For Substudy 1:

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

For Substudy 2:

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

Substudy 1 and 2:

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

Substudy 1 and 2

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

• Signed informed consent form (ICF) and ability to comply with protocol requirements.
• Known tumor TP53 mutation status from recent or archival sample.
• Histologically and/or cytologically confirmed solid tumor malignancy:
  • Safety lead-in portion:
    • Patients with histologically and/or cytologically confirmed diagnosis of advanced non-central nervous system (CNS) primary tumors that have progressed after first line treatment, who are intolerant to first line treatment, or who are unable to receive first line treatment, and for whom pembrolizumab, or pembrolizumab-based therapy, is considered appropriate in the opinion of the investigator. Primary CNS tumors are excluded. Patients with clinically stable, known metastatic tumors to the CNS are eligible. CNS radiography is not required in the absence of suspicion for clinical involvement.
  • Phase 2 Expansion portion:
    • Patients with histologically and/or cytologically confirmed diagnosis of advanced gastric or gastroesophageal junction (GEJ) tumors that have progressed after first line treatment, who are intolerant to first line treatment, or who are unable to receive first line treatment. Patients with clinically stable, known metastatic tumors to the CNS are eligible with Medical Monitor approval. CNS radiography is not required in the absence of suspicion for clinical involvement. Prior treatment with anti-PD1/anti-PD-L1 therapy is prohibited;
    • Patients with histologically and/or cytologically confirmed diagnosis of advanced bladder/urothelial tumors that have progressed after first line treatment, or who are intolerant to first line treatment, or who are unable to receive first line treatment with cisplatin-based chemotherapy. Patients with clinically stable, known metastatic tumors to the CNS are eligible with Medical Monitor approval. CNS radiography is not required in the absence of suspicion for clinical involvement. Prior treatment with anti-PD-1/anti-PD-L1 therapy is prohibited;
    • Patients with histologically and/or cytologically confirmed diagnosis of advanced non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy. Patients with clinically stable, known metastatic tumors to the CNS are eligible with Medical Monitor approval. CNS radiography is not required in the absence of suspicion for clinical involvement.
• Adequate organ function as defined by the following laboratory values:
  • Creatinine clearance > 30 mL/min (by Cockcroft-Gault method;
  • Total serum bilirubin < 1.5 × upper limit of normal (ULN) unless due to Gilbert’s syndrome, tumor involvement, hemolysis or considered an effect of regular blood transfusions;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 × ULN, unless due to involvement by the underlying malignancy.
• Age ≥ 18 years at the time of signing the ICF.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Projected life expectancy of ≥ 12 weeks.
• In the expansion portion, measurable disease meeting the following criteria:
  • At least 1 lesion of ≥ 10 mm in the longest diameter (LD) for a non-lymph node or ≥ 15 mm in the short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1;
  • Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation must show subsequent evidence of substantial size increase (ex., 20% increase in LD) to be deemed a target lesion.
• Negative serum or urine pregnancy test prior to study treatment initiation in female subjects of childbearing potential.
• Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception such as latex condom, hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter.

• Known history of untreated human immunodeficiency virus (HIV)/HIV with a detectable viral load or active hepatitis B or active hepatitis C infection.
• Any of the following cardiac 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 (LVEF) < 40%;
  • A history of familial long QT syndrome;
  • Symptomatic atrial or ventricular arrhythmias not controlled by medications;
  • QTcF ≥ 470 msec, unless due to underlying bundle branch block and/or pacemaker and with approval of the Medical Monitor.
• Concomitant malignancies or previous malignancies with less than a 1-year disease-free interval at the time of signing consent. Subjects with adequately treated basal or squamous cell carcinoma of the skin, or adequately treated carcinoma in situ (e.g, cervix) may enroll irrespective of the time of diagnosis. Patients with controlled, advanced prostate cancer are permitted.
• Pregnancy or lactation.
• Active uncontrolled systemic infection.
• An autoimmune condition requiring ≥ 10 mg (or equivalent corticosteroid) prednisone daily, or any other systemic immunosuppressive treatment within 28 days of first dose of study therapy.
• Known history of active tuberculosis.
• Current (non-infectious) pneumonitis, or a history of pneumonitis that required steroids.
• A live vaccine administered within 30 days of the first dose of study treatment.
• Receipt of any investigational product within 14 days or 5 half-lives prior to study treatment initiation, whichever is shortest.
• Prior intolerance to pembrolizumab or other anti-PD-1/PD-L1 agents.

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

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

• Are ≥ 18 years of age at the time of signing the informed consent.
  • In Japan, if a patient is < 20 years, the written informed consent from his/her parent or guardian will be required in addition to the patient’s written consent.
• Participants must have measurable or non-measurable but evaluable disease assessed by the Investigator. Participants must have histologically documented NSCLC who present with Stage III locally advanced, unresectable disease (International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology], v8).
• 3. Availability of tumor material (< 6 months old) adequate for biomarker analysis is mandatory for all participants and central laboratory confirmation is required. For participants enrolled in the safety run-in, PD-L1 expression will be tested retrospectively by a central laboratory. For participants enrolled in the expansion part of the study, PD-L1 expression must be tested by the central laboratory and results available before randomization. Only results from the central laboratory testing will be used for randomization and if PD-L1 status is non-evaluable, the participant is not eligible for this study. Tumor samples obtained by endoscopic biopsies, core needle biopsies, excisional biopsies, punch biopsies, and surgical specimens that are < 6 months old and adequate for biomarker analysis are acceptable. Biopsies obtained by fine needle aspiration are not acceptable.
• Participants with tumor harboring an EGFR sensitizing (activating) mutation, ALK translocation, ROS-1 rearrangement are eligible. These tests are not required for enrollment in the study.
• Participants with ongoing post-obstructive pneumonia due to the tumor are eligible.
• If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable T4 disease):
  • When pleural fluid is visible on both the CT scan and on a chest x-ray, a thoracentesis is required to confirm that the pleural fluid is cytologically negative;
  • Participants with exudative pleural effusions are excluded, regardless of cytology;
  • Participants with effusions that are minimal; i.e., are too small to safely tap are eligible.
• Participants must be at least 3 weeks from prior thoracotomy (if performed).
• Participants must have adequate pulmonary function defined as a forced expiratory volume in 1 second (FEV1) ≥ 1.2 liters or ≥ 50% of predicted normal volume measured within 3 weeks prior to randomization. If participants do not meet the above criteria, treatment with inhaled steroids and bronchodilators can be initiated if clinically indicated and eligibility can be reassessed after 1-2 weeks.
• ECOG performance status of 0 to 1 at Screening and on the day of first dose.
• Life expectancy ≥ 12 weeks.
• Have adequate organ function as indicated by the following laboratory values:
  • Adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL;
  • Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase (AST) level ≤ 3.0 × ULN, an alanine aminotransferase (ALT) level ≤3.0 × ULN and alkaline phosphatase ≤ 2.5 ULN;
  • Adequate renal function defined by creatine ≤ 1.5 × ULN or calculated creatinine clearance (CrCl) ≥ 50 mL/min for participant with Cr > 1.5 × ULN (GFR can also be used).
    • Note: CrCl  should be calculated per institutional standard. If no local guideline is available, CrCl should be calculated using the Cockcroft-Gault Method:
    • CrCl = ((140-age) * weight (kg) * (0.85 for females only)) / (72 * creatinine).
  • Adequate coagulation function defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy and activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless the participant is receiving anticoagulant therapy.
• Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.
  • Male Participants:
    • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e agree to the following during the study intervention period and for at least 6 months after the last dose of study intervention
    • Refrain from donating sperm; PLUS, either:
      • Abstain from intercourse with a WOCBP;
        • OR
      • Use a male condom: When having sexual intercourse with a WOCBP, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year, since a condom may break or leak.
  • Female Participants:
    • Are not pregnant or breastfeeding, and at least one of the following conditions applies:
      • Not a WOCBP.
        • OR
      • If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, for the following time periods:
        • Before the first dose of the study intervention(s), if using hormonal contraception:
        • Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses; OR
        • Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly sensitive assay.
        • During the intervention period.
      • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e., after the study intervention period (i.e., after the last dose of study intervention is administered) for at least 4 months after the last dose of study intervention and agree not to donate eggs (ova, oocytes) for reproduction during this period.
    • Have a negative pregnancy test, as required by local regulations, on W1D1 before the first dose of study intervention.
    • Additional requirements for pregnancy testing during and after study intervention are in SoA.
    • The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
• Can give signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.

