• Male and/or female.
• Age ≥ 18 years at the time of screening. For patients aged < 20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
• Confirmed HCC (by imaging or histopathologically from biopsy specimen).
• No evidence of extrahepatic disease on any available imaging.
• Disease not amenable to curative surgery or transplantation or curative ablation.
• Disease must be amenable to TACE and anticipated to require no more than 4 TACE treatments to treat sites of disease within a ≤ 16-week period (Permitted modalities are DEB-TACE or cTACE (using an emulsion of Lipiodol® and a permitted chemotherapeutic agent as per institutional practice, followed by embolizing agents).
• Child-Pugh score class A to B7.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment 10. Patients with HBV infection, which is characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥ 10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice. HBV antiviral therapy must be initiated prior to randomization and patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients must show evidence HBV stabilization or signs of viral response (e.g., reduction HBV DNA levels) prior to starting IP. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (< 10 IU/ml or under the limit of detection per local lab standard) do not require antiviral therapy prior to randomization. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/ml or above the limit of detection per local lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication.
• Patients with HCV infection must have management of this disease per local institutional practice throughout the study. HCV diagnosis is characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrollment.
• At least 1 measurable intrahepatic lesion suitable for repeat assessments according to the following mRECIST criteria:
  • Liver lesions that show typical features of HCC on IV contrast-enhanced CT or MRI scans; i.e., hypervascularity in the arterial phase with washout in the portal or the late venous phase;
  • Viable, non-necrotic portion (arterial phase IV contrast-enhancing) that can be accurately measured at baseline as ≥ 10 mm in the longest diameter.
• Adequate organ and marrow function as defined below. Criteria “a,” “b,” “c,” and “f” may not be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose:
  • Hemoglobin ≥ 9.0 g/dL;
  • Absolute neutrophil count ≥1000/µL;
  • Platelet count ≥ 75000/µL;
  • Total bilirubin ≤ 2.0 × the upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 × ULN;
  • Albumin ≥2.8 g/dL;
  • International normalized ratio ≤1.6;
  • 2+ proteinuria or less urine dipstick reading;
  • Calculated creatinine clearance (CL) ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine CL.
  • Males: Creatinine CL = Weight (kg) × (140
    •Age) (mL/min) 72 × serum creatinine (mg/dL);
  • Females: Creatinine CL = Weight (kg) × (140
    •Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL). 
• Must have a life expectancy of at least 12 weeks.
• Upper Endoscopy to evaluate varices and risk of bleeding is required within 6 months of randomization.
• Body weight >30 kg

• Any history of nephrotic or nephritic syndrome.
• Clinically significant (e.g., active) cardiovascular disease, including:
  • Unstable angina within ≤ 6 months of randomization;
  • New York Heart Association Grade ≥ 2 congestive heart failure;
  • Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG.
• Peripheral vascular disease Grade ≥ 3 (e.g., symptomatic and interfering with activities of daily living requiring repair or revision).
• Significant traumatic injury during 4 weeks prior to randomization.
• Known hereditary predisposition to bleeding or thrombosis; any prior or current evidence of bleeding diathesis.
• Systemic anticoagulation allowed, excluding Vitamin K antagonists.
• History of arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization 
• Non-healing wound, active ulcer, or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require wound examinations every 3 weeks.
• History of abdominal fistula or GI perforation, nonhealed gastric ulcer that is refractory to treatment, or active GI bleeding within 6 months prior to enrollment.
• Patients who have had any kind of surgery in the past 28 days (biopsy from any type of surgery within 28 days is not an exclusion criteria. Nor are procedures to treat varices.) 
• Uncontrolled hypertension defined by a systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg, with or without antihypertensive medication. Patients with initial blood pressure (BP) elevations are eligible if initiation or adjustment of antihypertensive medication lowers pressure to meet entry criteria.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
• Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose:
  • Patients with ascites that has required pharmacologic intervention (e.g., diuretics) and who have been on stable doses of diuretics for ascites for ≥ 2 months are eligible;
  • Major portal vein thrombosis visible on baseline/eligibility imaging, patients with Vp3 and Vp4 are excluded.
• Patients with infiltrative-type HCC.
• History of allogeneic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [eg, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, and uveitis]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia;
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement;
  • Any chronic skin condition that does not require systemic therapy;
  • Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician;
  • Patients with celiac disease controlled by diet alone.
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection (except for noted HBV or HCV as detailed above), symptomatic congestive heart failure, poorly controlled diabetes mellitus, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of IP and of low potential risk for recurrence;
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
  • Adequately treated carcinoma in situ without evidence of disease.
• History of leptomeningeal carcinomatosis.
• History of active primary immunodeficiency.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice) or human immunodeficiency virus (positive HIV 1/2 antibodies).
• Patients co-infected with HBV and hepatitis D virus (HDV). (HBV infection is indicated by the presence of HBsAg and/or anti-HBcAb with detectable HBV DNA ≥ 10 IU/mL or above the limit of detection per local lab standard ; HDV positive infection is indicated by the presence of anti-HDV antibodies.)
• Any unresolved toxicity National Cancer Institute (NCI) CTCAE v 5.0 Grade ≥ 2 from previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• History of allogeneic bone marrow transplant and active chronic graft versus host disease.
• Receipt of anti-PD-1, anti-PD-L1, or anti-CTLA-4 prior to the first dose of IP.
• Receipt of prior TACE, prior bland embolization, or prior radioembolization. Use of TACE or TAE as part of a curative therapy (e.g., in conjuntion with ablation or surgery) can be acceptable if it is used in the lesions where curative therapy was attempted. However, TACE or TAE cannot have been used as sole modalities in prior curative therapy.
• Receipt of prior systemic anticancer therapies for HCC.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
  • Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 90 days after the last dose of IP.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
• Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment group assignment.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of IP. Not engaging in sexual activity, as per the patient’s preferred and usual lifestyle, for the total duration of the treatment and 6 months after the last dose of study treatment is an acceptable practice.
• 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.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

• Age ≥ 18 years  old.
• Life expectancy of at least 2 months.
• ECOG Performance Status ≤ 2.
• Patients must be able to swallow capsules.
• Adequate hematologic parameters, unless cytopenias are disease caused.
• Adequate renal, liver and cardiac function parameters.

