• Age ≥ 11 years of age.
• Weight ≥ 40 kg.
• Scheduled complex cardiac surgery with planned use of median sternotomy. The procedure may be performed either on-pump or off-pump. For the purposes of this protocol "Repeat procedure" means that the subject had a previous cardiac surgery with median sternotomy. Procedures that qualify as complex cardiac surgery include the following:
  • Single Vessel Coronary Artery Bypass Graft, repeat procedure;
  • Multiple Coronary Artery Bypass Grafts, first or repeat procedure;
  • Single Valve Repair or Replacement, repeat procedure;
  • Multiple Valve Repair or Replacement, first or repeat procedure;
  • Surgery involving both Coronary Artery Bypass Graft(s) and Valve Repair(s), first or repeat procedure.
• One or more of the following procedures, with or without Coronary Bypass Graft(s): 
  • Left ventricular aneurysm repair;
  • Ventricular and/or atrial septal defect repairs;
  • Batista procedure (surgical ventricular remodeling);
  • Surgical ventricular restoration;
  • Congenital defect repair;
  • Aortic root procedures. 
• TRUST probability score (Alghamdi, Davis et al. 2006) ≥ 3, or currently on a regimen of aspirin, clopidogrel (or analogs) and/or GPIIb/IIIa inhibitors. 
• Female subjects of child-bearing potential must meet the 2 criteria below: 
  • Have negative serum or urine pregnancy tests prior to study treatment to rule out pregnancy;
  • Use at least one method of birth control that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner.
• Signed and dated informed consent form.

• Confirmed positive baseline serum/plasma antibody specific to IBS RBC (S-303 treated RBC) as determined by IBS RBC antibody screening panel prior to randomization.
• Pregnant or breast feeding.
• Refusal of blood products or other inability to comply with the protocol in the opinion of the Investigator or the treating physician.
• Treatment with any medication that is known to adversely affect RBC viability, such as, but not limited to dapsone, levodopa, methyldopa, nitrofurantoin, and its derivatives, phenazopyridine and quinidine.
• Planned surgery is minimally invasive.
• Planned cardiac transplantation.
• Active autoimmune hemolytic anemia.
• Left ventricular assist device (LVAD) or extracorporeal membrane oxygenation (ECMO) support pre-operatively or planned need post-operatively.
• Cardiogenic shock requiring pre-operative placement of an intra-aortic balloon pump (IABP).
  • NOTE: IABP done for unstable angina or prophylactically for low ejection fraction is not excluded.
• Planned use of autologous or directed donations.
• RBC transfusion during current hospitalization prior to enrollment and randomization (within 14 days).
• Participation in any one of the following types of clinical studies either concurrently or within the previous 28 days: investigational blood products, pharmacologic agents or imaging materials, including dyes, investigational surgical techniques, or devices. Studies of nutrition, psychology, or socioeconomic issues are not grounds for exclusion.
• Current diagnosis of either chronic kidney disease or acute kidney injury and with sCr ≥ 1.8 mg/dL at screening or requiring RRT.
• Current diagnosis of either chronic or acute hepatic insufficiency and with a total serum bilirubin greater than or equal to 2.0 mg/dL (≥ 34.2 μmol/L) at screening.
• Pre-existing antibody to RBC antigens that may make the provision of compatible study RBC components difficult.
• History of transfusion reactions requiring washed RBCs, volume reduced RBC, or RBCs with additive solution removed.
• Patients with documented IgA deficiency or a history of severe allergic reactions to blood products.
• Patients who require gamma-irradiated RBC blood components.
• Positive DAT as defined below:
  • A polyspecific DAT reaction strength > 2+; or
  • A polyspecific DAT (any strength) in conjunction with pan-reactivity with a commercial IAT antibody screening panel that precludes the identification of underlying alloantibodies or indicates the presence of autoantibody.

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

Eligibility last updated 3/28/23. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 7/8/22. Questions regarding updates should be directed to the study team contact.

• Subjects male or female aged 2 to 17 years, inclusive, who weigh ≥ 10 kg at the time of screening and enrollment into the study.
• Subjects with moderately to severely active CD diagnosed at least 1 month before screening, defined by a PCDAI > 30 and an SES-CD > 6 (or an SES-CD ≥ 4 if disease is confined to terminal ileum).
• Subjects who have failed, lost response to, or been intolerant to treatment with at least 1 of the following agents:
  • corticosteroids, immunomodulators (eg, AZA, 6-mercaptopurine, methotrexate), and/or TNF-α antagonist therapy (e.g., infliximab, adalimumab). This includes subjects who are dependent on corticosteroids or exclusive or partial enteral nutrition to control symptoms and who are experiencing worsening of disease in the moderate-to-severe range when attempting to wean off corticosteroids or discontinue exclusive enteral nutrition.
• Subjects with extensive colitis or pancolitis of > 8 years’ duration or left-sided colitis of > 12 years’ duration must have documented evidence of a negative surveillance colonoscopy within 12 months before screening.
• Subjects with vaccinations that are up-to-date based on the countrywide accepted schedule of childhood vaccines.

• Subjects who have had previous exposure to approved or investigational anti-integrins, including but not limited to natalizumab, efalizumab, etrolizumab, or AMG 181, or mucosal addressin cell adhesion molecule-1 (MAdCAM-1) antagonists or rituximab.
• Subjects who have had prior exposure to vedolizumab.
• Subjects with hypersensitivity or allergies to any of the vedolizumab excipients.
• Subjects who have received either:
  • an investigational biologic within 60 days or 5 half-lives before screening (whichever is longer); or
  • an approved biologic or biosimilar agent within 2 weeks before the first dose of study drug or at any time during the screening period.
• Subjects with active cerebral/meningeal disease, signs/symptoms or history of progressive multifocal leukoencephalopathy (PML) or any other major neurological disorders including stroke, multiple sclerosis, brain tumor or neurodegenerative disease.
• Subjects who currently require surgical intervention or are anticipated to require surgical intervention for CD during this study.
• Subjects who have had subtotal or total colectomy or have a jejunostomy, ileostomy, colostomy, ileo-anal pouch, known fixed stenosis of the intestine, short bowel syndrome, or > 3 small intestine resections.
• Subjects with a current diagnosis of indeterminate colitis.
• Subjects with clinical features suggesting monogenic very early-onset inflammatory bowel disease.

PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA

• Pathologically (histologically or cytologically) confirmed diagnosis of epithelioid or biphasic malignant pleural mesothelioma (MPM) within 90 days prior to Step 1 Registration -Imaging proof of clinical stage (American Joint Committee on Cancer [AJCC] 8th edition) I-IIIA MPM by PET/CT within 42 days prior to Step 1 Registration.
• MPM is amenable to resection by P/D as determined by a thoracic surgeon within 42 days prior to Step 1 Registration.
• History/physical examination within 42 days prior to Step 1 Registration.
• Karnofsky performance status ≥ 80 within 42 days prior to Step 1 Registration.
• Pulmonary function tests within 42 days prior to Step 1 Registration:
  • ≥ 40% predicted post-forced expiratory volume in 1 second (FEV1);
  • ≥ 40% predicted post-operative diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin [Hgb]).
• Leukocytes ≥ 3000 cells/mm^3 (within 30 days prior to Step 1 Registration).
• Absolute neutrophil count ≥ 1500 cells/mm^3 (within 30 days prior to Step 1 Registration).
• Platelets ≥ 100,000 cells/mm^3 (within 30 days prior to Step 1 Registration)..
• Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) (within 30 days prior to Step 1 Registration).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine a minotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 X ULN (within 30 days prior to Step 1 Registration).
• Glomerular filtration rate (GFR): ≥ 50 mL/min/1.73 m^2 (must be calculated using estimated creatinine clearance [CrCl] by the Cockcroft-Gault [C-G] equation [Nephron 1976;16:31-41]) (within 30 days prior to Step 1 Registration).
• Negative serum pregnancy test within 14 days of Step 1 Registration for pre-menopausal women of childbearing potential.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.
• EORTC QLQ-C30 and QLQ-LC13 within 42 days prior to Step 1 Registration.

PRIOR TO STEP 2 RANDOMIZATION INCLUSION CRITERIA

• Patients must have received at least 2 cycles of pemetrexed/platinum chemotherapy and undergone a pleurectomy/decortication with the goal of macroscopic complete resection following step 1 Registration.
• Karnofsky performance status ≥ 70 within 30 days prior to Step 2 Randomization.
• History/physical examination within 30 days prior to Step 2 Randomization.
• EORTC QLQ-C30 and QLQ-LC13 within 30 days prior to Step 2 Randomization.

PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA

• Pregnant or lactating women, or sexually active men or women not using effective contraception (risk for fetal defects from teratogenic chemotherapy and radiation therapy) within 14 days prior to Step 1 Registration
• Diagnosis of sarcomatoid mesothelioma.
• Severe, active co-morbidity defined as follows:
  • New York Heart Association (NYHA) class III or IV heart failure;
  • Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are allowed;
  • Unstable angina requiring hospitalization and/or transmural myocardial infarction within the last 3 months;
  • Interstitial lung disease;
  • Hemodialysis or peritoneal dialysis;
  • Concurrent active malignancy (with the exception of current or prior non-melanomatous skin cancer or low-grade malignancies followed observantly for which treatment has not or does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen).
• If evidence of disease < 3 years, institution must consult with the principal investigator, Andreas Rimner, Doctor of Medicine (MD)
• Hepatic impairment defined by ChildPugh class (ChildPugh class B & C);
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy within 30 days prior to registration, if indicated.
  • Note: HBV viral testing is not required for eligibility for this protocol.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured.
• For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 30 days prior to registration.
• Active tuberculosis.
• Patients on immunosuppressive therapy, for example history of organ or bone marrow transplant or chronic lymphocytic leukemia (CLL).
• CD4 count < 200 cells/microliter.
  • Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count  200 cells/microliter within 30 days prior to registration.
  • Note also that HIV testing is not required for eligibility for this protocol.
• Prior nephrectomy on the contralateral side of MPM.
• Ipsilateral thoracic electronic implant; e.g., pacemaker, defibrillator, unless switched to the contralateral side prior to initiation of radiation therapy (RT).
• Prior thoracic radiation therapy (patients with prior thoracic RT cannot be planned to 50-60 Gy without exceeding normal tissue constraints).

PRIOR TO STEP 2 RANDOMIZATION EXCLUSION CRITERIA

• Progressive disease.
• Supplemental oxygen use.
• Third space fluid that cannot be controlled by drainage or insufficient lung expansion after P/D (this prevents targeting the pleura without exceeding normal tissue constraints).
• Prior intrapleural therapy (i.e., intrapleural chemotherapy, photodynamic therapy); pleurodesis is permitted.
• Bulky residual disease in the major fissure preventing pleural IMRT.
• Patients who have undergone extrapleural pneumonectomy.
• Patients with active infection that requires systemic I.V. antibiotics, antiviral, or antifungal treatments.

Inclusion Criteria: 

• Under-represented minority (Black/African American, Native Hawaiian/Pacific Islander, Native American/Alaska native, more than 1 race, and Hispanic/LatinX).
• Received cancer care on an interventional treatment clinical trial at Mayo Clinic (enterprise-wide) between 2018-2020. 
• Consent to participate (for the survey and interview components).

• No specific exclusion criteria. 

• Patients age 4 -100 already scheduled to have a clinically indicated 12-lead ECG,  who are also seen in the Genetic Heart Rhythm Clinic may be included in the study. This will also include the potential to enroll age- and sex-matched patients who do not have LQTS (i.e. controls for the purpose of this study) who are also scheduled for a 12-lead ECG in either the Gonda subway, Baldwin building, or Saint Marys Hospital as part of their clinical care.
• Family members age 4-100 without a 12-lLead ECG, who are present at the Genetic Heart Rhythm clinic without consultation.

• Patients without the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study

• Signed and dated informed consent form.
• Male and female subjects from 18 to 85 years old (inclusive).
• With established diagnosis of inoperable CTEPH (i.e., technically non-operable) or persistent/recurrent CTEPH after pulmonary endarterectomy (PEA) and/or balloon pulmonary angioplasty (BPA), as confirmed by the corresponding adjudication committee.
• With pulmonary hypertension (PH) in WHO FC I-IV.
• Subject able to perform the 6-minute walk test (6MWT) with a minimum distance of 100 m and a maximum distance of 450 m at screening visit.
• Women of childbearing potential must have a negative pregnancy test at screening and randomization and must agree to undertake monthly urine pregnancy tests, and to use a reliable method of birth control from screening visit up to at least 30 days after study treatment discontinuation. If a hormonal contraceptive is chosen it must be taken for at least 1 month prior to randomization.