• Participants with mixed small cell with non-small cell lung cancer histology.
• Greater than minimal, exudative, or cytologically positive pleural effusions.
• Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of study drug.
• Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
• History of organ transplant that requires therapeutic immunosuppression.
• Significant acute or chronic infections including, among others:
  • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (testing at Screening is not required). If an Investigator has a strong suspicion of HIV infection without known history for a participant in Screening, however participant refuses testing, discuss with Medical Monitor to assess eligibility. (Note: HIV testing is not mandated for study inclusion; however, if it is performed at any point in Screening or while on study, a site must consent the participant for HIV testing as per local standard guidance);
  • Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA, or HBV core antibody positive alone with reflex to positive HBV DNA, or positive HCV antibody with reflex to positive HCV RNA) at Baseline. Discuss with the Medical Monitor if history of HBV or HCV  infection is known. If medically indicated, participants infected with HBV must be treated and on a stable dose of antivirals (e.g, entecavir, tenofovir, or lamivudine; adefovir or interferon are not allowed) at study entry and with planned monitoring and management according to appropriate labeling guidance. Participants on active HCV therapy at study entry must be on a stable dose without documented clinically significant impaired liver function test or hematologic abnormalities (must meet criteria above) and with planned monitoring and management according to appropriate labeling guidance. HBV and/or HCV viral titers must be monitored according to SoA in these participants.
  • Participants with active tuberculosis (history of exposure or history of positive tuberculosis test; plus presence of clinical symptoms, physical, or radiographic findings).
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, active uveitis or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for investigational drug treatment are also excluded.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
• Known clinical history of tuberculosis, lung sarcoidosis and Interstitial Lung Diseases.
• History of another primary malignancy within 3 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin, adequately treated carcinoma in situ, e.g., cancer of the cervix in situ, superficial bladder cancer. History of other localized malignancies treated with curative intent needs to be discussed with the Medical Monitor.
• Uncontrolled neuropathy Grade 2 or greater regardless of cause.
• Significant hearing loss and participants unwilling to accept potential for further hearing loss (Investigator should consider treating the participant with carboplatin/paclitaxel).
• Any prior systemic cytotoxic chemotherapy for their NSCLC or any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints) such as anti-PD-(L)1, or anti-CTLA-4 antibody.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of study drug, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the cCRT for locally advanced NSCLC is allowed.
• Active autoimmune disease that has required systemic treatment in past 1 year (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), OR is receiving systemic steroid therapy < 3 days prior to the first dose of study intervention or receiving any other form of immunosuppressive medication. Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at low doses (typically ≤ 10 mg of prednisone or equivalent per day). Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy. Corticosteroid use on study as a premedication for IV contrast allergies/reactions (related to scans) is allowed and must be documented. This must be discussed with Medical Monitors for clinical indications in which participants may require a higher dose. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes Type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.  Consult Medical Monitor for other autoimmune diseases.
• Receipt of live attenuated vaccination within 30 days of receiving study drug.
• Use of a prohibited concomitant drug within 4 weeks randomization.
• Known severe hypersensitivity (Grade ≥ 3 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) to study interventions or any components in their formulations, or uncontrolled asthma (i.e., 3 or more features of partially controlled asthma).
• Participation in another clinical study with an investigational product within the last 4 weeks.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
• ≥ 10% weight loss within the past month.
• Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study drug or interpretation of participant safety or study results.

• Adults and adolescents (aged ≥ 12 years.
• Children 6 to 11 years of age.
• Children 2 to 5 years of age.
• Infants and newborns from birth to < 2 years of age.
• Documented diagnosis of PH1 or PH2, confirmed by genotyping (historically available genotype information is acceptable for study eligibility).
• Estimated GFR at Screening < 30 mL/min normalized to 1.73 m^2 BSA.  For infants aged less than 12 months, serum creatinine above the 97th percentile of a healthy population (Boer et al., 2010).
• Median of 3 plasma oxalate values > 30 µmol/L during Screening.
• Less than 20% variation from the median Screening period Pox value.
• For participants receiving hemodialysis or peritoneal dialysis, total duration of hemodialysis or peritoneal dialysis must be less than or equal to 18 months and hemodialysis or peritoneal dialysis regimen must have been stable for at least 3 months prior to Screening.
• Body weight of:
  • Adults and adolescents aged ≥ 12 years: ≥ 31.0 kg;
  • Children 6 to 11 years of age: to be determined;
  • Children 2 to 5 years of age: to be determined;
  • Infants and newborns from birth to < 2 years of age: to be determined.
• Male participants: 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.
• Female participants: 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);OR
  • A WOCBP who agrees to follow the contraceptive guidance for the 4 weeks prior to randomization, during the treatment period, and for at least 12 weeks after the last dose of study intervention and agrees to refrain from harvesting/freezing eggs during this period. 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.
• Affiliated with or is a beneficiary of a health insurance system (if applicable per national regulations).

• Prior hepatic transplantation; or scheduled transplantation within 6 months of Day 1. Renal transplantation planned in the 6 months from Day 1. Prior renal transplantation is allowed.
• Known history of severe systemic oxalosis.
• Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially impact patient safety including, but not restricted to:
  • Severe intercurrent illness;
  • Known causes of active liver disease/injury (e.g., alcoholic liver disease, nonalcoholic fatty liver disease/steatohepatitis);
  • Non-PH related conditions contributing to renal insufficiency;
  • Physician concerns about intake of drugs of abuse or excessive alcohol intake, or history of excessive alcohol intake in the 2 years prior to enrollment (defined as ≥ 21 units of alcohol per week in men and ≥ 14 units of alcohol per week in women; where a “unit” of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1-ounce shot of hard liquor).
• Use of an RNAi drug, other than DCR-PHXC, within the last 6 months.
• 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 transaminase (ALT) or aspartate transaminase (AST) > 3 times 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.
• Participation in any clinical study in which they received an investigational medicinal product (IMP) other than DCR-PHXC within 4 months or 5 times the half-life of the drug (whichever is longer) before Screening.
• Liver function test abnormalities: ALT and/or AST >1.5 × ULN for age and gender.
• Positive anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody test at Screening.
• Known hypersensitivity to DCR-PHXC or any of its ingredients.
• Inability or unwillingness to comply with the specified study procedures, including lifestyle considerations.

• Participants must be 18 years or older.
• Participants must understand and cooperate with requirements of the study in the opinion of the investigators and must be able to provide written informed consent.
• Individuals who had no known COVID-19 exposure (for controls) or had PCR or antibody confirmed COVID-19 who present with neurological symptoms in the months after infection and fit one of the following criteria during the acute phase of the infection:
  • ambulatory with no or mild symptoms;
  • hospitalized but on no oxygen; or
  • hospitalized but on oxygen administered via a nasal cannula, mask or non-invasive ventilation; i.e., individuals with WHO Ordinal Scale40 scores 0-5. 
• English or Spanish speaking (based on self-stated primary language).
• Clear of any contraindications for MRI.

• Patients under 18 years of age.
• Medical conditions likely to interfere with the study, including chronic neurologic conditions, restless leg syndrome, structural abnormalities such as subdural hematoma, intracranial neoplasms, end-stage renal disease, severe chronic obstructive pulmonary disease (COPD) needing oxygen, end-stage liver disease, active psychiatric illness, active drug abuse, stroke unrelated to COVID-19 or heart attack 6 months before study enrollment, active cancer, concurrent illnesses or treatments interfering with cognitive function such as dementia or normal pressure hydrocephalus.
• Individuals who had COVID-19 and required mechanical ventilation.
• Pregnant women.
• Inability to undergo MRI scanning, including but not limited to claustrophobia, unable to remain still in an MRI scanner for more than 30 minutes, presence of paramagnetic substances or pacemakers in body, weight over 300 lbs.
• Inability to adhere to study protocol for whatever reason.

• Provisions of signed and dated informed consent form.
• Patient is 18 years of age and older.
• Patient has a diagnosis of Stage 3 PC cytologically or pathologically confirmed per American Joint Committee on Cancer (AJCC) staging criteria.
• Patient has a tumor evaluated as Stage 3 according to National Comprehensive Cancer Network (NCCN) guidelines, based on radiographic imaging or exploratory surgery.
• Maximum axial and anterior to posterior tumor dimension of ≤ 3.5cm after SOC.
• Patient has received 3 months of SOC per each participating institution’s guidelines.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Patient has an American Society of Anesthesiologists (ASA) classification of physical health status of 1, 2, 3 or 4.
• Patients at IRE sites who are deemed eligible for IRE and receive ablation using the NanoKnife System.
• Patient shows no evidence of disease progression based on NCCN guidelines after completing three (3) months of SOC.

• Participation in an interventional trial for pancreatic cancer during the study data collection period.
• Pregnant or lactating patients or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of chemotherapy.
• Patients who are unable to tolerate general anesthetic with full skeletal muscle blockade.
• Patients with the presence of implanted cardiac pacemakers, defibrillators, electronic devices or implanted devices with metal parts in the thoracic cavity at the time of IRE.