• Patients with GVHD requiring systemic immunosuppressive therapy.
• Uncontrolled leptomeningeal disease, auto-immune hemolytic anemia and uncontrolled and clinical significant disease related metabolic disorde.r 
• Clinically significant intravascular coagulation. 
• Treatment with other investigational drugs within 14 days prior to first study treatment administration.

Inclusion Criteria
•Part 1:

• Patients must be informed about the study and fully consent to participation as demonstrated by signing the written informed consent form (ICF) before any screening procedures.
• Male or female patients 18 years or older at the time of consent.
• Confirmed diagnosis of MM per the revised IMWG diagnostic criteria.
• Patients with RRMM who have failed treatment with, are intolerant to, or are not candidates for available therapies that are known to confer clinical benefit.
• Must meet all of the following criteria for prior therapy:
  • Must be refractory to ≥ 1 proteasome inhibitor (PI), ≥ 1 immunomodulatory drug (IMiD), and ≥ 1 steroid;
  • Must either have received ≥ 3 prior lines of therapy or ≥ 2 prior lines of therapy if 1 line included a combination of PI and IMiD (prior treatment with an anti-CD38 therapy is permitted).
• With measurable disease, defined as ≥ 1 of the following:
  • Serum M-protein ≥ 500 mg/dL (≥ 5 g/L) on serum protein electrophoresis (SPEP);
  • Urine M-protein ≥ 200 mg/24 h on urine protein electrophoresis (UPEP).
  • Serum FLC assay result with an involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) if serum FLC ratio is abnormal.
• Patients with serum M-protein, urine M-protein, or involved immunoglobulin FLC not meeting the measurable disease criteria above will be eligible if they have ≥ 1 of the following:
  • PET imaging with ≥ 1 plasmacytoma lesion with a single diameter of ≥ 2cm;
• • Bone marrow (BM) aspirate/biopsy with plasma cell percentage ≥ 30%
• With Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
• With normal QT interval corrected by the Fridericia method (QTcF) on screening electrocardiogram (ECG)[ QTcF of ≤ 450 millisecond (ms) in males or ≤ 470 ms in females].
• Must meet the following clinical laboratory criteria at entry:
  • Total bilirubin ≤1.5 x the upper limit of the normal range (ULN), except for Gilbert's syndrome (direct bilirubin must be < 2.0 x ULN);
  • Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x ULN;
  • Estimated glomerular filtration rate (eGFR) ≥ 30 (mL/min/1.73 square meter [m^2]), using the modification of diet in renal disease (MDRD) equation;
  • Absolute neutrophil count (ANC) ≥ 1000 per cubic millimeter (/mm^3) (≥ 1.0*10^9 per liter [/L]); ≥ 750/mm^3 (≥ 0.75 x 10^9/L) may be acceptable for participants with > 50% of plasma cells in BM;
  • Platelet count ≥ 75,000/ mm^3 (≥ 75 x 10^9/L); ≥ 50,000/ mm^3 (≥ 50 X 10^9/L) may be acceptable for participants with > 50% of plasma cells in BM;
  • Hemoglobin ≥ 7.5 g/dL without transfusion within 7 days before the lab test;
  • Serum albumin ≥ 2.5 g/dL.
• Female patients who:
  • are postmenopausal for at least 1 year prior to screening; OR
  • are surgically sterile; OR
  • If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time from study entry through 30 days after the last dose of study drug; OR
  • agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together].
• Male patients, even if surgically sterilized (postvasectomy) who:
  • Agree to practice effective barrier contraception during the entire study and through 90 days after the last dose of study drug; OR
  • Agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods. Female and male condoms should not be used together].

Inclusion Criteria Part 2 (both RRMM and RRNHL patients):

• ECOG performance score of 0 or 1.
• Normal QTcF on screening ECG, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
• Must meet the following clinical laboratory criteria at study entry:
  • Total bilirubin ≤ 1.5 x the ULN, except for Gilbert's syndrome (direct bilirubin must be < 2.0 x ULN);
  • Serum ALT and AST ≤ 2.5 x ULN;
  • eGFR ≥ 30 mL/min/1.73 m^2(MDRD equation);
  • ANC ≥ 1000 mm^3 (≥ 1.0 x 10^9 /L); a count of ≥ 750/mm^3 (≥ 0.75 x 10^9/L) may be acceptable for participant with > 50% of plasma cells in BM;
  • Platelet count ≥ 75,000/ mm63 (≥ 75 x 10^9/L); a value of ≥ 50,000/ mm3(≥ 50 x 10^9/L) may be acceptable for participants with > 50% of plasma cells in BM;
  • Hemoglobin ≥ 7.5 g/dL without transfusion within 7 days before the lab test;
  • Serum albumin ≥ 2.5 g/dL.
• Female patients who:
  • are postmenopausal for at least 1 year prior to screening; OR
  • are surgically sterile; OR
  • If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time from study entry through 30 days after the last dose of study drug; OR
  • agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together].
• Male patients, even if surgically sterilized (postvasectomy) who:
  • Agree to practice effective barrier contraception during the entire study and through 90 days after the last dose of study drug; OR
  • Agree to practice true abstinence if in line with the preferred and usual lifestyle [periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable. Female and male condoms should not be used together].