• Planned or current treatment with another investigational treatment up to 3 months prior to randomization.
• Any co-morbid condition that may influence the ability to perform a reliable and reproducible 6MWT, including use of walking aids (cane, walker, etc.).  If a patient uses a walking aid from time to time but does not have any co-morbid condition, and is able to perform a reliable and reproducible 6MWT on their own (i.e., without any walking aids), then they can be included.
• Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation.
• Known concomitant life-threatening disease with a life expectancy <12 months.

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

Eligibility last updated 4/26/23. Questions regarding updates should be directed to the study team contact.

• Must either be currently receiving treatment with, or have a history of having failed to respond to, or have a medical contraindication to at least 1 of the following therapies: oral or intravenous corticosteroids, 6-mercaptopurine, methotrexate or azathioprine OR must either have or have had a history of corticosteroid dependency (that is an inability to successfully taper corticosteroids without a return of the symptoms of ulcerative colitis [UC]) OR required more than 3 courses of corticosteroids in the past year.
• Moderately to severely active UC (as defined by baseline Mayo score of 6 through 12 [endoscopy {sigmoidoscopy or colonoscopy} sub score assigned by local endoscopist], inclusive), including a (sigmoidoscopy or colonoscopy) sub score greater than or equal to (≥ 2).
• If receiving enteral nutrition, must have been on a stable regimen for at least 2 weeks prior to the first administration of study intervention at Week 0. Participants who receive parenteral nutrition are not permitted to enroll in the trial.
• No history of latent or active tuberculosis prior to screening.
• Acceptable evidence of immunity to measles, mumps, rubella, and varicella.

• History of liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric (including suicidality), or metabolic disturbances.
• History of malignancy or macrophage activation syndrome or hemophagocytic lymphohistiocytosis.
• Have UC limited to the rectum only or to < 20 percent (%) of the colon.
• Presence of a stoma.
• Presence or history of a fistula.
• Contraindications to the use of golimumab or infliximab or anti-tumor necrosis factor (TNF-alpha) therapy per local prescribing information.

• Patients must be English language proficient.
• Patients must be > 18 years old.
• Must be able to provide informed consent.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.

NAC Cohort

• Newly Diagnosed stage III or IV invasive serous ovarian cancer, grades 2, 3 or poorly differentiated. 

PD Cohort

• Patients with an 75% or greater probability of having advanced HGSC based on the clinical judgement of investigator after review of imaging and CA 125 values and who are schedule to undergo a PD surgery;
• Patients who have advanced HGSC confirmed at PD surgery and who undergo any attempt at surgical debulking will be considered eligible and enrolled in the PD cohort;
• Patients with advanced HGSC confirmed at surgery and undergo diagnostic biopsy only without any debulking will be considered eligible and enrolled into the NAC cohort;
• Patients who have benign ovarian disease confirmed at surgery will be considered eligible and enrolled as benign surgical controls (n=10 total). 

• Scheduled to receive i.v. or combined i.v./i.p. platinum and taxane combination chemotherapy with or without bevacizumab within 4 weeks of study enrollment.
• Patients must have Abdominal-Pelvic CT or MRI scan within 28 days of study enrollment
• Organ function must include the following pre-treatment parameters: 
  • white blood count (WBC) > 3,000/ul;
  • Hb > 9 gm/dl %;
  • Platelet count > 100,000/ul;
  • serum creatinine < 1.5 mg/dl;
  • serum albumin > 3.5 gm/dl;
  • serum total bilirubin < 1.5 mg/dl;
  • alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)/ alkaline phosphatase < 2 x ULN.

• Patients who have received treatment of any type including systemic chemotherapy, irradiation, hormonal treatment, immunotherapy, and/or debulking surgery for their ovarian cancer prior to study enrollment. 
• Non-HGSC including adenocarcinomas of mucinous, clear cell, endometrioid or low-grade serous histology.
• Borderline ovarian cancer of any histologic subtype.
• Unable to provide bio-specimens as required by the study protocol.
• Any medical conditions that increase risk of complications from a blood draw including hemophilia or other bleeding disorders or serious anemia.
• Currently pregnant.
• Inability to provide informed consent as assessed by the study investigator or research staff.
• Other active malignancy defined as any treatment for invasive cancer of any type (excluding hormone therapy) within the last 5 years.  Exemptions include localized cancers that are considered to be cured by local excision or destructive measures (eg, basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix).
• Concurrent participation in another research study is potentially allowed but requires formal PI review and approval to ensure it does not conflict with the goals of the current study. 

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

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

• Patients with gastroparesis or functional dyspepsia
• Age 18-70 years
• Patients will be identified from among Mayo Clinic patients.
• Patients will have symptoms consistent with gastroparesis based on a national guideline for gastroparesis (symptoms PLUS delayed gastric emptying of solids).
• Patients with Rome IV criteria for postprandial distress syndrome (a subset of functional dyspepsia) will be selected based on gastric emptying of solids which is NOT delayed, in addition to standard FD criteria:
  • Symptoms fulfilled for the last 3 months with onset greater than 6 months before diagnosis;
  • One or more symptoms being bothersome: postprandial fullness, early satiation, epigastric pain or burning;
  • Must include one or both of the following at least 3 days per week: bothersome postprandial fullness (i.e., severe enough to impact on usual activities) or bothersome early satiation (i.e., severe enough to prevent finishing a regular-size meal);
  • No evidence of organic, systemic, or metabolic disease to explain the symptoms on routine investigations;
  • Participants will have previously undergone test of gastric emptying of solids using the standardized Mayo Clinic scintigraphic method
• Ability to provide informed consent
• Absence of other diseases (structural or metabolic) which could interfere with interpretation of the study results
• Body mass index of 18-35 kg/m2
• Several medication classes, particularly those affecting gastrointestinal transit or motor functions, will be excluded, including GLP-1 receptor or amylin agonists in patients with diabetes mellitus. Stable doses of thyroid replacement, estrogen replacement, low-dose aspirin for cardioprotection, and birth control (but with adequate backup contraception, as drug interactions with birth control have not been conducted for secretin PAM) are permissible.