• Male or female.
• 12 years or older.
• Within 72 hours before randomization, blood culture positive for S. aureus determined by rapid diagnostic test or conventional method, or Gram stain showing Gram-positive cocci in clusters and either positive tube coagulase test or positive latex slide agglutination test from blood culture specimens.
  • Note: The 72-hour time period starts at the time the specimen is collected for blood culture. Any S. aureus-positive blood culture collected within the 72 hours before randomization can be used to support enrollment of the patient.
• At least two of the following signs or symptoms attributable to S. aureus BSI/IE within approximately 24 hours before randomization. If more than one measurement is taken within approximately 24 hours before randomization, the most abnormal value is used for inclusion:
  • Shortness of breath;
  • Sweating;
  • Chills and/or rigors;
  • Fatigue;
  • Confusion;
  • Pain associated with metastatic foci;
  • Fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) or hypothermia (oral temperature equivalent 10,000/µL) [CTCAE 2017], leukopenia (WBC 10% immature neutrophils [bands] regardless of total peripheral WBC);
  • Tachycardia (heart rate >100 bpm)
  • Tachypnea (respiratory rate >20 breaths/min);
  • Hypotension (systolic blood pressure < 90 mmHg).
• Patient must have:
  • Known or suspected R-IE (involvement of pulmonic and/or tricuspid valve[s]) based on Modified Duke Criteria (defined in protocol); or
  • Known or suspected complicated S. aureus BSI, demonstrated as one or more of the following:
  • Blood culture positive for S. aureus on more than one day;
  • Clots in the vein at the catheter site seen on ultrasound;
  • Signs or symptoms of metastatic foci of S. aureus infection (e.g., splenic abscess, deep tissue abscess not associated with open wound or other local source of infection, septic pulmonary emboli) or hematogenous seeding (e.g., of the renal system evidenced by S. aureus bacteriuria [in absence of other source such as indwelling ureteral catheter], septic arthritis, osteomyelitis) confirmed by physical examination, imaging, and/or culture (as described in the study procedures sections of the protocol);
  • Persistent fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) for 72 hours or more;
  • Met criteria for sepsis or septic shock using the Sequential (sepsis-related) Organ Failure Assessment (SOFA) score (definition in protocol [adapted from Singer 2016]) during the time of diagnosis/presumptive diagnosis of BSI. If the SOFA score is the only criteria for complicated S. aureus BSI that is met, contact the Medical Monitor prior to randomization;
  • Significantly immunocompromised:
  • AIDS (HIV positive with an AIDS-defining condition or a CD4 count < 200 cells/mm³);
  • Severe leukopenia defined as absolute neutrophil count (ANC)  < 500 cells/mL for ≥ 3 days in the 7 days prior to the qualifying blood culture;
  • Post organ-transplantation including autologous bone marrow transplantation;
  • On treatment for active graft vs. host disease;
  • On immunosuppressive therapy (e.g., ≥15 mg of prednisone or equivalent for more than 5 days, biologics such as infliximab, monoclonal antibodies such as daclizumab, methotrexate, cyclophosphamide, or similar agents);
  • On myelosuppressive chemotherapy; or
  • At least one of the following risk factors for complicated S. aureus BSI:
  • Preexisting right-sided valvular heart disease;
  • Surgery (e.g., orthopedic, cardiothoracic, or intraabdominal surgery) within the previous 30 days that puts the patient at risk for nosocomial bacteremia;
  • Extravascular foreign material.
  • Note: Catheters including ports, AV fistulas and related dialysis access points are considered intravascular foreign material;
  • Hemodialysis.
• Patient is not pregnant or breastfeeding and meets one of the following criteria:
  • A female patient who is not of childbearing potential is eligible without requiring the use of contraception. This includes female patients who have not undergone menarche or who are documented to be surgically sterile (e.g., hysterectomy, or removal of both ovaries, or tubal ligation) or postmenopausal (i.e., amenorrhea >1 year and follicle stimulating hormone [FSH] >40 mIU/mL) with a negative pregnancy test. FSH and pregnancy testing is not required in postmenopausal females with amenorrhea for > 2 years;
  • Female patients of childbearing potential and male patients with partners of childbearing potential must agree to remain abstinent* or use 2 methods of contraception and refrain from donating sperm (male patients) from screening through 30 days after receiving the study drug.
  • *Abstinence is defined as refraining from heterosexual intercourse from screening through 30 days after receiving the study drug; the Investigator will consider whether abstinence is consistent with the preferred and usual lifestyle of the patient. Acceptable methods of contraception include either:
  • Hormonal contraception (injection, implant, pill, patch, or vaginal ring) and a condom or diaphragm with spermicide; or
  • Intrauterine device (IUD) and a condom or diaphragm;
  • A male patient who is not of reproductive potential is eligible without requiring the use of contraception. This includes males who have undergone a successful vasectomy, defined as (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post vasectomy.
• Willing and able to provide written informed consent or assent. If the patient is not able to provide written informed consent or assent, written informed consent may be provided by the patient’s legally acceptable representative as permissible based on local laws and regulations. For patients 12 to < 18 years of age, written informed consent from the patient’s parent/guardian or other legally acceptable representative will be obtained according to the site’s IRB requirements. For emancipated minors, written informed consent will be obtained according to the site’s IRB requirements.

Exclusion Criteria:

• Previously received exebacase.
• Known or suspected left-sided IE (involvement of mitral and/or aortic valve[s]) based on Modified Duke Criteria (defined in protocol). Note: In patients that have clinical findings suggestive of L-IE (new murmur, worsening cardiac function, and/or peripheral or central nervous embolic phenomenon), a TEE will be performed before randomization to rule out mitral and/or aortic valve vegetation(s) or the patient will be excluded from the study.
• Treatment with any potentially effective systemic anti-staphylococcal antibiotic for more than 72 hours within 7 days before randomization.
• Exception:  Documented S. aureus resistance to the prior systemic antibiotics and/or persistent S. aureus-positive blood cultures while on the systemic antibiotics.
• Current or planned treatment within the 14 days after randomization with dalbavancin or oritavancin.
  • Note:  Patients who are receiving teicoplanin, linezolid, telavancin, beta-lactam/beta-lactam inhibitors (e.g., piperacillin-tazobactam), carbapenems, fourth- or fifth-generation cephalosporins (e.g., cefepime, ceftaroline fosamil), and/or sulfamethoxazole/ trimethoprim are eligible for the study provided that treatment is switched to a protocol-specified appropriate SoCA (appropriate SoCA includes daptomycin and vancomycin for MRSA and semi-synthetic penicillins [e.g., nafcillin, oxacillin, cloxacillin, flucloxacillin] and first-generation cephalosporins [e.g., cefazolin] for MSSA;
  • Daptomycin or vancomycin may be used for patients with MSSA with a known history of beta-lactam allergy or other reason that beta-lactam cannot be used);
  • Patients with persistent S. aureus bacteremia for which ceftaroline fosamil or other nonprotocol recommended antibiotic (e.g., rifampin, gentamicin, other beta lactam) has already been added to a protocol-recommended SoCA prior to randomization, the patient may remain on the non-protocol recommended antibiotic (plus SoCA) after randomization, if approved by the Medical Monitor;
  • Vancomycin or daptomycin used in combination with beta-lactams has not been shown to offer benefit and may increase the risk of kidney injury [Tong 2020]; therefore, this combination should not be used.
• Presence of any removable or surgically managed infection source (e.g., intravascular catheter, abscess) that will not be removed or debrided based upon standard medical practice within approximately 72 hours after randomization.
  • Note: Other hemodialysis access types (i.e., AV fistulas or AV grafts) and surgically managed infection sources that are known or suspected to be infected will be evaluated for removal/replacement, if clinically feasible. If removable/ debridement is not feasible based on standard medical practice, the patient should be discussed with the Medical Monitor.
• Presence of prosthetic valve or cardiac valve support ring, or presence of known or suspected infected orthopedic hardware, prosthetic joint, or cardiac device (e.g., implantable cardioverter defibrillator [ICD], permanent pacemaker).
  • Note: Patients who have S. aureus bacteremia after the removal of infected hardware or cardiac device may be included in the study.
• Known or suspected brain abscess or meningitis.
• Patient with BOTH asplenia and creatinine clearance (CrCl) < 60 mL/min including those on dialysis (risk for reduced ability to catabolize exebacase).
  • Note: CrCl will be calculated by Cockcroft-Gault formula (provided in protocol) using ideal body weight in patients with BMI ≥ 30 kg/m^2 and serum creatinine result obtained locally.
• Patient receiving continuous renal replacement therapy (CRRT) within 4 hours prior toat the time of dosing and/or within 248 hours after dosing.
• Known polymicrobial BSI (i.e., more than one pathogen in the blood).
  • Note: Culture results that include organisms that are considered contaminants do not exclude the patient.
• Patient with known, ongoing systemic infection caused by other bacterial pathogen(s) (i.e., other than S. aureus) and/or fungal pathogen(s) and/or patient who has a known positive coronavirus disease 2019 (COVID-19) diagnostic test at the time of screening. Patients who previously had COVID-19 and are COVID-19-negative by diagnostic test are eligible for enrollment. Note: COVID-19 testing should be performed as clinically indicated in accordance with local standard medical practice.
• Patient is not expected to survive through Day 14 of the study due to underlying comorbidity (e.g., terminal end-stage cancer) and/or patient has an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of > 2530.
• Patient participated or plans to participate in another interventional investigational drug, device, or diagnostic trial involving administration of an investigational agent within 30 days or 5 half-lives of investigational drug, whichever is longer, prior to or during the study.
• Other comorbid condition or laboratory abnormality that would, in the opinion of the Investigator, pose a safety risk for the patient to participate or pose a risk to the patient’s ability to complete the study.
• Patient is employed by the Sponsor or a member of the investigational site study team (i.e., on the Delegation of Authority Log) or is a first degree relative of a person employed by the Sponsor or a member of the investigational site study team (i.e., on the Delegation of Authority Log). Patient is institutionalized by administrative or court order.
• Patient is not willing or able to comply with the protocol requirements.