Inclusion Criteria Part 2 for RRNHL patients:

• Pathologically confirmed diagnosis of the following NHL subtype based on local pathology report:
  • Mantle cell lymphoma (MCL) - Nodal MCL;
  • Diffuse large B-cell lymphoma (DLBCL), DLBCL- NOS, Plasmablastic lymphoma (PbL), Primary effusion lymphoma (PEL),  Primary effusion lymphoma (PMBL);
  • Follicular lymphoma;
  • Burkitt lymphoma (BL);
  • Peripheral T-cell lymphoma (PTCL) - PTCL-NOS (eligible at MTD/RPTD if biopsy evidence of CD38 positivity), Angioimmunoblastic T-cell lymphoma (AITL);
  • Extranodal NK/T-cell lymphoma (ENKTL)-nasal type.
• RRNHL, having failed treatment with, is intolerant to, or is determined not to be a candidate for available therapies considered standard of care (SOC) or are known to confer clinical benefit.
• At least 1 measurable site of disease according to the Lugano classification for lymphoma:
  • A measurable nodal lesion with longest diameter (LDi) greater than 1.5cm; OR
  • A measurable extranodal lesion with LDi greater than 1.0cm.
• Evidence of a CD38 positive tumor. Any of the following are acceptable:
  • Evidence of CD38 expression from most recent biopsy or blood sample [either flow cytometry (FCM) or immunohistochemistry (IHC)]; OR
  • The most recently archived tissue assessed for CD38 expression by IHC; OR
  • Fresh biopsy for CD38 expression assessment by IHC within 35 days of Cycle 1 Day 1; OR
  • Fresh blood sample with circulating NHL cells assessed by FCM within 35 days of Cycle 1 Day 1 (BM biopsy excisional lymph node biopsy, core biopsy of any involved organ are all acceptable methods, find needle aspirate is not. Any level of positive CD38 expression is eligible).

Inclusion Criteria Part 2 for RRMM patients:

• Confirmed diagnosis of MM per IMWG diagnosis criteria:
  • RRMM, having failed treatment with, is intolerant to, or is determined not to be a candidate for available therapies considered SOC or are known to confer clinical benefit.
• Must meet the following criteria for prior therapy:
  • Refractory or intolerant to ≥1 PI and ≥ 1 IMiD;
  • Receipt of ≥ 3 prior lines of therapy or ≥ 2 prior lines of therapy if 1 of those lines included a combination of a PI or IMiD (prior treatment with anti-CD38 therapy is permitted except for patients enrolled in the anti-CD38 therapy naïve cohort);
  • Daratumumab RR cohorts: RR to daratumumab at any time during treatment. Patients RR to other anti-CD38 therapies are excluded;
  • Anti-CD38 therapy naïve cohort: must not have received any prior anti CD-38 therapy.
• Measurable disease, defined as ≥ 1 of the following:
  • Serum M-protein ≥ 50 mg/dL (≥ 5 g/L) on SPEP;
  • Urine M-protein ≥ 200 mg/24 hours on UPEP.;
  • Serum FLC assay result with and involved FLC level ≥ 10 mg/dL (≥ 100mg/L), provided the serum FLC ratio is abnormal.
• Serum M-protein, urine M-protein or involved immunoglobulin FLC not meeting measurable disease criteria if at least 1 of the following criteria is met:
  • BM aspirate/biopsy showing plasma cell percentage ≥ 30%;
  • PET imaging showing at least 1 plasmacytoma lesion with a single diameter ≥ 2 cm.

Exclusion Criteria for Part 1 (RRMM patients only):

• With polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, or Immunoglobulin M (IgM) myeloma.
• With sensory or motor neuropathy of NCI CTCAE V5 Grade ≥ 3.
• Have received final dose of any of the following treatments/procedures within the following interval before the first dose of MT-0169:
  • Myeloma-specific therapy, including PIs and IMiDs: 14 days;
  • Anti-CD38 (a) therapy: Isatuximab 90 days; daratumumab 60 days;
  • Corticosteroid therapy for myeloma: 7 days;
  • Radiation therapy for localized bone lesions: 14 days;
  • Major surgery:30 days;
  • Autologous stem cell transplant: 90 days;
  • Investigational therapy: 30 days.
• Have received an allogeneic stem cell transplant or organ transplantation.
• Have not recovered to Grade ≤ 1 or baseline, from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) excluding alopecia and Grade 2 neuropathy.
• With clinical signs of central nervous system (CNS) involvement of MM.
• With a history of myelodysplastic syndrome or another malignancy other than MM except for the following: any malignancy that has been in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for ≥ 1 year before the start of study therapy.
• With known or suspected light chain amyloidosis of any organ (amyloid on the BM biopsy without other evidence of amyloidosis is acceptable).
• With any of the following cardiovascular conditions:
  • Congestive heart failure (NYHA) class ≥ II or left ventricular ejection fraction (LVEF < 40%, cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris or myocardial infarction or clinically significant arrhythmia requiring therapy including anticoagulants within the past 6 months or at screening;
  • Resting tachycardia (heart rate of > 100 bpm) at screening;
  • Clinically significant uncontrolled hypertension at screening;
  • Cardiac MRI at screening demonstrates evidence of infiltrative disease of the myocardium.
• With a history of document significant pleural or pericardial effusions within 3 months before the start of treatment, including:
  • Pericarditis (any Grade);
  • Pericardial effusion (Grade ≥ 2);
  • Non-malignant pleural effusion (Grade ≥ 2);
  • Malignant pleural effusion (Grade ≥ 2).
• Patients with a history of noncardiogenic pulmonary edema associated with diffuse peripheral edema and a history of intravascular hypovolemia associated with systemic antineoplastic therapy.
• With chronic or active infection requiring systemic therapy, history of symptomatic viral infection that has not been fully cured.
  • With HIV and an undetectable viral load and CD4+ T-cell (CD4+) counts ≥ 350 cells/mL may be allowed but patient must be taking appropriate opportunistic infection prophylaxis if clinically relevant;
  • With positive HBV serology may be allowed if undetectable viral load, receiving antiviral prophylaxis for potential HBV reactivation per institutional guidelines;
  • With positive HCV serology may be allowed if quantitative PCR for plasma HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.
• Have received a live attenuated vaccine within 28 days of first dose of MT-0169.
• With a history of ≥ Grade 2 systemic inflammatory response syndrome (SIRS)/ cytokine release syndrome (CRS) reactions following infusion with any monoclonal antibodies or Chimeric Antigen Receptor (CAR) T therapy.
• With a chronic condition requiring systemic corticosteroids at > 10 mg/day of prednisone or equivalent.
• Are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or patients of reproductive potential who are not employing an effective birth control.
• With a concurrent medical or psychiatric illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, uncontrolled and active infection, uncontrolled risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease, alcoholic liver disease, or primary biliary cirrhosis.
• With known allergy or intolerance to any of the drugs used in the study or excipients in the MT-0169 formulation.
• With a history of hypersensitivity or serious toxic reaction to kanamycin or another aminoglycoside.