Exclusion Criteria:

• Patients with current H. pylori infection will be excluded.
• Pregnancy or lactation.
• Rapid metabolizers for CYP3A4 or CYP2C19 [estimated prevalence of 17% and 18% respectively based on literature review (36)] will be excluded since this could impact assessment of effects of cannabidiol.
• Patients with abnormal baseline liver transaminases (any value above UNL), since up to 3-fold, dose-related elevations of liver transaminases (ALT and/or AST) occur in 13% of treated patients (vs. 1% placebo).
• Hypersensitivity to cannabidiol or any of the ingredients in EPIDIOLEX.
• Concomitant use of valproate, CNS depressants and alcohol, other hepatotoxic drugs.
• The subject has HbA1c > 12%
• The subject is unable to withdraw any of the following medications listed in table 1a 48 hours prior to the study
• The subject has participated in another interventional clinical study within the past two weeks.
• History of recent surgery (within 60 days of screening)
• The subject has a history diagnosis of post-surgical gastroparesis
• A subject who in the determination of the investigator, possesses any condition that the investigator believes would put the subject at risk or would preclude the subject from successfully completing all aspects of the study.
• Concomitant use of CNS depressants and/or alcohol within 48 hours of GI testing, unless able to maintain a consistent dosage throughout the study.

Eligibility last updated 6/3/22. Questions regarding updates should be directed to the study team contact.

• Willing and able to provide signed informed consent at the screening visit as well as comply with all study visits and requirements through the end of the study.
• Male or female, age ≥ 18 years at the screening visit.
• Have a diagnosis of PBC in line with the AASLD guidelines as demonstrated by having at least 2 of the following (Lindor et al. 2019):
  • History of sustained increased ALP levels > ULN first recognized at least 6 months prior to the screening visit (sustained ALP elevations at the time of screening is not required, recognizing that the ALP may have decreased on UDCA therapy);
  • Documented positive AMA titer (> 1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay) or PBC-specific ANA immuno-fluorescence patterns (multiple nuclear dots and/or punctuate nuclear rim);
  • Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts. Liver biopsy could have been done at any time in the past.
• Those treated with UDCA will be allowed to enroll if they meet one of the following criteria at Visit 1:
  • A minimum of 8 weeks of stable treatment at a dose of ≤ 20 mg/kg/day; OR
  • A minimum of 8 weeks off treatment and consequently determined by the investigator to be clinically stable
• Systemic therapies intended to address cholestatic pruritus, specifically fibrates, SSRIs, rifampin/rifampicin, gabapentin, cholestyramine, and opioid-receptor antagonists are allowed if one of the following criteria is met at the screening visit:
  • A minimum of 8 weeks of stable treatment (12 weeks of stable treatment for cholestyramine) OR b. A minimum of 4 weeks off treatment.
• Average daily Adult ItchRO score ≥ 4 during screening to be enrolled in the study at Visit 2.
• Overall compliance of ≥ 80% in daily completion of the Adult ItchRO assessments during the screening period.
• To be eligible for randomization, participants must meet the following additional criteria specific to the 4-week, single-blind, placebo run-in period:
• Completion of ≥ 80% of Adult ItchRO assessments during the single-blind, placebo run‑in period.
• Study drug compliance of ≥ 80% during the single-blind, placebo run-in period

• Pruritus associated with an etiology other than PBC.
• Evidence or clinical suspicion of decompensated cirrhosis or a history of decompensation events (e.g., variceal bleeding, ascites, hepatic encephalopathy, hepatorenal syndrome).
• Current symptomatic cholelithiasis or inflammatory gallbladder disease. Those with history of cholecystectomy ≥ 3 months before the screening visit may be eligible for enrollment.
• History of small bowel surgery/resection impacting the terminal ileum (e.g., ileostomy, ileo-anal pouch, or other surgeries/conditions) that may disrupt the enterohepatic circulation.
• Evidence, history, or suspicion of other liver diseases, including but not limited to:
  • Active hepatitis A or E infection;
  • Active hepatitis B infection as defined by the presence of hepatitis B surface antigen (HBsAg) or presence of hepatitis B virus DNA;
  • c. Hepatitis C as defined by the presence of hepatitis C virus (HCV) antibody and positive HCV RNA. Infection documented to have been cured for >1 year prior to the screening visit may be eligible;
  • Secondary sclerosing cholangitis, autoimmune hepatitis, PSC, immunoglobulin G4-related cholangitis, Wilson disease, alpha-1-antitrypsin deficiency, or hemochromatosis;
  • Suspected or proven cholangiocarcinoma or hepatocellular carcinoma;
  • History of liver transplantation;
  • Histologically confirmed diagnosis of NASH;
  • Alcohol-related liver disease.
• Unstable and/or serious medical disease that is likely to impair the participant’s ability to participate in all aspects of the study, confound efficacy and/or safety assessments, or result in substantially shortened life expectancy (e.g., any active malignancy including hematological malignancy, end-stage heart failure, active infection, acute and chronic diarrhea):
  • Previous history of malignancy, adequately treated/in remission, that in opinion of investigator and medical monitor does not impact participant safety and participation in the study, may be allowed. The investigator should contact the sponsor medical monitor to discuss these cases and seek approval before the screening period.
• Moderate alcohol consumption as defined for this study by > 1 and > 2 standard drinks on average per day for women and men, respectively, within 24 weeks of screening visit. A standard drink is defined as 1.5 oz (one shot) of liquor, 5 oz of nonfortified wine, or 12 oz of beer (1 oz=29.57 mL; NIAAA).
• Drug abuse within the 24 weeks prior to, or a positive drug screening result, at the screening visit unless it can be explained by a drug prescription:
  • Use of cannabinoids (legal, prescribed, or otherwise) is allowed, provided use is stable for at least 12 weeks prior to screening and throughout the entire study.
• Women who are pregnant or nursing. Specific criteria for defining childbearing potential and acceptable methods of birth control are outlined in the protocol.
• Known intolerance/hypersensitivity to volixibat or its excipients.
• History of nonadherence to medical regimens, unreliability, medical condition, mental instability, or cognitive impairment that, in the opinion of the investigator, could compromise the validity of informed consent, compromise the safety of the participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures.
• Participation in an interventional clinical study within 4 weeks OR, if applicable, 5 times the half-life, whichever is greater, prior to the screening visit. Always adhere to other eligibility criteria that apply to specified concomitant medication.

Eligibility Criteria
•Open-Label Extension:

To maintain eligibility for the OLE, participants must:

• Have successfully completed the 24-week double-blind study drug treatment period.
• Have not experienced an AE(s) or SAE(s) related to volixibat during the double-blind study treatment period that led to permanent discontinuation.
• Have no changes in their medical condition or treatment that would preclude their participation in the LTE period at the discretion of the investigator or medical monitor.
• Complete ≥ 80% of Adult ItchRO assessments during the double-blind study treatment period.

