ≥ 12 years of age and < 18 years of age (adolescents) must weigh ≥ 40 kg at the time of signing the informed consent (assent).
• Participants must have an Eastern Cooperative Oncology Group performance status of ≤ 1/Lansky Performance Score ≥ 80% for adolescents (≥ 12 to < 18 years of age).
• Participants must have histologically confirmed Stage III (unresectable) or Stage IV (metastatic) melanoma, per the American Joint Committee on Cancer staging system (8th edition).
• Participants must be treatment-naïve (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma).
  • Note that the following prior adjuvant or neoadjuvant melanoma therapies are allowed if all related adverse events have either returned to baseline or stabilized.
• Anti-PD-1 or anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) therapy with at least 6 months between the last dose and date of recurrence.
• Interferon therapy with the last dose at least 6 weeks prior to randomization. 
• BRAF- or MEK-inhibitor-containing adjuvant therapy regimens with at least 6 months between the last dose and date of recurrence.
• Participants must have measurable disease by computed tomography or magnetic resonance imaging per Response Evaluation Criteria In Solid Tumors version 1 (RECIST v1.1).
• Participants must have a documented LDH result during the screening period within 14 days prior to randomization to be used for randomization.
• Participants with known BRAF V600 mutation status, or who consent to BRAF V600 mutation testing per local institutional standards during the Screening Period with the sample collected within 3 months prior to randomization. All BRAF statuses (ie, BRAF wild-type or BRAF 600 mutation positive) are eligible.
• A formalin-fixed paraffin-embedded tissue block or a minimum of 15 unstained slides (20 preferred) of tumor tissue from core biopsy, punch biopsy, excisional biopsy, or surgical specimen obtained during screening or prior to randomization (within 3 months of enrollment with no intervening systemic anti-cancer treatment between time of acquisition and enrollment), with an associated pathology report, must be sent to the central laboratory prior to randomization. Fine needle aspirates or other cytology samples are not acceptable. Biopsies of bone lesions that do not have a soft tissue component are not acceptable. If an insufficient amount of tumor tissue from an unresectable or metastatic site is available prior to the start of the screening phase, participants must consent to allow the acquisition of additional tumor tissue during the screening period for biomarker testing. Assessment of tumor-cell PD-L1 expression by immunohistochemistry (IHC) also must be performed by central laboratory using pre-treatment tissue sample and results must be reported to IRT prior to randomization. PD-L1 status as determined using a 1% threshold will be a stratification criterion for randomization. Participants with indeterminate or unevaluable PD-L1 results will not be permitted to randomize to a treatment arm.
• Participant Re-enrollment: This study permits the re-enrollment of a participant that has discontinued the study as a pre-treatment failure (ie, participant has not been randomized). If re-enrolled, the participant must re-consent.

• Participants must not have active brain metastases or leptomeningeal metastases. Participants with brain metastases are eligible if these are:
  • Asymptomatic;
  • Have been treated and participants have neurologically returned to baseline (except for residual signs or symptoms related to the central nervous system [CNS] treatment); and
  • There is no MRI evidence of progression for at least 4 weeks after CNS directed therapy is complete and within 28 days prior to first dose of study treatment administration;
  • In addition, participants must have been either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization;
  • Participants with brain disease treated with whole brain radiation are not eligible.
• Participants must not have ocular melanoma.
• Participants must not have an active, known, or suspected autoimmune disease. Participants may enroll with the following conditions:
  • Type 1 diabetes mellitus;
  • Hypothyroidism only requiring hormone replacement therapy;
  • Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment;
  • Conditions not expected to recur in the absence of an external trigger.
• Participants must not have a history of myocarditis, regardless of etiology.
• Participants must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Participants must not have a concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to randomization (i.e., participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before randomization and the participant has no evidence of disease). Participants with history of prior early stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have undergone definitive treatment at any time are also eligible.
• Participant must not have had prior treatment with an anti-PD-1 (except if given as adjuvant or neoadjuvant therapy for melanoma), anti- PD-L1, anti-programmed death-ligand 2, antiCTLA-4 antibody (except if given as adjuvant or neoadjuvant therapy for melanoma), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways (except for interferon given as adjuvant or neoadjuvant therapy for melanoma) within 6 months prior to start of study treatment.
• Participant must not have had prior treatment with relatlimab or any other lymphocyte activation gene 3-targeted agents.
• Prior radiation therapy within 2 weeks prior to first study treatment. Participants must have recovered (i.e., Grade ≤ 1 or at baseline) from radiation-related toxicities prior to first study treatment.
• Participants who are pregnant or breastfeeding.
• Troponin T (TnT) or I (TnI) > 2 × institutional upper limit of normal (ULN). Participants with TnT or TnI levels between > 1 × to 2 × ULN will be permitted if repeat levels within 24 hours are ≤ 1 × ULN. If TnT or TnI levels are between > 1 × to 2 × ULN within 24 hours, the participant may undergo a cardiac evaluation and be considered for treatment, based on a favorable benefit/risk assessment by the Investigator. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac evaluation and be considered for treatment, based on a favorable benefit/risk assessment by the Investigator. Notification of the decision to enroll the participant has to be made by the BMS Medical Monitor or designee.
• Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by either transthoracic echocardiogram (TTE) or multigated acquisition scan (TTE preferred test) within 6 months prior to start of study treatment.