Exclusion Criteria for Part 2 NHL patients only:

• With known CNS lymphoma (exception allowed if history of CNS disease and evidence of SD on neuroimaging separated in time by at least 4 weeks and within 4 weeks of Cycle 1 Day 1).   
• Have received a final dose of any of the following treatments/procedures within the following minimum interval before the first dose of MT-0169:
  • Nitrosoureas: 6 weeks;
  • Chemotherapy: 4 weeks;
  • Small molecules (< 0.9 kDa): 5 half-lives or at least 2 weeks:
  • Therapeutic antibodies: 4 weeks;
  • Radio/toxin -immunoconjugates: 12 weeks;
  • Radiation therapy to a target lesion (measurable disease): 4 weeks
  • Radiation therapy to a nontarget lesion (radiation therapy to non-target lesions may be permitted): 2 weeks
  • Investigational chemotherapeutic agents or antibodies: 4 weeks
  • Daratumumab: 60 days
  • Isatuximab: 90 days
  • (MCL) Bruton's tyrosine kinase inhibitors: 2 weeks or 5 half-lives, whichever is longer
  • Major surgery (determined by the principal investigator with the Sponsor): 4 weeks
  • Autologous stem cell transplant: 100 days
  • Allogenic stem cell transplant: 180 days (patients with graft vs host disease > Grade 1 will be excluded).
• With a history of myelodysplastic syndrome or malignancy (other than NHL) except for the following: any malignancy in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for ≥ 1 year before the start of study therapy.

Exclusion Criteria for Part 2 RRMM patients only:

• With POEMS syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, IgM myeloma.
• Have received a final dose of any of the following treatments/procedures within the following interval before the first dose of MT-0169:
  • Myeloma-specific therapy, including PIs and IMiDs: 14 days;
  • Anti-CD38 therapy
    •Isatuximab: 90 days;
  • Anti-CD38 therapy
    •Daratumumab: 60 days;
  • Corticosteroid therapy for myeloma: 7 days;
• • Radiation therapy for localized bone lesions: 14 days;
  • Major surgery: 30 days;
  • Autologous stem cell transplant: 90 days;
  • Investigational therapy: 30 days.
• Have received an allogenic stem cell or organ transplant.
• With clinical signs of CNS involvement of MM.
• With a history of myelodysplastic syndrome or another malignancy other than MM except or any malignancy in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, or asymptomatic prostate cancer without known metastatic disease and not requiring therapy or requiring only hormonal therapy and with normal prostate-specific antigen level for >1 year before the start of study therapy.
• With known or suspected light chain amyloidosis of any organ (amyloid on BM biopsy without other evidence of amyloidosis is acceptable).

Exclusion Criteria for Part 2 (both RRMM and NHL patients):

• Failed to recover to Grade ≤ 1 or baseline from adverse reactions to prior treatment or procedures (chemotherapy, immunotherapy, radiation therapy) excluding alopecia and stable Grade 2 neuropathy.
• With any of the following cardiovascular conditions:
  • Congestive heart failure (NYHA) class ≥ II LVEF < 40%, cardiac myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris or myocardial infarction or clinically significant arrhythmia requiring therapy including anticoagulants within the past 6 months or at screening;
  • Resting tachycardia (heart rate of >100 bpm) at screening;
  • Clinically significant uncontrolled hypertension at screening;
  • Cardiac MRI at screening demonstrating infiltrative disease of the myocardium 12. With a history of documented significant pleural or pericardial effusions, specifically any of the following within 3 months before the start of study treatment:
  • Pericarditis (any grade);
  • Pericardial effusion (Grade ≥ 2);
  • Non-malignant pleural effusion (Grade ≥ 2); OR
  • Malignant pleural effusion (Grade ≥ 3).
• With a history of noncardiogenic pulmonary edema associated with peripheral edema and a history of intravascular hypovolemia associated with antineoplastic therapy.
• With chronic or active infection requiring systemic therapy and a history of symptomatic viral infection that is not fully controlled or cured. The following exceptions apply for those with positive serologies of HIV, HBV, or HCV:
  • With HIV and undetectable viral load and CD4+ T-cell (CD4+) counts ≥ 350 cells/mL may be enrolled, but must be taking appropriate opportunistic infection prophylaxis, if clinically relevant;
  • With positive HBV serology are eligible if they have an undetectable viral load and the patient will receive antiviral prophylaxis for potential HBV reactivation per institutional guidelines;
  • With positive HCV serology are eligible if qPCR for plasma HCV RNA is below the lower limit of detection. Concurrent antiviral HCV treatment per institutional guidelines is allowed.
• Have received a live attenuated vaccine within 28 days of the first dose of MT-0169.
• With a history of Grade ≥ 2 SIRS/CRS reactions following infusion with any mAbs or CAR T therapy.
• With a chronic condition requiring systemic corticosteroids ≥ 10 mg/day of prednisone or equivalent.
• With a known allergy or intolerance to any of the drugs in the study or excipients in the MT-0169 formulation.
• Are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or male or female patients of reproductive potential who are not employing effective birth control.
• With a concurrent medical or psychiatric illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, uncontrolled and active infection, uncontrolled risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease, alcoholic liver disease, or primary biliary cirrhosis.
• With a history of hypersensitivity or serious toxic reactions to kanamycin or another aminoglycoside.