Eligibility last updated 12/20/23. Questions regarding updates should be directed to the study team contact.

• Male or female age ≥ 18 years.
• Is able and willing to provide written informed consent, which includes compliance with study requirements and restrictions listed in the consent form.
• Have a ≥ 6-month history of documented sarcoidosis including histological confirmation in the subject’s medical records.
• Have high-resolution computed tomography (HRCT) and PET scan consistent with active pulmonary sarcoidosis of the lung parenchyma confirmed by central read.
• Have FVCp ≥ 50% to ≤ 90% and DLCO ≥ 50%.
• If receiving prednisone (or equivalent), dose must have been ≤25 mg, and dose must have been stable for at least 4 weeks prior to randomization.
• Symptomatic as indicated by mMRC Dyspnea scale >1 (i.e., Grade 2 or more) in the prior year.
• If receiving methotrexate and/or other immunosuppressive therapy (IST) dose must have been stable for ≥ 3 months prior to randomization.
• Female subjects must agree to use an approved highly effective birth control (BC) method (< 1% failure rate per year) throughout the study, unless documented to have a reproductive status of non-childbearing potential or is postmenopausal:
  • Non-childbearing potential defined as pre-menopausal female with medical history of bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries), or hysterectomy; hysteroscopic sterilization;
  • Postmenopausal defined as 12 months of spontaneous amenorrhea; otherwise, a follicle stimulating hormone (FSH) confirmation will be required. For females with questionable menopausal history (e.g., irregular menstrual periods and age > 40 years) a documented serum FSH level must be ≥ 30 mIU/mL;
  • Woman of childbearing potential (WCBP) who is already using an established method of highly effective contraception or agrees to use one of the allowed BC methods, for at least 28 days prior to the start of dosing, throughout the study, and for 4 months following the last dose of study drug.
• Males who are sexually active must agree to use one of the allowed BC methods. Male subjects must also agree to sufficiently minimize the risk of pregnancy throughout study participation (and for 4 months following the last dose of study drug).
• Body Mass Index (BMI) 18 to 40 kg/m^2 at screening.
• Subjects must agree to steroid taper, and cessation of their IST therapy at randomization.
• Completion of vaccination for COVID-19 at least 2 weeks prior to randomization.

Exlusion Criteria:

• Hospitalized for any respiratory illness ≤ 30 days prior to screening.
• Prednisone dose > 25 mg/day at any time in the previous 4 weeks.
• ≥ 20% fibrosis as indicated on CT-scan that has been confirmed by central read prior to randomization.
• eGFR ≤30 mL/min/1.73 m^2 (MDRD equation) or requiring hemofiltration or dialysis.
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 3 × upper limit of normal range (ULN).
• Platelet count <100,000 per mm^3.
• Hemoglobin ≤ 9.5 g/dL.
• Absolute neutrophil count < 1,000 per mm^3.
• History of known anti-GM-CSF autoAb or tests positive at screening, or history of pulmonary alveolar proteinosis (PAP).
• Use of biologic — approved or investigational agents (e.g., anti-TNFα, anti-IL-1, anti-IL-6, anti-IL-17, anti-IL-12/23 or specific anti-IL-23 inhibitors, anti CD20, anti-IL-18) within the 6 months prior to screening.
• Prior use of immunoglobulin within 6 months prior to screening.
• Prior use of any investigational immunomodulator (e.g., NRP2 modulator) within 6 months of screening.
• Prior use of any JAK inhibitor within 3 months of screening.
• Participation in another interventional clinical trial within 6 months prior to screening.
• Known left ventricular ejection fraction (LVEF) ≤30% or NYHA class III or IV heart failure.
• ECG abnormalities that warrant further investigation, in the opinion of the Investigator.
• Pulmonary hypertension requiring therapy.
• Systolic blood pressure (SBP)  < 90 or > 180 mm Hg; Diastolic blood pressure (DBP) < 60 or > 110 mm Hg.
• Known COVID-19 infection within 3 months prior to screening.
• Have received any live virus or bacterial vaccinations < 3 months of screening. Age-appropriate non-live vaccinations may be administered during screening so long as the last vaccine dose is administered at least 2 weeks prior to planned randomization.
• Any infection requiring antibiotics or pulse of OCS where completion of treatment has been < 30 days prior to screening.
• History of 3 or more lower respiratory tract infections requiring anti-microbial therapy in the past year.
• Any history of mycetoma or fungal respiratory infection.
• Requirement for supplemental oxygen at rest.
• Prior history of, or likely to have any organ transplantation during study including OLE.
• History of smoking (or vaping) in the prior year or current use. Occasional use (defined as less frequently than once per month) is allowable, though subjects should be counseled to remain abstinent during the study including OLE.
• Other significant pulmonary disease likely to interfere with the primary endpoint, in the opinion of the Investigator.
• Other autoimmune disease likely to require therapy during the study.
• Symptoms and features of extra-PS that may warrant treatment in addition to that required for lung involvement.
• Significant ischemic heart disease (i.e., myocardial infarction within 6 months, unstable angina or PCTA/stent within 1 month or planned intervention during study).
• Known or suspected active and untreated/inadequately treated tuberculosis (TB), human immunodeficiency virus (HIV), hepatitis B or C infection. Subjects with latent TB may be enrolled if anti-TB therapy is commenced prior to randomization.
• For women: pregnant or planning to become pregnant during the study or currently breastfeeding.
• Prior history of any malignancy or lymphoproliferative disorder (not including fully resected basal cell carcinoma of the skin, fully resected intra-epithelial neoplasia or carcinoma in situ) within the past 5 years.

Eligibility last updated 12/23/21. Questions regarding updates should be directed to the study team contact.

• 18 years of age or older.
• Patients who are able and willing to sign the informed consent.
• A negative urine pregnancy test within 48 hours prior to PET imaging procedures in females of childbearing potential.
• Patients who are scheduled and considered eligible (according to MRI safety policies) for a clinically-indicated PET/MR epilepsy or dementia study.

• Individuals < 18 years of age.
• Patients who are unable to lay still for an additional 15 minutes.

Eligibility last updated 1/26/22. Questions regarding updates should be directed to the study team contact.