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

Eligibility last updated 11/16/22. Questions regarding updates should be directed to the study team contact.

• Male or female patients 18 years of age and older.
• Documented diagnosis of erythromelalgia, as characterized by redness, warmth, and burning pain of the extremities (most commonly feet), typically precipitated by heat or exercise and relieved by cooling.
• Mean pain attack intensity, measured on the 11-point NPRS, of ≥4 and ≤9 at baseline and ≥4 pain attacks per week as documented through eDiary use during the 3 weeks prior to randomization (Day -21 to Day -1).
• Use of concomitant medications, with the exception of topical agents applied to the hands or feet, are permitted if the dose has been stable for at least 4 weeks preceding the screening visit and is planned to be maintained at the same regimen during the course of the study (prior treatment includes pharmacological and nonpharmacological treatments).
• Patients having signed a written informed consent prior to any study related procedure.
• Male patients should agree to use a condom along with another medically acceptable contraceptive method, where applicable according to local guidelines, if he is engaged in sexual activity with a woman of childbearing potential (WOCBP) from the day of the signature of the informed consent and up to 90 days after the end-of-study visit. Male patients should agree not to donate sperm until 90 calendar days after the last dose of study drug.
• Females must comply with the following in order to be enrolled:
  • WOCBP with negative pregnancy test results can be enrolled only if willing to use an acceptable contraceptive method, i.e. oral contraceptives, patch contraceptives, injection contraceptives, implantable hormonal contraceptives,male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, vaginal contraceptive ring, intrauterine device or system, surgical sterilization (hysterectomy, bilateral oophorectomy, and/or bilateral salpingectomy), tubal ligation/ occlusion, vasectomized partner, or sexual abstinence, if this is the patient's current practice, from at least 14 days prior to the screening visit and throughout the study and for at least 30 days after the completion of the study;
  • Or surgically sterilized for at least 6 months; or
  • Menopausal for at least 1 year.

• Clinical evidence of a pre-existing pain disorder in the extremities resulting from another cause than erythromelalgia; e.g. complex regional pain syndrome (CRPS), diabetic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN).
• Evidence of skin breakdown, ulcers, papules and > +2 pitting edema of the affected limbs.
• Presence of glaucoma.
• Presence of urinary retention (or significant prostatic hypertrophy at risk of urinary retention).
• History of coronary artery disease.
• History and /or presence of major depressive episode.
• The patient has suicidal risk in the opinion of the investigator based upon clinical interview and the Columbia Suicide-Severity Rating Scale.
• Pregnant or lactating women.
• Abnormality in the 12-lead electrocardiogram (ECG) at screening that in the opinion of the investigator increases the risk of participating in the study, such as a corrected QT Fridericia (QTcF) interval >430 ms for males or >450 ms for females.
• A history of additional risk factors for Torsade de Pointe (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
• The use of concomitant medications within 24 weeks prior to Day 1 and/or during the study or the equivalent of 5 half-lives that prolong the QT/QTc interval, eg, Class 1 antiarrhythmics (e.g., quinidine, disopyramide, procainamide) and Class 3 antiarrhythmics (e.g., amiodarone, sotalol), antihistamines, antipsychotics known to prolong QT interval, and antimalarials (e.g., mefloquine, quinine),  tricyclic antidepressants (e.g., AMT), tetracyclic antidepressants (e.g., maprotiline), cisapride.
• The use of monoamine oxidase inhibitors within 24 weeks (or the equivalent of 5 half-lives) prior to Day 1 and/or during the study.
• The use of opioids within 4 weeks (or the equivalent of 5 half-lives) prior to Day 1 and/or during the study.
• History of illicit drug use or confirmed drugs of abuse at screening. Positive urine drug screen for prescribed medication is allowed at the discretion of the investigator.
• Use of more than 2 analgesics (regardless of the route of administration) from different drug classes (including antidepressants and antiepileptics) on top of study drug.
• Treatment with oral or topical amitriptyline or nortriptyline in the past 4 weeks or current treatment with any other tricyclic antidepressant.
• Any known hypersensitivity to amitriptyline (regardless of the route of administration) in any salt form or to any constituent of the topical formulation.
• Any topical treatment on treated extremities for any indication, other than cosmetic use of creams and lotions, within the 12 weeks prior to screening.
• Any topical treatment for pain including use of:
  • over-the-counter capsaicin on extremities within 12 weeks of screening; and/or
  • Qutenza within 24 weeks of screening; and/or
  • nonsteroidal anti-inflammatory drugs, menthol, methyl salicylate, local anesthetics within 1 week of screening.
• Implanted active medical device (e.g., spinal cord stimulator, intrathecal pump, or peripheral nerve stimulator) for the treatment of pain or any etiology.
• Regional anesthetic block for pain of any etiology within 3 months prior to screening.
• Intake in the 4 weeks preceding screening visit of any medication susceptible to inhibit or induce cytochrome P450 CYP2D6.
• Poor metabolizers of CYP2D6 substrates.
• Treatment with an investigational drug in the previous 4 weeks or greater, according to local requirements
• Any condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated, such as, but not limited to, hyperthyroidism, convulsive disorder, advanced hepatic disease, pylorus, stenosis, or paralytic ileus.
• The investigator considers the patient unfit for the study as a result of the medical interview, physical examination, or screening  investigations, in particular any status or disease making the patient unable to follow instructions.
• The patient is unable to apply the study drug on feet and/or hands.
• The patient is an employee of the investigator, study site, sponsor, or contract research organization with direct involvement in the proposed study or other studies under the direction of the investigator, study site, or sponsor, or a family member of the site employee or the Investigator.