Eligibility last updated 10/20/21. Questions regarding updates should be directed to the study team contact.

• Male or female patients aged ≥ 18 years.
• A diagnosis of CD with minimum disease duration of 6 months with involvement of the ileum and/or colon documented on colonoscopy
• Have an endoscopically-confirmed active Crohn's disease with active disease defined by SES-CD > 6 (>4 if ileal only), AND active symptoms of Crohn's disease (CDAI score >220) 
• Homozygous for CARD9 SN12 risk allele, without the protective exon 11 polymorphism
• Subjects receiving oral aminosalicylates (at a stable dose for 2 weeks prior to baseline), immunomodulators (at a stable dose for 4 weeks prior to baseline), anti-TNF, anti IL12/23, or anti-integrin therapy (at stable maintenance doses for > 8 weeks) may continue their use during the study.
• Subjects receiving oral corticosteroids may continue their use during the study provided the dose (prednisone up to 20 mg/day, budesonide up to 9 mg/day) has been stable for two weeks prior to screening.
• Have had age-appropriate and disease-duration-appropriate colon cancer screening1 without unresected dysplasia.
• Women of childbearing age, excluding those with prior bilateral tubal ligation or at least one-year post-menopause, must not be pregnant, lactating, or planning to become pregnant. They must agree to use effective contraception throughout the study period.
• Subjects must be able to provide informed consent and understand, agree with, and be able to adhere to daily diary entries, all scheduled visits, tests, procedures, and protocol in English.

• Known hypersensitivity or allergy to posaconazole or other azole antifungal agents
• Concomitant medications primarily metabolized by CY3PA4 including:
  • HMG-CoA inhibitors primarily metabolized by CY3PA4 (increases risk of rhabdomyolysis);
  • Sirolimus;
  • Ergot alkaloids;
  • Vincristine.
• Proarrhythmic conditions.
• Moderate or severe renal impairment (Cr Clearance < 50).
• Current diagnosis of ulcerative colitis, indeterminate colitis, ischemic colitis, infectious colitis, or microscopic colitis.
• Fulminant colitis, toxic megacolon, peritonitis, ileostomy or colostomy.
• Stool sample positive for pathogens including ova and parasites, Salmonella, Shigella, and C. difficile at screening.
• History of any clinically significant neurological, renal, hepatic, gastrointestinal, pulmonary, metabolic, cardiovascular, psychiatric, endocrine, hematological disorder or disease or any other medical condition that, in the Investigators opinion, would prevent the subject from participation in the study.
• Treatment with antibiotics, antifungal agents, probiotics, or prebiotics within two weeks of screening.
• Alcohol or drug abuse (in the opinion of the Investigator) that would interfere with compliance.
• Any other investigational therapy or treatment within four weeks of screening.

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

Eligibility last updated 1/25/23. Questions regarding updates should be directed to the study team contact.

• High-risk disease defined as an IPI score of 4 or 5 at initial diagnosis.
• Histologically confirmed LBCL based on 2016 World Health Organization (WHO) classification by local pathology lab assessment, including one of the following:
  • Diffuse large B-cell lymphoma, NOS;
  • High-grade B-cell lymphoma (HGBL) (including HGBL with MYC and BCL2 and/or BCL6 rearrangements (DHL/THL) based on FISH analysis, and HGBL-NOS);
    • Note: Transformed DLBCL from follicular lymphoma or from marginal zone lymphoma is eligible if no prior treatment with anthracycline-containing regimen.
• Ann Arbor Stage III or IV disease.
• Have received only 1 cycle of R-chemotherapy.
• At least 1 measurable lesion per the Lugano Classification {Cheson 2014} on anatomical imaging such as computed tomography (CT) imaging (functional imaging such as PET may not be used to identify a measurable lesion). A measurable lesion is defined as greater than 1.5 cm LDi for lymph node and greater than 1.0 cm LDi for extranodal lesion.
• Adequate tumor biopsy specimen available for central pathology review (detailed sample collection requirement is in central pathology laboratory manual).
• Age 18 years or older.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of randomization;
  • Note: ECOG > 1 at diagnosis is acceptable.
• Adequate bone marrow, renal, hepatic, pulmonary, and cardiac function as indicated by:
  • Absolute neutrophil count (ANC) ≥ 1000/μL;
  • Platelet count ≥ 75,000/μL;
  • Absolute lymphocyte count ≥ 100/μL;
  • Creatinine clearance (as estimated by any local institutional method) ≥ 60 mL/minute;
  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 x ULN if documented liver involvement of lymphoma;
  • Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert’s Syndrome or documented LBCL liver or pancreatic involvement where ≤ 3.0 times the ULN;
  • Left ventricular ejection fraction (LVEF) ≥ 50% and no evidence of clinically significant pericardial effusion, and no clinically significant abnormal electrocardiogram (ECG) findings;
  • No evidence of Grade 2 (per Common Terminology Criteria for Adverse Events [CTCAE] 5.0) or greater pleural effusion or ascites (subjects with Grade 1 ascites or pleural effusion are eligible);
  • Baseline oxygen saturation > 92% on room air.
• Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential).

• Any prior treatment for LBCL other than the 1 cycle of R-chemotherapy.
• The following WHO 2016 subcategories by local assessment:
  • T-cell/histiocyte-rich LBCL;
  • Primary DLBCL of the CNS;
  • Primary mediastinal (thymic) LBCL;
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma;
  • Burkitt lymphoma.
• History of severe immediate hypersensitivity reaction attributed to aminoglycosides.
• Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple bacterial infections are permitted if responding to active treatment and after consultation with the Kite medical monitor.
• History of acute or chronic active hepatitis B or C infection. If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
• Positive for human immunodeficiency virus (HIV) unless taking appropriate anti-HIV medications, with an undetectable viral load by PCR and with a CD4 count > 200 cells/uL.
• Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted.
• Presence of detectable cerebrospinal fluid (CSF)-malignant cells, brain metastases, or a history of central nervous system (CNS) involvement of lymphoma.
• Presence of CNS disorder such as dementia, autoimmune disease with CNS involvement, cerebral edema with confirmed structural defects by appropriate imaging, or seizure disorders requiring active anticonvulsive medication. History of stroke, transient ischemic attack, or posterior reversible encephalopathy syndrome (PRES) within 12 months prior to enrollment.
• Presence of cardiac atrial or ventricular lymphoma involvement.
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac disease within 12 months before enrollment.
• Presence of primary immunodeficiency A.
• History of autoimmune disease (eg, Crohn’s disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
• History of non-line associated, clinically significant (CTCAE 5.0 Grade 2 or greater) deep vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within 6 months of randomization.
• Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
• History of severe immediate hypersensitivity reaction to any of the agents used in this study, including the lymphodepletion chemotherapy (cyclophosphamide or fludarabine).
• Live vaccine ≤ 6 weeks before the planned start of the lymphodepletion chemotherapy regimen.
• Females of childbearing potential who are pregnant or breastfeeding (due to potentially dangerous effects of the preparative chemotherapy on the fetus or infant).
• Not willing to practice birth control from the time of consent through at least 6 months after the last dose of axicabtagene ciloleucel or SOCT 20) In the investigator’s judgment, the subject is unlikely to complete all study-specific visits or procedures, including follow-up visits, or comply with the study requirements for participation.

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

• 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.

• ≥ 20 years of age.
• Last chemotherapy more than 3 years ago.
• Scheduled to receive moderate to highly emetogenic chemotherapy with or without targeted therapies including immunotherapies.

• Concurrent radiation therapy.
• Concurrent antibiotic treatment.

Eligibility last updated 10/5/22. Questions regarding updates should be directed to the study team contact.

Key

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

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

• Signed informed consent must be obtained prior to participation in the study.
• Age ≥ 18 years at the date of signing the informed consent form (ICF).
• Newly diagnosed with AML based on 2016 WHO classification (Arber et al 2016) and not suitable for intensive chemotherapy defined as:
  • age ≥ 75;
  • ECOG performance Status 2 or 3, or any of the following comomorbitities: severe cardiac comorbities (including congestive heart failure, LVEF ≤ 50%, chronic stable Angina) , pulmonary comorbidity (DLCO ≤ 65% or FEVI ≤ 65%);
  • moderate hepatic impairment (with total Bilirubin >1.5 to 3x ULN);
  • renal impairment (eGFR ≥ 30 ml/min/1.73m^2 to 45 30 ml/min/1.73m^2); or
  • any other comorbidity (to be documented in the CRF) that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Novartis Medical Monitor before study enrollment.
• Not planned for hematopoietic stem-cell transplantation (HSCT).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 , 2 or 3.
• AST and ALT ≤ 3 × upper limit of normal (ULN).
• Total bilirubin ≤ 3.0 × ULN (except in the setting of isolated Gilbert syndrome, in which case higher total bilirubin is allowed provided that conjugated bilirubin is ≤ 3.0 x ULN).
• Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73 m^2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)
• Subject is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures.
• WBC < 25 x10^9 /L (may be reduced with leukopheresis or hyroxyurea).

• Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine. Previous treatment for AML, MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera, with the exception of hydroxyurea, growth factors, and supportive care ruxolitinib.
• Prior exposure to TIM-3 directed therapy.
• Subjects with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA and patients with AML secondary to Down's syndrome.
• Subjects with CNS leukemia or neurologic symptoms suggestive of CNS leukemia (unless CNS leukemia has been excluded by a lumbar puncture).
• Subjects with concurrent or prior malignancy, except:
  • subject with history of MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera;
  • subject with history of adequately treated malignancy for which the subject has been disease free (absence of residual disease) for at least 1 year and if no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Patients who are receiving adjuvant therapy such as hormonotherapy are eligible.
• History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or MGB453) or monoclonal antibodies (mAbs) and/or their excipients.
• Any concurrent severe and/or uncontrolled medical condition; e.g., active uncontrolled infection or severe infectious disease requiring parenteral antibacterial, antiviral or antifungal therapy (such as severe pneumonia, meningitis, or septicemia).
• Active autoimmune disease requiring systemic therapy (e.g., corticosteroids).
• Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment (C1D1).
• Current use, or use within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy.
• Live vaccine administered within 30 days prior to the first day of study treatment (C1D1).
• Cardiac or cardiac repolarization abnormality, including but not limited to any of the following:
  • History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment;
  • QTcF > 470 ms at screening (based on mean of triplicate ECG), long QT syndrome or family history of unexplained cardiac death;
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block);
• HIV infection not controlled by standard therapy and/or with known history of opportunistic infection. For countries where HIV status is mandatory: HIV status will be tested during screening using a local test.
• Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Subjects whose disease is controlled under antiviral therapy should not be excluded.
• Other co-morbidity that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.
• Sexually active males unless they use a condom during intercourse while taking azacitidine and for 3 months after stopping this drug. They should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. In addition, male participants must not donate sperm for the time period specified above.
• Subject is pregnant or breastfeeding.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study treatment and for 30 days after the last dose of venetoclax, 90 days after the last dose of azacitidine (or as per their respective local labels, whichever is longer) and 150 days after the last dose of MBG453. It is currently unknown whether venetoclax may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method. Highly effective contraception methods include:
  • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception;
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment;
  • Male sterilization (at least 6 months prior to screening/baseline). For female subjects on the study the vasectomized male partner should be the sole partner;
  • Use of oral (estrogen and progesterone), injected or implanted combined hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.
• In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post-menopausal and not of child bearing potential if they have had over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate [generally age from 40 to 59 years], history of vasomotor symptoms) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy) or bilateral tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.

Eligibility last updated 11/4/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years at the time of consent.
• Signed written informed consent.
• JCAR017 monotherapy and ibrutinib + JCAR017 combination cohorts must have diagnosis of:
  • CLL with an indication for treatment based on the Investigator’s opinion and measurable disease (any of the following: bone marrow involvement by ≥ 30% lymphocytes, peripheral blood lymphocytosis > 5 × 10^9 /L, and/or measurable lymph nodes ≥ 1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly); or
  • SLL (lymphadenopathy and/or splenomegaly and < 5 × 10^9 CD19+ CD5+ clonal B lymphocytes/L [< 5000/µL] in the peripheral blood at diagnosis with measurable disease defined as at least one lesion ≥ 1.5 cm in the greatest transverse diameter) that is biopsy-proven SLL Venetoclax + JCAR017 combination cohorts must have diagnosis of:
  • CLL or SLL with an indication for treatment based on the Investigator’s opinion and measurable disease (any of the following: measurable lymph nodes ≥ 1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly), and demonstration of CLL cells in the peripheral blood by flow cytometry.
• Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received and failed BTKi treatment or have been deemed ineligible for BTKi therapy due to requirement for full dose anticoagulation or history of arrhythmia. Failure to BTKi is defined as having stable disease or progressive disease (PD) as best response, or progression after previous response, or discontinuation due to intolerance. Intolerance is defined as failure to tolerate treatment due to unmanageable toxicity.
• Subjects in the JCAR017 monotherapy cohorts must have received previous treatment as follows:
  • Subjects with CLL or SLL and high-risk features, defined as having complex cytogenetic abnormalities (3 or more chromosomal abnormalities), 17p deletion, TP53 mutation, or unmutated immunoglobulin heavy chain variable region (IGHV), must have failed at least 2 lines of prior therapy;
  • Subjects with CLL or SLL and standard-risk features must have failed at least 3 lines of prior therapy.
• Subjects in the ibrutinib + JCAR017 combination cohorts must either:
  • be receiving ibrutinib, or other BTKi, and progressing at the time of study enrollment; or
  • be receiving ibrutinib, or other BTKi, for at least 6 months with a response less than CR and have high-risk features, as defined in inclusion criterion 5a; or
  • have BTK or phospholipase C gamma 2 (PLCγ2) mutations per local laboratory assessment, with or without progression on ibrutinib; or
  • have previously received ibrutinib, or other BTKi, and have no contraindications to initiate or reinitiate ibrutinib (i.e., ibrutinib was not discontinued due to intolerability and subject has no medical contraindications such as arrhythmia or need for anticoagulation) Subjects in the ibrutinib + JCAR017 combination therapy cohorts enrolled under at least amendment 5, must also meet the below criteria:
  • have progressed on a BTKi and f. have received prior therapy with venetoclax which is considered if they meet one of the following criteria:
    • the subject continued on venetoclax due to disease progression or intolerability and if the subject’s disease met indications for further therapy per iwCLL 2018 criteria; or
    • the subject failed to achieve an objective response within 3 months of initiating therapy. Subjects in the venetoclax + JCAR017 combination cohorts must:
  • Have failed at least 1 prior line of therapy, including having failed BTKi therapy or have been deemed ineligible to receive BTKi, as defined in Inclusion Criterion #4;
  • Be venetoclax naïve (required for dose expansion cohort); or
    • If prior venetoclax, (only for dose escalation cohort) (1) have no contraindications to reinitiation of venetoclax based on prior intolerance and (2) have had at least 6 months elapsed since the last dose of venetoclax, if either of the following criteria are met:
    • the best response was stable disease; or
    • the subject experienced disease progression on venetoclax within 6 months of venetoclax discontinuation.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
• Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy.
• Adequate organ function, defined as:
  • Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance (Cockcroft and Gault) > 30 mL/min;
  • Alanine aminotransferase (ALT) ≤ 5 × ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert’s syndrome or leukemic infiltration of the liver);
  • Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air;
  • Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) scan performed within 30 days prior to determination of eligibility Subjects in the venetoclax + JCAR017 combination dose escalation and expansion cohorts must have:
    • Hemoglobin ≥ 9 g/dL, absolute neutrophil count (ANC) ≥ 500/mm^3 , and platelets ≥ 75,000/mm^3 , unless cytopenias judged by the Investigator to be due to CLL infiltration of the bone marrow.
• Subject either currently has central vascular access or is a candidate to receive central vascular access or peripheral vascular access for leukapheresis procedure.
• If prior CD19-targeted therapy has been administered, subject must have CD19-positive disease confirmed by immunohistochemistry or flow cytometry since completing the prior CD19-targeted therapy.
• Females of childbearing potential must either commit to true abstinence from heterosexual contact or agree to use one highly effective method of contraception from screening until at least 1 year after receiving lymphodepleting chemotherapy.
• Females of childbearing potential must have a negative serum beta human chorionic gonadotropin (ß-hCG) pregnancy test result at screening and within 48 hours prior to the first dose of lymphodepleting therapy.
• Males who have partners of childbearing potential must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 1 year after receiving lymphodepleting chemotherapy even if he has undergone a successful vasectomy.