• Histologically or cytologically confirmed solid tumor malignancy that is advanced or metastatic or is surgically unresectable. 
• Radiographically measurable disease (per RECIST v1.1 or RANO for primary brain tumors). Tumor lesions located in a previously irradiated area or in an area subjected to other loco-regional therapy are considered measureable if progression has been clearly demonstrated in the lesion. 
• Documentation of an FGFR1-3 gene mutation or translocation. 
• Objective progression after at least 1 prior therapy and no therapy available that is likely to provide clinical benefit. Participants who are intolerant to or decline the approved therapy are eligible only if they have no therapy available that is likely to provide clinical benefit. 
• Eastern Cooperative Oncology Group performance status 0 to 2.
• Baseline archival tumor specimen (if < 12 months from date of screening) or willingness to undergo a pretreatment tumor biopsy to obtain the specimen. Must be a tumor block or approximately 15 unstained slides from biopsy or resection of primary tumor or metastasis. 
• Willingness to avoid pregnancy or fathering children.

• Prior receipt of a selective FGFR inhibitor in the past 6 months. 
• Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of pemigatinib. 
• Cannot be a candidate for potentially curative surgery. 
• Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. 
• Radiation therapy administered within 2 weeks of enrollment/first dose of study treatment.
• Untreated brain or central nervous system (CNS) metastases or brain or CNS metastases that have progressed (e.g., evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). 
• Known additional malignancy that is progressing or requires active treatment. 
• History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues.
• Clinically significant or uncontrolled cardiac disease. 
• Active chronic or current infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 2 weeks before enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed). 
• Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as elevated transaminases or cirrhosis; chronic HBV/HCV infection with no cirrhosis and no elevated transaminases is allowed). 
• Known HIV infection. 
• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or five half-lives (whichever is longer) before the first dose of study drug/treatment. 
• Women who are pregnant or breastfeeding.

• Signed written informed consent granted prior to initiation of any study-specific procedures. 
• 18 years of age and older.
• For the dose escalation cohorts, relapsed or refractory subjects with a diagnosis of B-cell NHL, CLL/SLL and WM who have received at least two prior systemic therapies . Subjects must have failed or are intolerant to standard therapies and cannot be a candidate for standard salvage regimens. Subjects with low grade lymphoma must be progressing and requiring treatment.. 
• For the expansion cohorts, the following criteria must be met:
  • Cohort A: Relapsed/Refractory (R/R) CLL/SLL subjects with at least 2 prior systemic therapies and previously treated with a covalent BTKi who must have a documented BTK mutation on C481 residue;
  • Cohort B: R/R CLL/SLL subjects who have failed or were intolerant to a BTKi with documentation of the absence of BTK mutation on C481 residue. In this study, intolerance to standard therapy is defined as having experienced a grade 3 or higher adverse event that was caused by the standard therapy and resulted in treatment discontinuation;
  • Cohort C: Richter's transformation subjects who have failed at least one prior therapy;
  • Cohort D: Follicular Lymphoma (FL) subjects who have failed at least 2 prior systemic therapies and are histology grade 1, 2, or 3A;
  • Cohort E: Mantle Cell Lymphoma (MCL) subjects who have failed at least 2 prior systemic therapies;
  • Cohort F: Marginal Zone Lymphoma (MZL) subjects who have failed at least 2 prior systemic therapies;
  • Cohort G: High-grade B-cell lymphoma subjects who have failed at least 2 prior systemic therapies and have known MYC and BCL2 and/or BCL6 translocations;
  • Cohort H: Waldenström macroglobulinemia (WM) subjects who have failed at least 2 prior systemic therapies.
• Disease status requirement: 
  • For CLL subjects, symptomatic disease that mandates treatment (Hallek et al. 2018); 
  • For B-cell NHL subjects, measurable disease by imaging scan;
  • For WM, serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of normal (ULN). 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
• Good organ function:
  • Creatinine clearance of ≥ 60 mL/min as estimated by the Cockcroft-Gault equation or by 24-hour urine collection;
  • Total bilirubin ≤ 1.5 x institutional ULN (total bilirubin of ≤ 3 x institutional ULN in subjects with documented Gilbert's syndrome);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × institutional ULN;
  • Platelet count ≥ 50,000/µL;
  • Absolute neutrophil count (ANC) ≥ 1000/µL;
  • Hemoglobin (Hgb) ≥ 8.0 g/dL, stable for ≥ 1 week.
• For men and women of child-bearing potential, willing to use adequate contraception (e.g., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire duration of the study.
• Female subjects of child-bearing potential must have a negative serum pregnancy test within 14 days of the first day of drug dosing.
• Ability to swallow oral medications without difficulty.