Eligibility last updated 9/14/23. Questions regarding updates should be directed to the study team contact.

- Willing to return to enrolling institution for study follow-up visit

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

- Willing to return to enrolling institution for study follow-up visit

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

- Willing to return to enrolling institution for study follow-up visit

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

• Adult patients who have clinical indication for limited liver MRI study that includes PDFF estimation.

• Contra-indications to MRI study.
• Participants who are unable to undergo MR (claustrophobia, implanted device, etc.), pregnancy, obesity (> 400 lb).

• Age ≥ 18 years.
• Diagnosis of AML, HR-MDS, or high marrow blast MDS/MPN (including CMML).
• Prior treatment history must include 1-4 prior lines of therapy.
• Adequate organ function evidenced by the following laboratory values:
  • Creatinine clearance (CL) ≥ 60 mL/min;
  • Total serum bilirubin < 1.5 × upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) ;
  • Aspartate aminotransferase(AST) < 2.5 × ULN;
  • White blood cell count at the time of the first dose < 10 k/µL.
• Eastern Cooperative Oncology Group performance status ≤ 2.
• Female patients of childbearing potential must have a negative pregnancy test within 7 days before study treatment initiation and if sexually active, agree to use a highly effective form of contraception throughout their participation during study treatment and up to 4 months after the last dose of study drug
• Male patients with female partners of childbearing potential must, even if surgically sterilized, agree to practice effective barrier contraception during the entire study treatment period and through four months after the last dose of study drug, or practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant.

• Diagnosis of acute promyelocytic leukemia.
• Isolated extramedullary relapse (phase 2 only).
• Active central nervous system (CNS) leukemia.
• History of other malignancy.
• Any of the following cardiopulmonary abnormalities:
  • Myocardial infarction within six months prior to registration;
  • New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction < 50%;
  • A history of familial long QT syndrome;
  • Symptomatic atrial or ventricular arrhythmias not controlled by medications;
  • QTcF ≥ 470 msec calculated according to institutional guidelines, unless due to underlying bundle branch block and/or pacemaker and with approval of the medical monitor;
  • Known moderate to severe and clinically significant chronic obstructive pulmonary disease, interstitial lung disease and/or pulmonary fibrosis (e.g., requiring home oxygen therapy).
• Pregnancy and/or lactation.
• Major surgery (excluding placement of vascular access) within 4 weeks prior to first dose of CTX-712.
• History of allogeneic organ transplantation (excluding cornea).
• History of allogenic hematopoietic stem cell transplantation within 6 months of planned study treatment initiation and/or graft-versus host disease grade ≥ 1 following allogenic hematopoietic stem cell transplantation.
• History of or chimeric antigen receptor T-cell therapy or other modified T cell therapy.
• Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, hepatitis C virus, known human immunodeficiency virus, or acquired immunodeficiency syndrome related illness. Infections controlled with oral anti-infective agents, including prophylactic treatments, are allowed. Patient must be viral load negative.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
• Concomitant use of strong CYP3A4 inhibitors (Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers | FDA) within 5 half-lives of the drug of interest prior to the initiation of study treatment, or consumption of St John’s wort, grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit, within 3 days prior to the initiation of study treatment. Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole or fluconazole) is permitted.
  • Note: Concomitant use of azole antifungals will be evaluated in separate cohorts after RP2D determination.
• Concomitant use of breast cancer resistance protein (BCRP) inhibitors and proton pump inhibitors (PPIs), within 7 days prior to the initiation of study treatment.
  • Note: Concomitant use of PPI will be evaluated in separate cohorts after RP2D determination.

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

Inclusion Criteria
•Patient Enrollment:

- 6 months to < 22 years at enrollment.

- Diagnosed with ALL, AML, or MDS for which an allogeneic hematopoietic stem cell
transplant is indicated. Complete Remission (CR) status will not be confirmed at the
time of enrollment. CR as defined in these sections is required to proceed with the
actual HCT treatment plan.

- Has not received a prior allogeneic hematopoietic stem cell transplant.

- Does not have a suitable human leukocyte antigen (HLA)-matched sibling donor available
for stem cell donation.

- Has an eligible haploidentical related family donor based on at least intermediate
resolution HLA typing.

- Patients who also have an eligible 8/8 MUD adult donor based on confirmatory high
resolution HLA typing are eligible for randomization to Arm A or Arm B.

- Patients who do not have an eligible MUD donor are eligible for enrollment to Arm
C.

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

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

- Co-Enrollment on other trials.

- Patients will not be excluded from enrollment on this study if already enrolled
on other protocols for treatment of high risk and/or relapsed ALL, AML and MDS.
This is including, but not limited to, COG AAML1831, COG AALL1821, the EndRAD
Trial, as well as local institutional trials. We will collect information on all
co-enrollments.

- Patients will not be excluded from enrollment on this study if receiving
immunotherapy prior to transplant as a way to achieve remission and bridge to
transplant. This includes chimeric antigen receptor (CAR) T cell therapy and
other immunotherapies.