• Subjects with known active central nervous system (CNS) involvement by malignancy. Subjects with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment with no evidence of symptomatic disease and stable abnormalities on repeat imaging.
• History of another primary malignancy that has not been in remission for at least 2 years. (The following are exempt from the 2-year limit: nonmelanoma skin cancer, completely resected stage 1 solid tumor with low risk for recurrence, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely resected.).
• Subjects with Richter’s transformation.
• Prior treatment with any gene therapy product.
• Active hepatitis B, or active hepatitis C (Subjects with a negative polymerase chain reaction (PCR) assay for viral load for hepatitis B or C are permitted; subjects positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody with negative viral load are eligible and should be considered for prophylactic antiviral therapy), or history of or active human immunodeficiency virus (HIV) infection.
• Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Presence of acute or extensive chronic graft versus host disease (GVHD).
• History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease.
• History or presence of clinically relevant CNS pathology such as epilepsy, generalized seizure disorder, aphasia, stroke with current neurologic sequelae, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, cerebral edema, or psychosis.
• Pregnant or nursing (lactating) women.
• Use of any of the following medications or treatments within the noted time prior to leukapheresis:
  • Alemtuzumab within 6 months prior to leukapheresis;
  • Allogeneic hematopoietic stem cell transplant within 100 days prior to leukapheresis;
  • Cladribine within 3 months prior to leukapheresis;
  • Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis;
  • Radiation including large bone marrow fields such as sternum or pelvis within 6 weeks prior to leukapheresis;
  • Fludarabine within 4 weeks prior to leukapheresis;
  • GVHD therapies such as calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate mofetil, rapamycin, or immunosuppressive antibodies (such as anti-tumor necrosis factor-α [TNFα], anti-interleukin-6 [IL-6], or anti-interleukin-6 receptor [IL-6R]) within 4 weeks prior to leukapheresis;
  • Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2 weeks prior to leukapheresis;
  • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis;
  • Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis;
  • Venetoclax within 4 days prior to leukapheresis;
  • Idelalisib or duvelisib within 2 days prior to leukapheresis;
  • Lenalidomide or acalabrutinib within 1 day prior to leukapheresis;
  • Experimental agents, including off-label use of approved drugs, within 4 weeks prior to leukapheresis unless progression is documented on the experimental therapy and at least 3 halflives have elapsed prior to leukapheresis.
• Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or subject unwillingness or inability to follow the procedures required in the protocol.
• Progressive vascular tumor invasion, thrombosis, or embolism.
• Venous thrombosis or embolism requiring treatment but not managed on a stable regimen of anticoagulation.
• For subjects in the venetoclax + JCAR017 combination cohorts only, concomitant treatment with CYP3A moderate/strong inducers or moderate/strong inhibitors which cannot be discontinued.

Key

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

Eligibility last updated 6/20/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 8/3/22. Questions regarding updates should be directed to the study team contact.

-  of seizure or convulsions, except history of childhood febrile seizures.

- Higher risk of seizure, as determined by the investigator (including, but not limited to, history of stroke; known Alzheimer’s disease or non-Alzheimer’s dementia; structural brain disease including arteriovenous malformations or other mass lesions; clinical diagnosis of traumatic brain injury or concussion within previous 6 months).

Patients on concomitant medications known to increase the risk of seizure may continue taking those medications, provided they have not previously experienced a seizure at or below the dose level being administered prior to initiation of GDC-8264.

Eligibility last updated 10/9/23. Questions regarding updates should be directed to the study team contact.

• Males and females, ≥ 12 years of age.
• Diagnosed with non-histaminergic normal C1-INH angioedema at the time of enrollment into the antecedent Study SHP643-303.  
• Participants must have completed the treatment period (through Visit 26/Day 182) of Study SHP643-303 without reporting a clinically significant TEAE that would preclude subsequent exposure to lanadelumab.
• Agree to adhere to the protocol-defined schedule of treatments, assessments, and  procedures.
• Males, or non-pregnant, non-lactating females who are of child-bearing potential and who agree to be abstinent or agree to comply with the applicable contraceptive requirements of this protocol for the duration of the study; or females of  non-childbearing potential, defined as surgically sterile (status post hysterectomy,  bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least  12 months.  
• The participant (or the participant's parent/legal guardian, if applicable) has provided written informed consent approved by the institutional review board/research  ethics board/ethics committee (IRB/REB/EC) at any time prior to study start.
• If the  participant is a minor (i.e., less than 18 years of age), have a parent/legal guardian who is informed of the nature of the study provide written informed consent (i.e., permission) for the minor to participate in the study before any study-specific  procedures are performed.
• Assent will be obtained from minor participants.  

• Discontinued from Study SHP643-303 after enrollment but before Visit 26  for any reason.
• Presence of important safety concerns identified in Study SHP643-303 that would preclude participation in this study.  
• Dosing with an investigational product (IP, not including IP defined in antecedent  Study SHP643-303 or exposure to an investigational device within 4 weeks prior to Day 0.
• Participant has a known hypersensitivity to the investigational product or its  components.
• Have any condition (surgical or medical) that, in the opinion of the investigator or sponsor, may compromise their safety or compliance, preclude the successful conduct of  the study, or interfere with interpretation of the results (e.g., significant  pre-existing illness or other major comorbidities that the investigator considers may confound the interpretation of study results).

• Histologically confirmed invasive carcinoma of the breast of any of the following histologies (ductal, lobular, mammary, medullary, or tubular). Patients with metaplastic breast cancer are not eligible.
• Patients will be staged according to the TNM staging system.
• For patients not receiving neoadjuvant chemotherapy, pathologic staging must be T0N1-2a, T1N1-2a, T2N1-2a, T3N0-2a, and all M0 status.
• For patients receiving neoadjuvant chemotherapy, clinical pre-chemo staging and post mastectomy pathological staging is required for all patients. Patients who have received neoadjuvant chemotherapy and are pathologically cT0-2 and N0 are only eligible if biopsy-proven clinically N1 or N2 disease is documented prior to the start of neoadjuvant chemotherapy. cT3N0 patients or ypT3N0 patients who receive neoadjuvant chemotherapy may be eligible based on clinical or pathological T stage, and do not require pathologically positive lymph nodes.
  • Note: Higher of the clinical or pathological T and N stage are used for final staging, if receiving neoadjuvant chemotherapy.
• All patients with clinical, radiographic or pathological T4, N3 or involved internal mammary disease (N1b, N1c, and N2b) are not eligible.
• No prior therapeutic radiation therapy to the chest, neck or axilla. Prior radioactive oral iodine is permitted.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed.
• No active collagen vascular diseases, such as: systemic lupus erythematous, scleroderma, or dermatomyositis.
• Negative inked histologic margins from mastectomy pathology (no invasive cells at margin).
• No significant post mastectomy complications in the ipsilateral or contralateral breast requiring an unplanned re-operation or admission for IV antibiotics. Re-operation for margins evaluation, nodal completion and routine reconstruction is acceptable.
• Radiation oncologist intends to treat all target volumes and respect all normal tissues in accordance with the dosimetric constraints described (simulation before registration recommended).
• Radiation oncologist is planning to treat regional lymph nodes including internal mammary nodes and meet acceptable protocol dosimetric requirements.
• Radiation oncologist is NOT planning to utilize a chest wall/scar boost.
• Patient must have undergone immediate reconstruction at the time of mastectomy or be planning to undergo reconstruction within 18 months after radiation.
• If a tissue expander is utilized it needs to be a fluid filled expander, NO air expander (unless completely deflated) during radiation therapy.
• For patients with diabetes, hemoglobin A1C test must have been performed ≤ 90 days prior to registration.
• No co-existing medical conditions with life expectancy < 5 years.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix.
• Negative serum or urine β-HCG in women of child-bearing potential ≤7 days prior to registration.
• A female of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 12 consecutive months.
• Women of child-bearing potential must agree to utilize a form of birth control or agree to undergo sexual abstinence during radiation therapy.
• ECOG (Zubrod) Performance Status 0-1
• Patient ≥ 18 years of age
• Patients must be able to read and comprehend English, in order to be able to complete study questionnaires. However, patients participating through CCTG institutions who can read and comprehend French are eligible.

• None.

• Histologically confirmed invasive carcinoma of the breast of any of the following histologies (ductal, lobular, mammary, medullary, or tubular). Patients with metaplastic breast cancer are not eligible.
• Patients will be staged according to the TNM staging system.
• For patients not receiving neoadjuvant chemotherapy, pathologic staging must be T0N1-2a, T1N1-2a, T2N1-2a, T3N0-2a, and all M0 status.
• For patients receiving neoadjuvant chemotherapy, clinical pre-chemo staging and post mastectomy pathological staging is required for all patients. Patients who have received neoadjuvant chemotherapy and are pathologically cT0-2 and N0 are only eligible if biopsy-proven clinically N1 or N2 disease is documented prior to the start of neoadjuvant chemotherapy. cT3N0 patients or ypT3N0 patients who receive neoadjuvant chemotherapy may be eligible based on clinical or pathological T stage, and do not require pathologically positive lymph nodes.
  • Note: Higher of the clinical or pathological T and N stage are used for final staging, if receiving neoadjuvant chemotherapy.
• All patients with clinical, radiographic or pathological T4, N3 or involved internal mammary disease (N1b, N1c, and N2b) are not eligible.
• No prior therapeutic radiation therapy to the chest, neck or axilla. Prior radioactive oral iodine is permitted.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed.
• No active collagen vascular diseases, such as: systemic lupus erythematous, scleroderma, or dermatomyositis.
• Negative inked histologic margins from mastectomy pathology (no invasive cells at margin).
• No significant post mastectomy complications in the ipsilateral or contralateral breast requiring an unplanned re-operation or admission for IV antibiotics. Re-operation for margins evaluation, nodal completion and routine reconstruction is acceptable.
• Radiation oncologist intends to treat all target volumes and respect all normal tissues in accordance with the dosimetric constraints described (simulation before registration recommended).
• Radiation oncologist is planning to treat regional lymph nodes including internal mammary nodes and meet acceptable protocol dosimetric requirements.
• Radiation oncologist is NOT planning to utilize a chest wall/scar boost.
• Patient must have undergone immediate reconstruction at the time of mastectomy or be planning to undergo reconstruction within 18 months after radiation.
• If a tissue expander is utilized it needs to be a fluid filled expander, NO air expander (unless completely deflated) during radiation therapy.
• For patients with diabetes, hemoglobin A1C test must have been performed ≤ 90 days prior to registration.
• No co-existing medical conditions with life expectancy < 5 years.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix.
• Negative serum or urine β-HCG in women of child-bearing potential ≤7 days prior to registration.
• A female of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 12 consecutive months.
• Women of child-bearing potential must agree to utilize a form of birth control or agree to undergo sexual abstinence during radiation therapy.
• ECOG (Zubrod) Performance Status 0-1
• Patient ≥ 18 years of age
• Patients must be able to read and comprehend English, in order to be able to complete study questionnaires. However, patients participating through CCTG institutions who can read and comprehend French are eligible.