• Had immunotherapy, radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 5 half-lives or four weeks (whichever is shorter) prior to treatment initiation, or oral therapy within 5 half-lives or one week (whichever is shorter) prior to treatment initiation. 
• Transformation of FL to a more aggressive subtype of lymphoma or grade 3b FL.
• Subjects currently being treated with the following drugs:
  • CYP 2C9 substrates with a narrow therapeutic index (such as warfarin, phenytoin);
  • CYP 2C8 substrates with a narrow therapeutic index (such as paclitaxel);
  • CYP 2C19 substrates with a narrow therapeutic index (such as S-mephenytoin);
  • CYP 2D6 substrates with a narrow therapeutic index (such as thioridazine, pimozide);
  • P-gp substrates with a narrow therapeutic index (such as digoxin)
    • Note: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a subject to be eligible for study enrollment. 
• Prior allogeneic bone marrow transplant. 
• Active central nervous system (CNS) involvement. 
• Pregnant or breast-feeding women. 
• Has significant, ongoing co-morbid conditions which would preclude safe delivery of the study drug. 
• Uncontrolled illness including but not limited to ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV heart failure), unstable angina pectoris, cardiac arrhythmia, cardiac infarction in the past six months, and psychiatric illness that would limit compliance with study requirements. 
• QTc prolongation (defined as a QTc > 450 msecs) or other significant electrocardiogram (ECG) abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min). If the screening ECG has a QTc > 450 msecs, the ECG can be submitted for a centralized, cardiologic evaluation. 
• Active human immunodeficiency virus (HIV) infection, Hepatitis B, or Hepatitis C infection. 
• Other medical or psychiatric illness or organ dysfunction which, in the opinion of the Investigator, would either compromise the subject's safety or interfere with the evaluation of the safety of the study agent.
• History of prior cancer within < 1 year, except for basal cell or squamous cell carcinoma of the skin, cervical cancer in situ or other in situ carcinomas.

Newly-Diagnosed

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) established following either a surgical resection or biopsy. An MRI scan with the required imaging sequences performed within 21 days prior to randomization preferably. The post-operative MRI scan performed within 96 hours of surgery or the MRI scan performed for radiation therapy planning may serve as the MRI scan performed during screening if all required imaging sequences were obtained.
• Karnofsky performance status ≥ 60%. performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from definitive surgery or biopsy.

Recurrent

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).
• Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria.
• Two scans to confirm progression are required: at least 1 scan at the time of progression and 1 scan prior to the time of progression.
• Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.

Newly-Diagnosed

• Received any prior treatment for glioma including:
  • Prior prolifeprospan 20 with carmustine wafer;
  • Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent;
  • Prior radiation treatment for GBM or lower-grade glioma;
  • Prior chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Recurrent

• Early disease progression prior to 3 months (12 weeks) from the completion of RT.
• More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is considered one line of chemotherapy).
• Received any prior treatment with lomustine, agents part of any of the experimental arms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF receptor-mediated targeted agent.
• Any prior treatment with prolifeprospan 20 with carmustine wafer.
• Any prior treatment with an intracerebral agent.
• Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Eligibility last updated 2/16/22. Questions regarding updates should be directed to the study team contact.

• Adult subjects with large B-cell lymphoma, including Diffuse large B-cell lymphoma (DLBCL) not otherwise specified, Primary mediastinal large B-cell lymphoma (PMBCL), High-grade B-cell lymphoma (HGBL), and Diffuse large B-cell lymphoma (DLBCL) arising from Follicular lymphoma (FL).
• Subjects must have relapsed disease after 2 or more lines of systemic therapy, OR chemorefractory disease defined as the following: No response to first-line therapy, including the following: PD as best response to first therapy, SD as best response after ≥ 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP), with SD duration no longer than 6 months from the last dose of therapy, Note: Subjects who are intolerant to first-line chemotherapy are excluded OR No response to ≥ 2 lines of therapy, including the following: PD as best response to most recent therapy, SD as best response after ≥ 2 cycles of last line of therapy.
• Subjects must have received adequate prior therapy including at a minimum: Anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and An anthracycline-containing chemotherapy regimen, Subjects with transformed FL must have chemorefractory disease after transformation to DLBCL.
• At least 1 measurable lesion according to the International Working Group (IWG) Lugano Classification {Cheson 2014}. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
• Magnetic resonance imaging of the brain showing no evidence of CNS lymphoma.
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists).
• Toxicities due to prior therapy must be stable and recovered to Grade ≤ 1 (except for clinically nonsignificant toxicities such as alopecia).
• Age 18 or older.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Additional Inclusion Criteria may apply.

• History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast) or FL unless disease free for at least 3 years.
• History of Richter’s transformation of chronic lymphocytic leukemia.
• Autologous stem cell transplant (SCT) within 6 weeks of planned axicabtagene ciloleucel infusion.
• History of allogeneic stem cell transplantation.
• Prior CD19 targeted therapy or prior CAR T cell therapy.
• History of PAP.
• History of severe, immediate hypersensitivity reaction attributed to aminoglycosides.
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous antimicrobials for management. Simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the Kite medical monitor.
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B (HBsAg positive) or hepatitis C (anti-HCV positive) infection. A history of hepatitis B or hepatitis C infection is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
• Additional Exclusion Criteria may apply.