Inclusion Criteria
•Patient to Proceed to HCT:

- Karnofsky Index or Lansky Play-Performance Scale ≥60 on pre-transplant evaluation.
Karnofsky scores must be used for patients ≥ 16 years of age and Lansky scores for
patients =< 16 years of age (within 4 weeks of starting therapy).

- A serum creatinine based on age/gender as follows:

6 months to < 1 year: 0.5 mg/dL (Male); 0.5 mg/dL (Female);

1. to < 2 years 0.6 mg/dL (Male); 0.6 mg/dL (Female);

2. to < 6 years 0.8 mg/dL (Male); 0.8 mg/dL (Female);

6 to < 10 years: 1 mg/dL (Male); 1 mg/dL (Female) 10 to < 13 years: 1.2 mg/dL (Male);
1.2 mg/dL (Female) 13 to < 16 years: 1.5 mg/dL (Male); 1.4 mg/dL (Female) >= 16 years:
1.7 mg/dL (Male); 1.4 mg/dL (Female); OR

- A 24 hour urine Creatinine clearance ≥ 60 mL/min/1.73 m^2; OR

- A glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2. GFR must be performed using
direct measurement with a nuclear blood sampling method OR direct small molecule
clearance method (iothalamate or other molecule per institutional standard).

- Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
are not acceptable for determining eligibility.

- Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] or
serum glutamate pyruvate transaminase (SGPT) aminotransferase [ALT] < 5 x upper limit
of normal (ULN) for age.

- Total bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome.

- Shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA); OR

- Ejection fraction of ≥ 50% by echocardiogram or radionuclide scan (MUGA), choice of
test according to local standard of care.

- Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and
corrected carbon monoxide diffusing capability (DLCO) must all be ≥ 50% of predicted
by pulmonary function tests (PFTs).

- For children who are unable to perform for PFTs (e.g., due to age or
developmental delay), the criteria are: no evidence of dyspnea at rest, oxygen
(O2) saturation (Sat) > 92% on room air by pulse oximetry, not on supplemental O2
at rest, and not on supplemental O2 at rest.

- ALL high-risk in first complete remission (CR1) for whom transplant is indicated.
Examples include: induction failure, treatment failure as per minimal residual disease
by flow cytometry > 0.01% after consolidation and not eligible for AALL1721 or
AALL1721 not available/unwilling to enroll, hypodiploidy (< 44 chromosomes) with MRD+
> 0.01% after induction, persistent or recurrent cytogenetic or molecular evidence of
disease during therapy requiring additional therapy after induction to achieve
remission (e.g. persistent molecular BCR-ABL positivity), T cell ALL with persistent
MRD > 0.01% after consolidation.

- ALL in second complete remission (CR2) for whom transplant is indicated. Examples
include: B-cell: early (≥ 36 months from initiation of therapy) bone marrow (BM)
relapse, late BM relapse (≥ 36 months) with MRD ≥ 0.1% by flow cytometry after first re-induction therapy; T or B-cell: early (< 18 months) isolated extramedullary (IEM),
late (≥ 18 months) IEM, end-Block 1 MRD ≥ 0.1%; T-cell or Philadelphia chromosome positive (Ph+): BM relapse at any time.

- ALL in ≥ third complete remission (CR3).

- Patients treated with chimeric antigen receptor T-cells (CART) cells for whom
transplant is indicated. Examples include: transplant for consolidation of CART, loss
of CART persistence and/or B cell aplasia < 6 months from infusion or have other
evidence (e.g., MRD+) that transplant is indicated to prevent relapse.

- AML in CR1 for whom transplant is indicated. Examples include those deemed high risk
for relapse as described in AAML1831:

- FLT3/ITD+ with allelic ratio > 0.1 without bZIP CEBPA, NPM1;

- FLT3/ITD+ with allelic ratio > 0.1 with concurrent bZIP CEBPA or NPM1 and with
evidence of residual AML (MRD >= 0.05%) at end of Induction;

- Presence of RAM phenotype or unfavorable prognostic markers (other than FLT3/ITD)
per cytogenetics, fluorescence in situ hybridization (FISH), next generation
sequencing (NGS) results, regardless of favorable genetic markers, MRD status or
FLT3/ITD mutation status;

- AML without favorable or unfavorable cytogenetic or molecular features but with
evidence of residual AML (MRD ≥ 0.05%) at end of Induction;

- Presence of a non-ITD FLT3 activating mutation and positive MRD (≥ 0.05%) at end
of Induction 1 regardless of presence of favorable genetic markers;

- AML in ≥ CR2;

- MDS with < 5% blasts by morphology and flow cytometry (if available) on the
pre-transplant bone marrow evaluation;

- Complete remission (CR) is defined as < 5% blasts by morphology and flow cytometry (if
available) on the pre-transplant bone marrow evaluation with minimum sustained
absolute neutrophil count (ANC) of 300 cells/microliter for 1 week or ANC > 500
cells/microliter. We will be collecting data from all approaches to MRD evaluation
performed including NGS and polymerase chain reaction (PCR).

Donor Eligibility Criteria:

- Matched Unrelated Donors:

Unrelated donor candidates must be matched at high resolution at a minimum of 8/8 alleles
(HLA-A, -B, -C, -DRB1). One-antigen HLA mismatches are not permitted. HLA matching of
additional alleles is recommended according to National Marrow Donor Program (NMDP)
guidelines,110 but will be at the discretion of local centers.