• Has an adequate comprehension of a GFD assessed by completion of a knowledge test after viewing of educational materials.
• Has at least 1 CeD-related GI symptom of moderate or greater severity, as measured by the CDSD, on at least 3 days out of any consecutive 7-day period during the screening period (Week -8 visit until Week -4 visit), felt by the investigator to be related to gluten exposure. The CeD-related symptom(s) may vary day by day as long as the severity of at least 1 symptom is moderate or greater. The participants must meet symptom criteria to undergo esophagogastroduodenoscopy (EGD)/video capsule endoscopy (VCE).
• Has been attempting to maintain a GFD for at least 12 months as self-reported by the participant.
• Has small intestinal villous atrophy on duodenal biopsy defined as Vh:Cd <2.5 at Week -4.
• The participant is human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8 positive.
• The participant is in a good general state of health according to clinical history and physical examination, in the opinion of the investigator.
• Have a body mass index (BMI) between 16 and 40 kilogram per meter square (kg/m^2), inclusive.
• The participant is willing and able to continue any current dietary and/or medical regimens (including gastric acid suppression) in effect at the first visit (Visit 1).

• There should be no changes to diet, medications (prescription or over-the-counter) or supplements during study participation.

  ---

  Exclusion Criteria:

• Has the presence of other inflammatory GI disorders or systemic autoimmune diseases (including but not limited to the following: inflammatory bowel disease, eosinophilic esophagitis, gastroenteritis or colitis, microscopic colitis diagnosed at screening or requiring treatment in the 6 months before screening, scleroderma, psoriatic or rheumatoid arthritis, lupus) other than those noted below:

  • Thyroid disease that has been well-controlled for at least 6 months.
  • Well-controlled type 1 diabetes (glycosylated hemoglobin <8% and no hospitalization or emergency room visit in the last 12 months for hyperglycemia or hypoglycemia).

• Has ongoing systemic immunosuppressant, systemic corticosteroid treatment excluding medication given for the endoscopies, or treatment with systemic immunosuppressants or systemic corticosteroids in the 12 weeks before Screening.

  • The participant is receiving immunosuppressive doses of corticosteroids: 3 mg per day or more of budesonide for more than 3 consecutive days within 3 months before Screening, more than 20 mg of prednisone given daily or on alternative days for 2 weeks or more within 6 months before the first dose, any dose of oral or intravenous (IV) corticosteroids within 30 days of the first dose, or high-dose inhaled corticosteroids (>960 micrograms per day [μg/day] of beclomethasone dipropionate or equivalent), or other systemic immunosuppressive agents.

• Has ongoing use of over-the-counter digestive enzymes or digestive supplements, other than lactase, including those for gluten digestion. Probiotics are allowable if they were started before Screening and not discontinued or changed in dose or type during the study.
• Has completed the CDSD on ≤75% of the days during Week -8 until randomization.

• Has active microscopic colitis requiring treatment in the 6 months before Screening.

  • Microscopic colitis detected at screening if sigmoidoscopy is performed would exclude the participant.

• Has known or suspected type 2 refractory CeD or ulcerative jejunitis.
• Has ongoing chronic use (defined as >7 days continuous use) of a nonsteroidal anti-inflammatory drug aside from <100 mg aspirin, daily, for prophylactic use.
• Has ongoing use, or use in the 3 months before screening, of medications known to cause villous abnormalities (e.g., mycophenolate mofetil, angiotensin receptor blockers, colchicine).
• Has used treatments for GI symptoms including antiemetics, antidiarrheals, antispasmodics, medical marijuana, and constipation agents other than fiber, within 2 weeks of Screening.
• Has a known or suspected severe enteric infection (viral, bacterial, or parasitic) within 6 months before randomization. Severe enteric infection is defined as requiring emergency room visit or hospitalization or treatment with antibiotics or anti-infectives due to infection. Non enteric viral infections, either resolved or well-controlled are not exclusionary.

• Has a contraindication to endoscopy with duodenal biopsy.

  --Contraindication to VCE (strictures, anastomoses, etc) is not an exclusion if the participant is able to complete the other aspects of the study.

• Has additional food allergies (tapioca syrup, oats, almonds, rice crisp, chocolate, almond, butter, wheat gluten, cocoa butter, oat flour, glycerin, sunflower lecithin, salt, and natural flavors) to nongluten ingredients in the SIGE bar study food or significant symptoms upon ingestion of the gluten-free SIGE bar during screening.
• Has a history of intolerance, hypersensitivity, or idiosyncratic reaction to an aminoglycoside.
• Has a known human immunodeficiency virus (HIV) infection or positive tests for hepatitis B or C. The participant has a known clinically significant chronically active hepatopathy of any origin, including cirrhosis, and participants with persistent positive hepatitis B virus surface antigen and quantitative hepatitis B virus polymerase chain reaction (PCR), or positive serology for hepatitis C virus (HCV) and quantitative HCV PCR within 6 months before the screening visit.
• Has known or suspected coronavirus disease 2019 (COVID-19) as determined by the investigator within the past month or COVID-19-related symptoms that have not resolved (direct viral or serologic testing may be performed according to site procedures at the discretion of the investigator).
• Has a known hypersensitivity reaction and/or allergy, including anaphylaxis, to wheat and/or gluten.

• Has known history of hypersensitivity, idiosyncratic reaction, or intolerance to any ingredients or excipients in TAK-062 and/or placebo.

  Region-specific

  ---

  Exclusion Criteria:

• Participant enrolling in a study in France is not affiliated to a social security scheme or a beneficiary of such a scheme.
• Participant enrolling in a study in France is deprived of their liberty by a judicial or administrative decision.

Eligibility last updated 6/21/23. Questions regarding updates should be directed to the study team contact.

Inclusion criteria:

• Pathological diagnosis CNS inflammatory demyelinating disease (IIDD) consistent with MS, confirmed by a pathologist
• FFPE tissue with sufficient area for pathological analyses

• Age ≥ 18 years old.
• ***Histologically documented Squamous Cell Carcinoma of the oropharynx (AJCC v7** Stage III-IV A,B).
• *Tumor tissue (primary or cervical metastasis) available for human papilloma virus (HPV) and/or p16 (in situ hybridization (ISH), immunohistochemistry (IHC) or genotyping testing).
• If you do not have enough leftover tumor tissue available, you will have a tumor biopsy for tumor marker testing.
• Eastern Cooperative Oncology Group (ECOG) performance status= 0, 1, or 2.
• Negative pregnancy test for women of child bearing potential.
• Concurrent chemotherapy.
• Bilateral neck radiation.