• Are ≥ 18 (or ≥ 20 in Japan and Taiwan or age legally considered to be an adult) years of age at the time of signing the informed consent. In Japan, a participant aged < 20 years of age but ≥ 18 years of age may participate if written informed consent from his/her parent or guardian is provided in addition to the participant’s written informed consent.
• Are participants with histologically or cytologically confirmed locally advanced or metastatic BTC, including intrahepatic CCA, extrahepatic CCA, gallbladder cancer, and ampulla of Vater’s cancer. The histological origin of ampullary carcinomas (intestinal, pancreaticobiliary, or other) will be collected.
• Naïve to chemotherapy, immunotherapy, and interventional radiological treatment (transarterial chemo-embolization, transarterial embolization, transarterial infusion) for locally advanced or metastatic BTC. Participants whose disease has recurred ≥ 6 months after completion of neoadjuvant or adjuvant treatments will be considered eligible.
• Availability of tumor tissue (primary or metastatic) (fresh or archival biopsies) before the first administration of study intervention. Availability of tumor tissue is mandatory except for the safety run-in part. Brush cytology and cell blocks are not acceptable. Tumor tissue (fresh or archival) must be suitable for biomarker assessment as described in the Laboratory Manual.
• At least 1 measurable lesion according to RECIST 1.1. Participants in the safety run-in part do not require a measurable lesion at baseline.
• ECOG PS of 0 or 1 at study entry and at Week 1, Day 1 prior to dosing.
• Life expectancy of ≥ 12 weeks, as judged by the Investigator.
•  Adequate hematological function defined by white blood cell count ≥ 2.0 × 10^9 /L with absolute neutrophil count ≥ 1.5 × 10^9 /L, lymphocyte count ≥ 0.5 × 10^9 /L, platelet count ≥ 100 × 10^9 /L, and hemoglobin (Hgb) ≥ 9 g/dL (participants may have been transfused) at study entry and at Week 1 Day 1 prior to dosing.
  • Previously transfused participants are allowed in the study with a stable Hgb of ≥ 9 g/dL at the time of study entry.
• Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase level ≤ 3.0 × ULN, and an alanine aminotransferase level ≤ 3.0 × ULN. For participants with liver involvement, aspartate aminotransferase ≤ 5.0 × ULN and alanine aminotransferase ≤ 5.0 × ULN are acceptable.
• Adequate renal function defined by an estimated creatinine clearance (CrCl) > 50 mL/min according to the Cockcroft-Gault formula or by measure of CrCl from 24-hour urine collection.
  • CrCl (mL/min) = (140-age) × weight (kg) / (72 × serum creatinine Cr[jaffe]);
  • If female, × 0.85 ;
  • If creatinine is measured by the enzymatic method, add 0.2 and use as Cr[jaffe] = 0.2 + Cr[enzyme].
• Albumin ≥ 2.8 g/dL.
• Adequate coagulation function defined as prothrombin time or international normalized ratio ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy.
• Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and on a stable dose of antivirals (e.g., entecavir, tenofovir, or lamivudine; adefovir or interferon is not allowed) at study entry and with planned monitoring and management including baseline HBV DNA quantity according to appropriate labeling guidance. Participants receiving active hepatitis C virus (HCV) therapy must be on a stable dose at study entry and with planned monitoring and management according to appropriate labeling guidance of approved antiviral.
• Are male or female:
  • Male Participants Agree to the following during the intervention period and for at least 4 months after the last dose of study intervention (35 days corresponding to the time needed to eliminate any study interventions; e.g., 5 terminal half-lives plus 90 days for spermatogenic cycle):
    • Refrain from donating sperm PLUS, either:  Abstain from any activity that allows for exposure to ejaculate; OR
    • Use a male condom:  When having sexual intercourse with a woman of childbearing potential who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year since a condom may break or leak;
    • When engaging in any activity that allows for exposure to ejaculate.
  • Female participants are not pregnant or breastfeeding and at least 1 of the following conditions applies: Not a woman of childbearing potential; OR
  • If a woman of childbearing potential, agree to use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency for the following time periods: 
    Before the first dose of study intervention(s), if using hormonal contraception:
    • Has completed at least one 4-week cycle of an oral contraceptive pill and has either had or has begun her menses; OR
    • Has used a depot contraceptive or extended-cycle contraceptive for at least 28 days and has a documented negative pregnancy test using a highly sensitive assay;
    • During the intervention period;
    • After the study intervention period (i.e., after the last dose of study intervention is administered) for at least 65 days (time needed to eliminate any study interventions, eg, 5 terminal half-lives plus 30 days for a menstrual cycle), and as indicated in the respective label (Summary of Product Characteristics [SmPC]) for gemcitabine and cisplatin. Participants have to agree to the following:
      • Women of childbearing potential should refrain from donating eggs from the start of dosing until 2 months after discontinuing study intervention.
      • The Investigator evaluates the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
    • Have a negative serum or highly sensitive urine pregnancy test, as required by local regulations, within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required.
    • The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early, undetected pregnancy.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and this protocol.

• Previous and/or intercurrent cancers. With the exception of: curatively-treated cancers with no recurrence in > 3 years or early cancers treated with curative intent, including but not limited to cervical carcinoma in situ, superficial, noninvasive bladder cancer, basal cell carcinoma, squamous cell carcinoma in situ, or endoscopically resected gastrointestinal cancers limited in mucosal layer.
• Rapid clinical deterioration not related to malignancy which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or study procedures at study entry and at Week 1 Day 1 prior to dosing.
• Participants with symptomatic central nervous system (CNS) metastases are excluded. Participants with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they are judged to have fully recovered from treatment.
• Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
• Significant acute or chronic infections including:
  • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (testing at Screening is not required). If an Investigator has a strong suspicion of HIV infection without known history for a participant in screening, but the participant refuses testing, discuss with Medical Monitor to assess eligibility.
    • Note: HIV testing is not mandated for study inclusion; however, if it is performed at any point in screening or while on study, a site must consent the participant for HIV testing as per local standard guidance.
    • Active tuberculosis (presence of clinical symptoms, physical or radiographic findings of active tuberculosis).
    • Uncontrolled biliary infection. Biliary tract obstruction should be released by stenting or percutaneous transhepatic biliary drainage (PTBD). Participants with biliary obstruction should have adequate biliary drainage with no evidence of ongoing infection without antibiotics treatment at the time of enrollment as well as on Cycle 1 Day 1.
    • Active bacterial, fungal, or viral infection (with the exception of hepatitis B and hepatitis C) requiring systemic therapy at study entry and at Week 1 prior to dosing.
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
  • Participants with type 1 diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. 
  • Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg of prednisone or equivalent per day.
  • Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) is acceptable.
• History of, or concurrent, interstitial lung disease.
• Known history of hypersensitivity reactions to bintrafusp alfa or its products or known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0), any history of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma.
• Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification ≥ Class II), or serious cardiac arrhythmia.
• Other severe, acute, or chronic medical conditions, including immune colitis, inflammatory bowel disease, immune pneumonitis, or psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior. Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for study intervention are also excluded.
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
• Participants who are candidates for liver transplantation and who can receive the transplantation within a medically acceptable period.
• Concurrent treatment with nonpermitted drugs. Participants who have completed prior adjuvant therapy > 6 months prior to randomization are eligible.
• Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints), including but not limited to anti-PD-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, or anti-4-1BB antibody is not allowed, inclusive of localized administration of such agents.
• Prior therapy with any antibody/drug targeting TGFβ/TGFβ receptor.
• Radiation within 28 days other than focal palliative bone-directed radiotherapy.
• Systemic therapy with immunosuppressive agents within 7 days before the start of study intervention; or use of any investigational drug within 28 days before the start of study intervention.
• Live vaccine administration within 4 weeks of study intervention administration.
• Unable to tolerate CT or magnetic resonance imaging (MRI) in the opinion of the Investigator and/or allergy to contrast material.