- Haploidentical Matched Family Members:

- Minimum match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1,
-DQB1 alleles). The following issues (in no particular order) should be
considered in choosing a haploidentical donor:

- Absent or low patient donor-specific antibodies (DSA);

- Mean fluorescence intensity (MFI) of any anti-donor HLA antibody by
solid phase immunoassay should be < 2000. Donors with higher levels are
not eligible;

- If a screening assay against pooled HLA antigens is used, positive
results must be followed with specificity testing using a single
antigen assay. The MFI must be < 2000 unless the laboratory has
validated higher threshold values for reactivity for HLA antigens
(such as HLA-C, -DQ, and -DP), that may be enhanced in
concentration on the single antigen assays. Donor anti- recipient
antibodies are of unknown clinical significance and do not need to
be sent or reported.

- Consult with Study Chair for the clinical significance of any
recipient anti-donor HLA antibody.

- If centers are unable to perform this type of testing, please
contact the Study Chair to make arrangements for testing.

- If killer immunoglobulin testing (KIR) is performed: KIR status by mismatch,
KIR-B, or KIR content criteria can be used according to institutional
guidelines.

- ABO compatibility (in order of priority):

- Compatible or minor ABO incompatibility

- Major ABO incompatibility

- CMV serostatus:

- For a CMV seronegative recipient: the priority is to use a CMV
seronegative donor when feasible.

- For a CMV seropositive recipient: the priority is to use a CMV
seropositive donor when feasible.

- Age: younger donors including siblings/half-siblings, and second degree
relatives (aunts, uncles, cousins) are recommended, even if < 18 years.

- Size and vascular access appropriate by center standard for peripheral blood stem cell
(PBSC) collection if needed.

- Haploidentical matched family members: screened by center health screens and found to
be eligible.

- Unrelated donors: meet eligibility criteria as defined by the NMDP or other unrelated
donor registries. If the donor does not meet the registry eligibility criteria but an
acceptable eligibility waiver is completed and signed per registry guidelines, the
donor will be considered eligible for this study.

- Human immunodeficiency virus (HIV) negative.

- MUD donors and post-transplant cyclophosphamide haplo donors should be asked to
provide BM. If donors refuse and other donors are not available, PBSC is allowed.
TCR-alpha beta/CD19 depleted haplo donors must agree to donate PBSC.

- Must give informed consent.

- Haploidentical matched family members: Institution standard of care donor consent
and Protocol-specific Donor Consent for Optional Studies.

- Unrelated donors: standard NMDP Unrelated Donor Consent.

- Not pregnant.

Exclusion Criteriam
•Patient Enrollment:

- Patients with genetic disorders (generally marrow failure syndromes) prone to
secondary AML/ALL with known poor outcomes because of sensitivity to alkylator therapy
and/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis
Congenita, etc). Patients with Downs syndrome because of increased toxicity with
intensive conditioning regimens.

- Patients with any obvious contraindication to myeloablative HCT at the time of
enrollment.

- Female patients who are pregnant are ineligible as many of the medications used in
this protocol could be harmful to unborn children and infants.

- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation.

Exclusion Criteria
•Patient to Proceed to HCT:

- Patients with uncontrolled fungal, bacterial, viral, or parasitic infections are
excluded. Patients with history of fungal disease during chemotherapy may proceed if
they have a significant response to antifungal therapy with no or minimal evidence of
disease remaining by computed tomography (CT) evaluation.

- Patients with active central nervous system (CNS) leukemia or any other active site of
extramedullary disease at the time of initiation of the conditioning regimen are not
permitted.

- Note: Those with prior history of CNS or extramedullary disease, but with no
active disease at the time of pre-transplant workup, are eligible.

- Pregnant or breastfeeding females are ineligible as many of the medications used in
this protocol could be harmful to unborn children and infants.

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

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

Key

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

Eligibility last updated 10/7/22. Questions regarding updates should be directed to the study team contact.

• Ages 18-75, inclusive.
• Assigned male or female at birth.
• Provision of informed consent before any study procedures are performed.
• English speaker.
• Documented clinical diagnosis for Bipolar I Disorder.
• Currently experiencing a manic or hypomanic episode as determined by primary clinical staff.

• Age under 18 or greater than 75 years.
• Positive urine drug screen for amphetamines or cocaine.
• Expressing paranoid delusions regarding electronic surveillance corresponding to YMRS question 8 > 6.
• Documented clinical diagnosis of neurologic disorder causing dysarthria.
• Documented clinical diagnosis of developmental delay or congenital hearing impairment.
• Currently involuntarily hospitalized.
• Deemed by clinical staff to not be appropriate for voice recording.
• YRMS > 30.
• Failure to comprehend study objectives via comprehension questionnaire.'
• Individuals who have a guardian or are otherwise unable to consent for themselves.
• Current communicable disease requiring isolation.

Eligibility last updated 12/11/23. Questions regarding updates should be directed to the study team contact.

• Hospitalization within 3 months for COPD related causes (exacerbation (including COVID) and/or pneumonia)
• Adults 40 years of age or older..

• Individuals not able to be reached by telephone.