• None.

• Histologically confirmed invasive carcinoma of the breast of any of the following histologies (ductal, lobular, mammary, medullary, or tubular). Patients with metaplastic breast cancer are not eligible.
• Patients will be staged according to the TNM staging system.
• For patients not receiving neoadjuvant chemotherapy, pathologic staging must be T0N1-2a, T1N1-2a, T2N1-2a, T3N0-2a, and all M0 status.
• For patients receiving neoadjuvant chemotherapy, clinical pre-chemo staging and post mastectomy pathological staging is required for all patients. Patients who have received neoadjuvant chemotherapy and are pathologically cT0-2 and N0 are only eligible if biopsy-proven clinically N1 or N2 disease is documented prior to the start of neoadjuvant chemotherapy. cT3N0 patients or ypT3N0 patients who receive neoadjuvant chemotherapy may be eligible based on clinical or pathological T stage, and do not require pathologically positive lymph nodes.
  • Note: Higher of the clinical or pathological T and N stage are used for final staging, if receiving neoadjuvant chemotherapy.
• All patients with clinical, radiographic or pathological T4, N3 or involved internal mammary disease (N1b, N1c, and N2b) are not eligible.
• No prior therapeutic radiation therapy to the chest, neck or axilla. Prior radioactive oral iodine is permitted.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed.
• No active collagen vascular diseases, such as: systemic lupus erythematous, scleroderma, or dermatomyositis.
• Negative inked histologic margins from mastectomy pathology (no invasive cells at margin).
• No significant post mastectomy complications in the ipsilateral or contralateral breast requiring an unplanned re-operation or admission for IV antibiotics. Re-operation for margins evaluation, nodal completion and routine reconstruction is acceptable.
• Radiation oncologist intends to treat all target volumes and respect all normal tissues in accordance with the dosimetric constraints described (simulation before registration recommended).
• Radiation oncologist is planning to treat regional lymph nodes including internal mammary nodes and meet acceptable protocol dosimetric requirements.
• Radiation oncologist is NOT planning to utilize a chest wall/scar boost.
• Patient must have undergone immediate reconstruction at the time of mastectomy or be planning to undergo reconstruction within 18 months after radiation.
• If a tissue expander is utilized it needs to be a fluid filled expander, NO air expander (unless completely deflated) during radiation therapy.
• For patients with diabetes, hemoglobin A1C test must have been performed ≤ 90 days prior to registration.
• No co-existing medical conditions with life expectancy < 5 years.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix.
• Negative serum or urine β-HCG in women of child-bearing potential ≤7 days prior to registration.
• A female of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 12 consecutive months.
• Women of child-bearing potential must agree to utilize a form of birth control or agree to undergo sexual abstinence during radiation therapy.
• ECOG (Zubrod) Performance Status 0-1
• Patient ≥ 18 years of age
• Patients must be able to read and comprehend English, in order to be able to complete study questionnaires. However, patients participating through CCTG institutions who can read and comprehend French are eligible.

• None.

STEP 1:

• Patients must have histologically confirmed T1N1-3M0 or T2-3N0-2M0 esophageal or gastroesophageal junctional adenocarcinoma (Siewert I and II).
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Patents must be deemed a surgical candidate by a thoracic surgeon, surgical oncologist, or surgeon who is qualified to perform an esophagectomy.
• Absolute neutrophil count ≥ 1,500/mcL (within less than or equal to 14 days prior to randomization).
• Platelets ≥ 100,000/mcL (within less than or equal to 14 days prior to randomization).
• Total bilirubin ≤ institutional upper limit of normal (ULN) (within less than or equal to 14 days prior to randomization).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional ULN (within less than or equal to 14 days prior to randomization).
• Serum creatinine ≤ 1.5 x institutional ULN (within less than or equal to 14 days prior to randomization).
• Hemoglobin (Hgb) ≥ 9 g/dL (within less than or equal to 14 days prior to randomization).
• Leukocytes ≥ 3,000/mm^3 (within less than or equal to 14 days prior to randomization).
• Patients may not have received prior chemotherapy or radiation therapy for management for this malignancy.
• Patients may not have received prior immunotherapy for management of this malignancy or for any other past malignancy.
• Patients must have no contraindication to receiving either carboplatin or paclitaxel chemotherapy.
• Patients must have no contraindication to receiving radiation therapy.
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue disease, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
• Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event).
• Patient must NOT have previous or concurrent malignancy. Exceptions are made for patients who meet any of the following conditions:
  • Non-melanoma skin cancer, in situ cervical cancer, superficial bladder cancer, or breast cancer in situ; OR
  • Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years; OR
  • Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years.
• Date of last evidence of disease.
• Patients must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses =< 10 mg/day prednisone equivalents are permitted in the absence of active autoimmune disease.
• Adequate cardiac function including electrocardiogram (EKG) and echocardiogram for any patient with a history of congestive heart failure (CHF) or at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs.
• For patients with evidence of CHF, myocardial infarction (MI), cardiomyopathy, or myositis, cardiac evaluation including lab tests and cardiology consultations including EKG, creatine phosphokinase (CPK), troponin, and echocardiogram.
• Patients must not have a positive test result for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection. Testing should be conducted to determine eligibility.
• Patients with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) must have no detectable viral load on a stable anti-viral regimen.
• Patients must not be receiving any other investigational agents.
• Patients with an uncontrolled intercurrent illness such as ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements will be excluded.
• Women must not be pregnant or breast-feeding due to potential harm to the fetus from carboplatin, paclitaxel, or nivolumab. All females of childbearing potential must have a blood test or urine study done within 2 weeks prior to registration to rule out pregnancy. Those enrolled on Arm B with nivolumab must agree to have a pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours of starting nivolumab to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Women of childbearing potential (WOCBP) and sexually active males must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both double barrier contraception and birth control pills or implants for at least one month (female patients) or one week (male patients) prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for female patients) and for 7 months after the last dose of study drug (for male patients who are sexually active with WOCBP). Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
• If patient says 'Yes' to "I choose to take part in the imaging study and will have the diffusion weighted magnetic resonance imaging (MRI) scans": patients must be able to tolerate MRI scans:
  • No history of untreatable claustrophobia;
  • No magnetic resonance (MR) incompatible implants/devices or metallic foreign bodies;
  • Weight compatible with limits imposed by the MRI scanner table.

STEP 2:

• Patient registration must not exceed 12 weeks from time of esophagectomy.
• Patients must have a post-operative ECOG performance status of 0-2
• Absolute neutrophil count ≥ 1,500/mcL (within less than or equal to 14 days prior to randomization).
• Platelets ≥ 100,000/mcL (within less than or equal to 14 days prior to randomization).
• Total bilirubin ≤ institutional upper limit of normal (ULN) (within less than or equal to 14 days prior to randomization).
• AST (SGOT)/ ALT (SGPT) ≤ 2.5 x institutional ULN (within less than or equal to 14 days prior to randomization).
• Serum creatinine ≤ 1.5 x institutional ULN (within less than or equal to 14 days prior to randomization).
• Patients must be disease free following esophagectomy as is demonstrated by having no evidence of disease on a post-surgical computed tomography (CT) scan. Patients must also have a negative surgical margin (R0 resection).
• Patients must not have an active, known or suspected autoimmune disease or a condition requiring treatment with steroids or immunosuppressive agents. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Patients must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalents) or other immunosuppressive medications with 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg/day prednisone equivalents are permitted in the absence of active autoimmune disease.
• Patients must not be receiving any other investigational agents.
• Patients with an uncontrolled intercurrent illness such as ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements will be excluded.
• Women must not be pregnant or breast-feeding due to potential harm to the fetus from nivolumab or ipilimumab. All females of childbearing potential must have a blood test or urine study done (minimum sensitivity 25 IU/L or equivalent units of HCG) within 2 weeks prior to registration to rule out pregnancy. All patients must also agree to have a pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours of starting nivolumab to rule out pregnancy. Those enrolled on Arm D with ipilimumab must agree to have pregnancy tests within 72 hours of each ipilimumab administration to rule out pregnancy.
• Women of childbearing potential (WOCBP) and sexually active males must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both double barrier contraception and birth control pills or implants for at least one month (female patients) or one week (male patients) prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for female patients) and for 7 months after the last dose of study drug (for male patients who are sexually active with WOCBP). Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy.