• Previous radiation treatment for head and neck mucosal primary cancers within the past 5 years (i.e., oropharynx, nasopharynx, hypopharynx, larynx, and oral cavity).
• Pregnant or breast-feeding females.
• Clinically significant uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal or hematologic disease but not limited to:
  • Symptomatic congestive heart failure, unstable angina, or cardiac dysrrhythmia not controlled by pacer device;
  • No myocardial infarction within 3 months of registration.
• Distant metastases (AJCC v7** Stage IV C, any T, any N and M1).
• Previous surgical resection or neck dissection for oropharyngeal cancer, administered with therapeutic intent.

*    If you do not have enough leftover tumor tissue available, you will have a tumor biopsy for tumor marker testing.
**  American Joint Committee on Cancer (AJCC) 7th edition.
*** For clinically visible or radiographically diagnosed oropharynx cancer, neck mass biospy/US FNA is acceptable.

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

• PRIOR TO STEP 1 REGISTRATION
• A diagnostic contrast-enhanced magnetic resonance imaging (MRI) (no other scan type allowed) of the brain must be performed postoperatively within 72 hours of resection; the enhancing tumor must have a maximal diameter of 5 cm; the tumor diameter will be the greatest diameter as measured on the contrast-enhanced postoperative MRI and will include residual disease and/or the postoperative surgical cavity as appropriate; for cases where residual disease or postoperative surgical cavity is NOT identifiable (e.g., polar glioblastomas [GBMs] where a polar lobectomy is performed), the patient will be excluded from the trial
• The GBM tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed)
• Patients must provide study-specific informed consent prior to step 1 registration
• PRIOR TO STEP 2 REGISTRATION
• Histologically proven diagnosis of glioblastoma (World Health Organization [WHO] grade IV) confirmed by central review prior to step 2 registration
• Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient quantity for analysis of O6-methylguanin-DNA-methyltransferase (MGMT) status
  • Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; at least 1 cubic centimeter of tissue composed primarily of tumor must be present
  • Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy or cavitron ultrasonic suction aspirator (CUSA) technique are not allowed
• History/physical examination within 28 days prior to step 2 registration
• The patient must have recovered from effects of surgery, postoperative infection, and other complications within 28 days prior to step 2 registration
• Documentation of steroid doses within 28 days prior to step 2 registration
• Karnofsky performance status ≥ 70 within 28 days prior to step 2 registration
• Age ≥ 18
• Absolute neutrophil count (ANC) ≥ 1,800 cells/mm^3
• Platelets ≥ 100,000 cells/mm^3
• Hemoglobin ≥ 10.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) ≥ 10.0 g/dl is acceptable)
• Bilirubin ≤ 1.5 upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN
• Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
• Recurrent or multifocal malignant gliomas
• Any site of distant disease (for example, drop metastases from the GBM tumor site)
• Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide)
• Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted
• Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
• Severe, active co-morbidity, defined as follows:
  • Unstable angina at step 2 registration
  • Transmural myocardial infarction within the last 6 months prior to step 2 registration
  • Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 28 days prior to step 2 registration
  • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
  • Serious and inadequately controlled arrhythmia at step 2 registration
  • Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
  • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
  • Any other severe immunocompromised condition
  • Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
  • End-stage renal disease (ie, on dialysis or dialysis has been recommended)
  • Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
• Patents treated on any other therapeutic clinical protocols within 30 days prior to step 2 registration
• Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia)
• Postoperative tumor plus surgical bed size exceeds 5 cm in maximum diameter.

Part 1 Dose Escalation:

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

Part 2 Dose Expansion for Combination Therapy with Rituximab:

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

Part 2 Dose Expansion for Combination Therapy with Pembrolizumab:

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

All Subjects:

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

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

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

• Age 18 years or older;
• At least one measurable lesion according to RECIST v1.1 OR evaluable disease for a limited number of patients (up to 10) in Group H.
• Performance status of ECOG 0, 1 or 2.
• Estimated life expectancy of at least 12 weeks;
• Toxicities incurred as a result of previous anti-cancer therapy resolved to ≤ Grade 1 (as defined by NCI CTCAE v4.03) except for alopecia, Grade 2 sensory neurotoxicity, or any other toxicity that in the opinion of the Investigator does not affect the assessment of adverse events related to the study drug.
• Treatment with anti-cancer medication or investigational drugs within the following intervals before the first dose of MCLA-128:
  • > 14 days or > 5 half-lives prior to study entry, whichever is shorter;
  • > 14 days for radiotherapy.
  • Note: A less than 1-week wash-out period is permitted only for palliative radiation to non-CNS disease with Sponsor approval.
• Patient has recovered from prior surgery or other procedure or complication to ≤ Grade 2 or to baseline condition that in opinion of the Investigator does not affect the assessment of adverse events related to the study drug;
• Laboratory values at Screening:
  • Absolute neutrophil count ≥ 1.5 x 10^9 /L without colony stimulating factor support for at least 7 days prior to Screening;
  • Platelets ≥ 100 x 10^9 /L without transfusion support for at least 7 days prior to Screening;
  • Hemoglobin ≥ 8 g/dL or ≥ 5 mmol/L;
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) and total bilirubin ≤ 1.5 x ULN; in cases of metastatic liver involvement, ALT/AST ≤ 5 x ULN and total bilirubin ≤ 2 x ULN will be allowed; in cases of antecedents of Gilbert’s syndrome when total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN will be allowed;
  • Estimated glomerular filtration rate (GFR) of > 30 mL/min based on the Cockroft-Gault formula.
• Able to provide at baseline a mandatory tumor biopsy sample (FFPE), preferably a block. If safe/feasible, a fresh FFPE biopsy sample is preferred; archival tissue is acceptable (preferably not more than 2 years old).
  • NOTE #1: For patients who received afatinib or other HER-targeting agents, a biopsy collected after the last line of treatment is strongly preferred to assess for mechanisms of acquired resistance.
  • NOTE #2: For patients with a locally confirmed NRG1 gene fusion, when archival tissue is not available and collection of a fresh biopsy is not safe or feasible during the screening period, these patients will be allowed to enroll in the MCLA128-CL01 trial provided they meet all other inclusion/exclusion criteria.
• Negative pregnancy test results available as defined by a blood human chorionic gonadotropin (hCG) test during Screening and within 7 days of Cycle 1, Day 1 in women of childbearing potential (defined as women ≤50 years of age or history of amenorrhea for ≤12 months prior to study entry).
  • NOTE: Women with amenorrhea associated with prior treatment with antineoplastic medications are still considered as being of child-bearing potential.
• Sexually active male and female patients of childbearing potential must agree to use one of the following highly effective methods of birth control during the entire duration of the study and for 6 months after final administration of MCLA-128:
  • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
    • oral;
    • intravaginal;
    • transdermal.
  • progestogen-only hormonal contraception associated with inhibition of ovulation 1:
    • oral;
    • injectable;
    • implantable.
  • intrauterine device (IUD);
  • intrauterine hormone-releasing system (IUS);
  • bilateral tubal occlusion;
  • vasectomized partner;*
  • sexual abstinence;**
  • Note that double barrier methods are not considered to be highly effective birth control methods.
  • * Note that sterility in female patients must be confirmed in the patients’ medical records and be defined as any of the following: surgical hysterectomy with bilateral oophorectomy, bilateral tubular ligation, natural menopause with last menses > 1 year ago; radiation induced oophorectomy with last menses > 1 year ago; chemotherapy induced menopause with 1-year interval since last menses; 1Note that a vasectomized partner is only a highly effective birth control method provided that partner is the sole sexual partner of the woman of childbearing potential trial participant and that the vasectomized partner has received medical assessment of the surgical success.
  • ** Note that sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the clinical trial and the preferred and usual lifestyle of the subject.
• Ability to give written, informed consent prior to any study-specific Screening procedures, with the understanding that the consent may be withdrawn by the patient at any time without prejudice.
• Capable of understanding the mandated and optional protocol requirements, is willing and able to comply with the study protocol procedures and has signed the main informed consent document. For any optional biopsy sampling (tissue and/or blood) and long-term sample storage, additional consent is required.
• Patients must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy or no satisfactory alternative treatment options are available.
• Histologic or cytologic diagnosis of locally-advanced, unresectable or metastatic solid tumor malignancy with a documented NRG1 gene fusion, identified through molecular assays such as next generation sequencing-based assays [DNA or RNA], as routinely performed at CLIA or other similarly-certified laboratories. The following tumor types are included:
  • Group F: NSCLC;
  • Group G: pancreatic adenocarcinoma;
  • Group H: any other solid tumor.
  • NOTE: Patients harboring fusions that are predicted to be non-functional; i.e., lack of EGF-domain, will not be included in the study. For equivocal cases, including those with NRG1 as the upstream partner, the Sponsor will manually review genomic results and may request collateral testing, approve, or deny the case.