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

Inclusion for Patients Dianosed with Advanced Solid Tumors

• Understand and sign written IRB-approved informed consent form and be willing to comply with all study procedures.
• Diagnosed with unresectable, locally advanced, or metastatic solid tumor for which no standard therapy is recognized or for which standard therapy has failed. Planned tumor types for evaluation include:
  • Platinum resistant* ovarian cancer (including
    •primary peritoneal cancer and fallopian tube cancer);
  • Breast cancer;
  • Papillary thyroid cancer;
  • Head and neck cancer;
  • Gastric cancer;
  • Non-small cell lung cancer (NSCLC);
  • Mesothelioma: Pleural and peritoneal;
  • Esophageal;
  • Endometrial cancer;
  • Cervical;
  • Melanoma;
  • Colorectal cancers (colon, rectal).
• Platinum-resistant is defined as disease that may have responded to a platinum-containing chemotherapy regimen, but there is documentation of demonstrated recurrence within 6 months following the completion of that platinum-containing regimen. Progressive disease of epithelial ovarian cancer (EOC) following platinum-based therapy can be documented by physical examination, computed tomography (CT) scans, or a doubling of cancer antigen 125 (CA-125) levels from either:
  • upper limit of normal (ULN); or
  • most recent nadir value (per the Rustin criteria [Rustin et al., 2011]). For CA-125 to be used as a criterion for progressive disease, the CA-125 level nadir must have been above the ULN. In addition, the CA-125 nadir level must have been confirmed by a second measurement at least 1 week after the initial measurement.
• Must be > 18 years of age.
• Histologically or cytologically documented disease.
• Has evaluable or measurable disease by RECIST v1.1 or mRECIST criteria.
• Provide tumor tissue from biopsy taken during Screening period.
• Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale.

Patients Diagnosed with Diffuse Intrinsic Pontine Glioma or Diffuse Midline

• Glioma (Must also meet other generally noted criteria as noted within the protocol.
• For patients < 18 years of age, the parents or legal guardians must understand and sign the written IRB-approved informed consent form (ICF). The patient, if able, must understand and sign the IRB-approved consent (assent) and be willing to comply with all study procedures.
• For patients ≥ 18 years of age, the patient must understand and sign written IRB-approved ICF and be willing to comply with all study procedures.
• Diagnosed with DIPG or DMG.
• Any anatomic site of origin is acceptable.
• Must be ≥ 12 years of age and > 40 kg in body weight.
• Radiologically documented disease.
  • Patient with refractory or progressive DIPG or DMG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons, are eligible without histologic confirmation;
  • Patients with brainstem tumors that do not meet radiographic criteria or are not considered to be typical DIPG or DMG will be eligible if the tumors have been biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, H3 K27M-mutant DMG).
• Has evaluable or measurable disease by RANO or RAPNO criteria.
• Provide cerebrospinal fluid (CSF) sample. Patients with pontine lesions for whom a radiological diagnosis of DIPG, DMG or high-grade gliomas is made will be eligible without a CSF sample, although CSF sample is strongly encouraged.
•  P:erformance score:
  • Patients >16 years of age, Karnofsky score ≥ 50%;
  • Patients ≥12 and ≤16 years of age, Lansky ≥ 50%.
  • Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy:
  • Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea);
  • Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta) or 7 days for short-acting growth factor;
  • Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair;
  • Immunotherapy: At least 42 days after the completion of any type of vaccination;
  • Monoclonal antibodies: > 21 days must have elapsed from the infusion of last dose of antibody and toxicity related to antibody therapy must be recovered to Grade ≤1;
  • Radiation therapy: Patients must have had their last fraction of craniospinal or focal irradiation a minimum of 8-12 weeks prior to enrollment;
  • Stem cell transplant: Patients must be ≥ 3 months since autologous stem cell transplant. Patients who received allogenic stem cell transplant or solid organ transplant are not eligible for study.

All Patients
•All patients are required to meet these inclusion exclusion

• Patient is able to take oral medications and willing to use an at-home infusion pump.
• Must have adequate bone marrow and renal/hepatic function at the screening and baseline visits, defined as: 
  • Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L without granulocyte colony-stimulating factor (G-CSF) support within 7 days preceding the lab assessment;
  • Platelet ≥ 100 × 10^9/L, without transfusion within 7 days preceding the lab assessment;
  • Hemoglobin ≥ 9 g/dL, without transfusion support within 7 days preceding the lab assessment;
  • Activated partial thromboplastin time/ partial thromboplastin time (aPTT/PTT) ≤ 1.5 × ULN;
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (if liver metastases are present, then ≤ 5 × ULN is allowed);
  • Total serum bilirubin ≤ 1.5 × ULN, (except for patients with known Gilbert's Syndrome in whom ≤ 3 × ULN is permitted).  Confirmation of Gilbert's diagnosis requires elevated unconjugated (indirect) bilirubin values; normal complete blood count in previous 12 months, blood smear, and reticulocyte count; normal aminotransferases and alkaline phosphatase in previous 12 months;
  • The patient is clinically euthyroid;
  • Renal: Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients with serum creatinine levels > 1.5 × ULN;
  • Any Grade 3 or higher lab abnormalities should be discussed and approved by the Medical Monitor prior to enrollment (even if not considered clinically significant).
• Active secondary malignancies will not be allowed, with the exception of:
  • Adequately treated basal cell carcinoma, SCC of the skin, or in situ cervical cancer;
  • Adequately treated Stage 1 cancer from which the subject is currently in remission and has been in remission for ≥ 2 years;
  • Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 ng/mL; or
  • Any other cancer from which the patient has been disease-free for ≥ 3 years.
• Patient compliance and geographic proximity (as determined by the Principal Investigator [PI]) to allow adequate follow-up.
• Both male and female patients must be willing to consent to using highly effective contraception prior to study entry, while on treatment, and at least 3 months thereafter.