Eligibility last updated 1/6/22. Questions regarding updates should be directed to the study team contact.

• Subject has histologically confirmed diagnosis of advanced (loco-regionally recurrent and not amenable to curative therapy, or metastatic (stage IV)) TNBC.
• Subject has either a measurable disease per RECIST 1.1 criteria or, if no measurable disease is present, then at least one predominantly lytic bone lesion or mixed lytic-blastic bone lesion with identifiable soft tissue component (that can be evaluated by CT/MRI) must be present Part B1: patients must have measurable disease.
• Subject has adequate tumor tissue to identify the PIK3CA mutation status (either carrying a mutation or without a mutation) and the PTEN loss status; both of which will determine whether the subject can be allocated to Part A
• PIK3CA mutation regardless of PTEN status; or to Part B.
• PTEN loss without a PIK3CA mutation.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Subject has received no more than one line of therapy for metastatic disease.
• Subject has adequate bone marrow and organ function

• Subject has received prior treatment with any PI3K, mTOR or AKT inhibitor.
• Subject has a known hypersensitivity to alpelisib, nab-paclitaxel or to any of their excipients.
• Subject has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤ 1; with the exception of alopecia.
• Subject has central nervous system (CNS) involvement.
• Subject with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on Fasting Plasma Glucose and HbA1c.
• Subject has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) based on investigator discretion.
• Subject has a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
• Subject has currently documented pneumonitis/interstitial lung disease.
• Subject has a history of severe cutaneous reactions, such as Steven-Johnson Syndrome (SJS), erythema multiforme (EM),Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS).
• Subject with unresolved osteonecrosis of the jaw.
• Other protocol-defined inclusion/exclusion criteria apply.

Inclusion Criteria
•STRIVE Platform:

• Age ≥ 18 years.
• Informed consent for trial participation.
• Hospital admission (or boarding in an emergency department or other area awaiting hospital admission) with signs and/or symptoms of a respiratory infection.

Exclusion Criteria
•STRIVE Platform:

• The patient is expected to be discharged from the hospital within the next 24 hours.
• Medical condition other than the acute respiratory infection (and its manifestations) that is likely to result in death within 7 days of randomization.
• Moribund condition, defined as prior cardiac arrest during this hospitalization and life expectancy less than 48 hours of randomization.
• Patient undergoing comfort care measures only such that treatment focuses on end-of-life symptom management over prolongation of life.
• Expected inability or unwillingness to participate in study procedures.
• In the opinion of the investigator, participation in a trial is not in the best interest of the patient.

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

Eligibility last updated 11/9/22. Questions regarding updates should be directed to the study team contact.

1. Signed informed consent by the parent(s) or legally designated representative and assent from developmentally capable children prior to initiation of any study-mandated procedure.
2. Males or females between ≥ 2 years and < 18 years of age.
3. Subjects with body weight ≥ 10 kg at randomization.
4. Pulmonary arterial hypertension (PAH) diagnosis, confirmed by historical right heart catheterization (mPAP ≥ 25 mmHg, and PAWP ≤ 15 mmHg, and PVRi > 3 WUxm2).
5. PAH belonging to the Nice 2013 Updated Classification Group 1 (including subjects with Down syndrome) and of following etiologies:
   • idiopathic PAH
   • heritable PAH
   • PAH associated with congenital heart disease (CHD)
   • Drug or toxin induced PAH
   • PAH associated with HIV
   • PAH associated with connective tissue diseases (PAH-aCTD)
6. WHO Functional class I to III.
7. Females of childbearing potential must have a negative pregnancy test at Screening and at Baseline, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) up to the end of study (EOS).

1. Subjects with PAH due to portal hypertension, schistosomiasis, or with pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn.
2. Subjects with PAH associated with Eisenmenger syndrome, or with moderate to large left-to-right shunts.
3. Subjects receiving a combination of > 2 PAH-specific treatments at randomization.
4. Treatment with i.v. or s.c. prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing.
5. Hemoglobin or hematocrit <75% of the lower limit of normal range
6. Serum AST and/or ALT > 3 times the upper limit of normal range'
7. Pregnancy (including family planning) or breastfeeding.
8. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

• Patients aged 6 or older that have completed participation on active drug and demonstrated adequate safety and meaningful clinical benefit (efficacy) in a previous setmelanotide study for obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway.
  • Note: The index study may have a primary endpoint relied on efficacy, safety or tolerability. Patient will be eligible for extension study if the Primary Investigator believes the patient exhibited a clinically meaningful benefit (i,e, efficacy) to setmelanotide treatment, and would benefit from continued treatment, after discussion with the Sponsor.
• Study participant and/or parent or guardian is able to communicate well with the investigator, to understand and comply with the requirements of the study, and to understand and sign the written informed consent/assent. The patient must assent/consent to participate in the trial.
• Female participants of child-bearing potential must agree to use contraception as outlined in the protocol.
• Female participants of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), post-menopausal for at least 12 months (and confirmed with a screening FSH level in the postmenopausal lab range), or have delayed pubertal development and failure to have achieved menarche, do not require contraception during the study.
• Any female participant in this latter category of having failed to reach menarche upon study entry and who now suspects this status may have changed should promptly inform the investigator and undergo pregnancy testing. All patients must agree to follow requirements for contraception.

• Pregnant and/or breastfeeding women.
• Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a screening comprehensive skin evaluation performed by a qualified dermatologist. Any concerning lesions identified during the screening period will be biopsied and results known to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient may need to be excluded from the study.
• Patient is, in the opinion of the Study Investigator, not suitable to participate in the study. In addition, any patient who experiences a gap in treatment of at least one month between completing the Index study and Screening for this study, should have the following exclusion criteria evaluated:
• Current, clinically significant disease, if severe enough to interfere with the study and/or would confound the results. Any such patients should be discussed with the Sponsor prior to inclusion.
• Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders (DSM-III) disorders that the investigator believes will interfere significantly with study compliance.
• A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.
• Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS). Any lifetime history of a suicide attempt, or any suicidal behavior in the last month.
  • Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant neurocognitive defects may be enrolled in the study, as long as in the opinion of the Primary Investigator there are no clinical signs or symptoms of suicidal behavior.
• History of significant liver disease or liver injury, or a current liver assessment due to abnormal liver tests (as indicated by abnormal liver function tests, alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin > 1.5 × the upper limit of normal [ULN] for any of these tests) for an etiology other than non-alcoholic fatty liver disease (NAFLD). Thus, any underlying etiology besides NAFLD, including diagnosed non-alcoholic steatohepatitis (NASH), other causes of hepatitis, or history of hepatic cirrhosis is exclusionary, but the presence of NAFLD is not be exclusionary.
• Moderate to severe renal dysfunction as defined by a glomerular filtration rate (GFR) < 30 mL/min.
• History or close family history (parents or siblings) of skin cancer or melanoma (not including non-invasive/infiltrative basal or squamous cell lesion), or patient history of ocular-cutaneous albinism.

• Subjects with new-onset or relapsing/refractory GCA. 
• Westergren erythrocyte sedimentation rate > 30 mm/hour or c-reactive protein ≥ 1 mg/ dL. 
• Remission of GCA at or before Day 0. 
• Female subjects must be postmenopausal or permanently sterile following documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or tubal ligation or having a male partner with vasectomy as affirmed by the subject, or nonpregnant, nonlactating, and, if sexually active, having agreed to use a highly effective method of contraception. 
• Male subjects must have documented vasectomy or if sexually active must agree to use a highly effective method of contraception with their partners of childbearing potential.

• Transplanted organs (except corneal transplant performed more than 3 months prior to randomization). 
• Concurrent enrollment in another interventional clinical study. 
• Treatment with non-biologic investigational drug therapy within 4 weeks or 5 half-lives of the study agent, whichever was longer, prior to screening. 
• Cell-depleting biological therapies within 12 months prior to Day 0, or noncell-depleting biological therapies within 8 weeks (or 5 half-lives, whichever is longer) prior to screening.
• Treatment with alkylating agents within 12 weeks prior to screening. 
• Intramuscular, Intra-articular or IV corticosteroids within 4 weeks prior to screening.
• Receipt of live (attenuated) vaccine within the 4 weeks before Day 0. 
• Treatment with hydroxychloroquine, cyclosporine A, azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks of screening. 
• Female subjects who are pregnant, intending to become pregnant, or are breastfeeding. 
• Known history of allergy or reaction to any component of the mavrilimumab or placebo formulation or to any other biologic therapy or prednisone or any of its excipients. 
• Positive (or 2 indeterminate) QuantiFERON test results. 
• Clinically significant active infection or infection requiring hospitalization or IV antibiotics within 12 weeks before screening or opportunistic infection within 6 months before screening. 
• Chronic active hepatitis B infection. 
• Subjects at a high risk of infection, a history of an infected joint prosthesis still in situ, leg ulcers, indwelling urinary catheter, or persistent or recurrent chest infections. 
• History of cancer within the last 10 years, except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured. 
• Evidence of clinically-uncontrolled respiratory disease. 
• History of chronic respiratory tract infections.