• Pregnant or lactating.
• Presence of an active uncontrolled infection or an unexplained fever greater than 38.5°C during Screening up to the first scheduled day of dosing. At the discretion of the Investigator, patients with tumor fever or a clinically insignificant minor infection may be enrolled (i.e., mild upper respiratory infection).
• Known hypersensitivity to any of the components of MCLA-128 or history of severe hypersensitivity reactions to human or humanized monoclonal antibodies, including therapeutic antibodies.
• Patients with the following infectious diseases are excluded:
  • known HIV;
  • active Hepatitis B infection (HBsAg positive) without receiving antiviral treatment
  • Note: Patients with active hepatitis B (HBsAg positive) must receive antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral agents, starting at least ≥ 7 days before the initiation of the study treatment; Patients with antecedents of Hepatitis B (anti-HBc positive, HBsAg and HBV-DNA negative) are eligible;
  • positive test for Hepatitis C ribonucleic acid (HCV RNA)
  • Note: Patients in whom HCV infection resolved spontaneously (positive HCV antibodies without detectable HCV-RNA) or those that achieved a sustained response after antiviral treatment and show absence of detectable HCV RNA ≥ 6 months (with the use of IFN-free regimens) or ≥ 12 months (with the use of IFN-based regimens) after cessation of antiviral treatment are eligible;
• Known symptomatic or unstable brain metastases. Patients with asymptomatic brain metastases are eligible to participate if the metastases have been radiographically and clinically stable for at least one month. If on steroids for this indication, the patient must be on a stable dose for at least one month;
• Patients with leptomeningeal metastases;
• Previous or concurrent malignancy, excluding non-basal cell carcinoma of skin or carcinoma in situ of the uterine cervix unless the tumor was treated with curative or palliative intent and in the opinion of the Investigator, with Sponsor agreement, the previous or concurrent malignancy condition doesn’t affect the assessment of safety and efficacy of the study drug;
• Presence of NYHA Class III or IV congestive heart failure or LVEF < 50% or history of significant cardiac disease, unstable angina, congestive heart failure, myocardial infarction, or ventricular arrhythmia requiring medication.
• Presence of any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate or participate in the study, or interfere with the interpretation of the results.

• Diagnosis of clinical stage IIIB and IIIC (AJCC v7) metastatic melanoma, eligible for complete surgical resection of all metastases (surgically resectable).
• Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
• Males or females, age ≥ 18 years.
• ECOG Performance Status/WHO Performance Status ≤ 1.
• Life expectancy of > 24 months.
• Absolute neutrophil count > 1.5 x 10^9/L.
• Hemoglobin > 9.0 g/dL.
• Platelets > 100 x 10^9/L.
• Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl).
• ALT and AST ≤ 2.5 x the upper limit of normal (ULN).
• Serum creatinine < 1.5 x ULN .
• LDH serum level ≤ 1.5 x ULN.
• Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg, and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV negative serum HBV-DNA is also required.
• All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above.
• All women of childbearing potential (WOCBP) must have negative pregnancy test results at the screening. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods. WOCBP and effective contraception methods are defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence.  Pregnancy test will be repeated at the safety visit (only WOCBP and only for patients in Arm 1).
• Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e., spermicidal gel plus condom) from the screening to three months following the last study drug administration.
• Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
• Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

• Uveal melanoma or mucosal melanoma
• Evidence of distant metastases at screening.
• Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except: cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry.
• Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
• History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Inadequately controlled cardiac arrhythmias including atrial fibrillation.
• Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
• LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
• Uncontrolled hypertension.
• Ischemic peripheral vascular disease (Grade IIb-IV).
• Severe diabetic retinopathy.
• Active autoimmune disease.
• History of organ allograft or stem cell transplantation.
• Recovery from major trauma including surgery within 4 weeks prior to enrollment.
• Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
• Breast feeding female.
• Anti-tumor therapy (except small surgery) within 4 weeks before enrollment.
• Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment.
• Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment.
• Patient requiring or taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
• Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
• Previous enrolment and randomization in the same study.

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

• Patients who receive CRT-P or CRT-D device at Mayo Clinic since 1998

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

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