Patients Diagnosed with Advanced Solid Tumor(s)

• Have a seizure disorder where > 1 seizure has occurred within the last year.
• Patient with treated (surgically excised or irradiated) with stable brain metastases are eligible as long as the treatment was at least 4 weeks prior to initiation of study drug and baseline brain CT with contrast or magnetic resonance imaging (MRI) within 2 weeks of initiation of study drug is negative for new brain metastases.
• Patients with stable brain metastases must not require therapy with corticosteroids.
• Treatment with radiation therapy, surgery, chemotherapy, or immunotherapy within 4 weeks prior to study entry (6 weeks for nitrosoureas or Mitomycin C). Limited prior palliative radiation may be permissible no less than 2 weeks prior to C1D1 with approval from the Medical Monitor.

Patients Diagnosed with Diffuse Intrinsic Pontine Glioma or Diffuse Midline

• Glioma.
• Patients with seizure disorders may be enrolled if seizures are well-controlled, defined as no increase in seizure frequency in the prior 7 days.
• Anticonvulsants should be used as clinically indicated.
• The use of enzyme inducing anticonvulsants is not permitted.
• Patient with treated (surgically excised or irradiated) with stable brain metastases are eligible as long as the treatment was at least 8 to 12 weeks prior to initiation of study drug and baseline brain CT with contrast or MRI within 2 weeks of initiation of study drug is negative for new brain metastases. Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.

All Patients

• Have clinically significant cardiovascular disease (e.g., significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac arrhythmia or unstable angina, New York Heart Association Grade 3 or  greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater peripheral vascular disease, or history of cerebrovascular accident [CVA]) within 6 months of enrollment.
• History or presence of an abnormal ECG that, in the Investigator's opinion, is clinically meaningful.
  • Screening QTcF interval > 480 ms is excluded. In the event that a single QTcF is > 480 ms, the patient may enroll if the average QTcF for the 3 ECGs is < 480 ms;
  • For patients with an intraventricular conduction delay (QRS interval > 120 ms), the JTc interval may be used in place of the QTcF with Sponsor approval. The JTc must be < 340 ms if JTc is used in place of the QTcF.
• Patients with an intraventricular delay due to a left bundle branch block are excluded.
  • Note: QTcF prolongation due to pacemaker may enroll if the JTc is normal.
• Had major surgery, other than diagnostic surgery, within 4-weeks prior to Day 1.
• Have active bacterial, viral, or fungal infections requiring systemic therapy.
• Women who are pregnant or lactating.
  • Note: Women of childbearing potential (WOCBP) must have a "negative" serum pregnancy test within 1 week prior to treatment.
  • Women not OCBP is defined as: i. Postmenopausal with >1 year since last menses and:
  • If <65 years old, follicle-stimulating hormone (FSH) > 40 mIU/mL;
  • If ≥65 years old and not on hormone replacement therapy (HRT), FSH > 30 mIU/mL;
  • If ≥65 years old and on HRT, the FSH requirement in not applicable. Postmenopausal females on HRT will be allowed if HRT has been stable for ≥6 months prior to dosing of study drug(s);
  • Written medical documentation of being sterilized (e.g., hysterectomy, double oophorectomy, bilateral salpingectomy) with the procedure performed ≥6 months prior to dosing study drug(s).
  • Note: Tubal ligation is not considered a form of permanent sterilization.
• Patients may not have any unresolved toxicity > Grade 1 from previous anticancer therapy, except for stable chronic toxicities that are not expected to resolve (i.e., peripheral neuropathy, alopecia, etc.). Patients who have an ongoing requirement for thyroid replacement therapy from prior exposure to a checkpoint inhibitor but who are clinically euthyroid are permitted.
• Have an unwillingness or inability to comply with procedures required in this protocol.
• Current active liver disease from any cause, including hepatitis A (hepatitis A virus immunoglobulin M positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with a prior history of HBV are eligible if quantitative polymerase chain reaction (PCR) for HBV DNA is negative. Note that elevated levels of biotin may interfere with viral serology testing.
• Have a serious nonmalignant disease that, in the opinion of the Investigator or the Medical Monitor, could compromise protocol objectives.
• Patients who are currently receiving any other investigational agent or who have received an investigational agent within the last 28 days, with the exception of any patient who participated in Study AMXT1501-101A.
• Known GI disease or procedure that could interfere with the absorption of study drug, including inability to swallow whole capsules or conditions that may interfere with absorption. The Medical Monitor should be contacted for any questions regarding this exclusion criterion.
• Patients who have exhibited allergic reactions to a similar structural compound, biological agent, or formulation.
• Use of luteinizing hormone-releasing hormone (LHRH) agonist / antagonists are not permitted.
• Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 µg (NIH-ODS 2020).
  • Note: Patients who switch from a high dose to a dose of ≤30 µg/day are eligible for study entry.
• Infection with human immunodeficiency virus (HIV)-1 or HIV-2. Exception: Patients with well-controlled HIV (e.g., CD4 > 350/mm^3 and undetectable viral load) are eligible.

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

Eligibility last updated 9/8/22. Questions regarding updates should be directed to the study team contact.

• Male and female adults aged ≥ 18 years (at the screening visit) with capacity to consent.
• Diagnosis of moderate-to-severe Atopic Dermatitis (AD) as defined by the Hanifin and Rajka (1980) criteria.
• AD duration of at least 3 months.
• IGA score of 2 to 3 at the screening visit.
• Treatment naïve and/or willing to pursue 30-day wash-out period if they are using topical medications, oral medications, or injectable medications.
• For participants who sign photography consent, at least 1 target lesion that measures at least 5 cm2 at the screening visit. The target lesion must be representative of the participant's disease state but not located on the hands, feet, genitalia, face, scalp, or intertriginous areas.

• Unstable history of atopic dermatitis (spontaneously improving or rapidly deteriorating) as determined by the investigator over the previous 4 weeks before baseline/visit 0.
• Disease history concerns, i.e., lymphoma, immunodeficiency, chronic infections such as HIV, hepatitis, or tuberculosis, dialysis, and/or history of skin cancer within 5 years.
• Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline/visit 0.
• Active acute bacterial, fungal, or viral skin infection (e.g., herpes simplex, herpes zoster, chicken pox, clinically infected AD, impetigo) within 1 week before the baseline/visit 0.
• Insufficient area of uninvolved (control) skin.
• Relative contraindications to skin biopsy (e.g., serum platelets < 10; allergy to lidocaine).
• Atopic dermatitis exclusive to areas of the hands, feet, face, scalp, intertriginous areas, or genitalia.

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

Eligibility last updated 1/10/23. Questions regarding updates should be directed to the study team contact.

• Female age 21 or older.
• BMI < 30.
• Candidate for an NSM procedure with immediate reconstruction.
• Diagnosis of early stage brest cancer.
• Breast ptosis ≤ Grade 2.
• Cup size ≤ C.

• Previous breast surgery.
• Diagnosis of metastatic breast cancer.
• Prior radiation treatment to the chest.
• Current smokers.
• Contraindication for general anesthesia or surgery.
• Known bleeding or clotting disorder.
• Pregnant or suspected to be pregnant, or actively breastfeeding.

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

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

• ≥ 18 years of age. 
• Brain tumor referrals for presurgical brain mapping with fMRI

• < 18 years of age.

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

Eligibility last updated 1/26/23. Questions regarding updates should be directed to the study team contact.

• Adults ≥ 40 years of age.
• Pain at the thumb base brought on by direct pressure (grind test) and with movement.
• Pain resistant to previous conservative management with oral analgesics, NSAIDs, icing, and splinting.
• Radiological observation indicative of arthritis based on the Eaton-Littler classification system (stages 1 through 4).
• Patient understands the protocol and signed the informed consent.
• Patient is covered by health insurance.

• Known allergy to either of the treatment products.
• Patient’s analgesic treatment regimen was modified within four weeks before trial inclusion.
• Scaphoid-trapezial arthritis present.
• Localized or systemic infection.
• Previous thumb surgery on study thumb.
• Previous thumb injury on study thumb.
• Patient with inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis).
• Severe and/or uncontrolled hypertension.
• De Quervain tendinopathy present.
• History of injection to the trapeziometacarpal joint on study thumb within the previous 6 weeks.
• Uncontrolled diabetes.
• Pregnant or lactating females. Female participants of childbearing potential must have a negative pregnancy test before the injection. Women without childbearing potential (ie., surgically sterile with hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy OR ≥ 12 months of amenorrhea and at least 50 years of age) are eligible to participate without completing a pregnancy.
• Immunodeficient patients.
• Patients that are currently using nicotine products, or who have quit in the last 12 months.
• Patients under guardianship, curatorship, or are otherwise not self-sufficient.
• Patients participating in another clinical research trial which interferes with this study protocol or outcomes.
• Patients unable to follow the protocol in the investigators’ judgement.

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

Eligibility last updated 10/19/23. Questions regarding updates should be directed to the study team contact.

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

• Women ≥ 25 years of age.
• Women who had previously undergone salpingectomy or salpingo oophorectomy for any indication, including risk reduction, independent of final pathology including:
  • Morphologically unremarkable FTs;
  • STIC, pure (isolated) or concurrent with:
  • Histologic diagnosis of STIC has been confirmed by the GYN pathologist.
  • OHGSC.
• FFPE block is available for research.
• IRB approved informed consent for banking remnant tissue (taken during the course of routine care) for future use in research or waivers of consent and HIPAA Authorization for the release of information and biospecimens.
• Assessment of risk for ovarian cancer will be based on criteria derived from the inclusion criteria for the United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS).

• Patients who don’t satisfy the inclusion criteria listed above.
• Subjects with history of other malignancies, except:
  • Adequately treated non-melanoma skin cancer;
  • Curatively treated in-situ cancer of the cervix;
  • Other solid tumors curatively treated with no evidence of disease for > 5 years.

Eligibility last updated 7/17/23. Questions regarding updates should be directed to the study team contact.