Other Exclusions:

• Major surgery within 28 days before the start of study intervention (excluding prior diagnostic biopsy and stenting/PTBD for the purpose of releasing biliary tract obstruction).
• Pregnancy or breastfeeding.
• Known alcohol or drug abuse.
• Legal incapacity or limited legal capacity.

• Recurrent or progressive advanced stage non-small cell lung cancer (no small cell component) with most recent treatment being an FDA approved immune checkpoint inhibitor (pembrolizumab, atezolizumab, or nivolumab).
  • NOTE: Pathology reports documenting the diagnosis of NSCLC are required to be reviewed to confirm outside diagnosis.
• Sufficient tumor tissue available from original diagnosis or subsequent biopsy for analysis of estrogen receptor and aromatase.
• Tumor block or a minimum of 5 unstained slides.
• Failed at least 1 prior FDA approved treatment for advanced NSCLC. 
• Measureable disease by RECIST version 1.1.
• Post-menopausal defined as:
  • Age ≥ 55 years and 1 year or more of amenorrhea;
  •  Age < 55 years and 1 year or more of amenorrhea with an estradiol assay < 20 pg/mL;
  • Surgical menopause with bilateral oophorectomy.
• ECOG performance status 0, 1 or 2.
• Life expectancy of 3 months or more in the opinion of the enrolling investigator and documented in the medical record. 
• Adequate organ function within 14 days of study enrollment defined as: 
• Hematology:
  • Absolute neutrophil count (ANC) ≥ 1500/mm³;
  • Platelets ≥ 100,000/mm³;
  • Hemoglobin ≥ 8 g/dL.
• Biochemistry: 
  • Total Bilirubin within normal institutional limits.
  • AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN), except if there is known hepatic metastasis, wherein transaminases may be ≤ 5 x institutional ULN.
  • Serum creatinine ≤ 1.5 mg/dl or glomerular filtration rate > 50 ml/min.
• Must have recovered to CTCAE v 4 Grade 1 or better from the acute effects of any prior surgery, chemotherapy or radiation therapy. Chronic residual toxicity (i.e., peripheral neuropathy) is permitted. 
• A minimum time period must elapse between the end of a previous treatment and start of study therapy: 
  • 1 week from the completion of radiation therapy for brain metastases;
  • 4 weeks from the completion of chemotherapy or any experimental therapy;
  • 4 weeks from prior major surgery (such as open biopsy or significant traumatic injury).
• Voluntary written consent before any research related procedures or therapy.

• Known active CNS disease.
• If patient has history of brain metastases, the brain lesions must have been treated with radiation and/or surgery.
• Patients should be neurologically stable and requiring ≤ 10mg oral prednisone equivalence of steroids per day.
• Any toxicity from immune-related toxicity from prior immune therapy that would preclude further treatment with anti-PD-1/PDL-1 inhibitor or ongoing IR toxicity ≥ Grade 2.
• Requiring > 10 mg prednisone equivalence of steroids per day for immune-related toxicity.
• Inability or unwilling to swallow study drug.
• Any gastrointestinal condition causing malabsorption or obstruction (e.g., celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome).
• Currently using hormone replacement therapy (oral or patch) or/and phytoestrogen supplements (i.e., black cohosh).
• Known hypersensitivity to exemestane or its excipients.
• Any serious underlying medical condition that, in the opinion of the enrolling physician, would impair the ability of the patient to receive protocol treatment.
• Prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year disease-free interval.
• Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort as these may significantly reduce the availability of exemestane.

• Recurrent or progressive advanced stage non-small cell lung cancer (no small cell component) with most recent treatment being an FDA approved immune checkpoint inhibitor (pembrolizumab, atezolizumab, or nivolumab).
  • NOTE: Pathology reports documenting the diagnosis of NSCLC are required to be reviewed to confirm outside diagnosis.
• Sufficient tumor tissue available from original diagnosis or subsequent biopsy for analysis of estrogen receptor and aromatase.
• Tumor block or a minimum of 5 unstained slides.
• Failed at least 1 prior FDA approved treatment for advanced NSCLC. 
• Measureable disease by RECIST version 1.1.
• Post-menopausal defined as:
  • Age ≥ 55 years and 1 year or more of amenorrhea;
  •  Age < 55 years and 1 year or more of amenorrhea with an estradiol assay < 20 pg/mL;
  • Surgical menopause with bilateral oophorectomy.
• ECOG performance status 0, 1 or 2.
• Life expectancy of 3 months or more in the opinion of the enrolling investigator and documented in the medical record. 
• Adequate organ function within 14 days of study enrollment defined as: 
• Hematology:
  • Absolute neutrophil count (ANC) ≥ 1500/mm³;
  • Platelets ≥ 100,000/mm³;
  • Hemoglobin ≥ 8 g/dL.
• Biochemistry: 
  • Total Bilirubin within normal institutional limits.
  • AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN), except if there is known hepatic metastasis, wherein transaminases may be ≤ 5 x institutional ULN.
  • Serum creatinine ≤ 1.5 mg/dl or glomerular filtration rate > 50 ml/min.
• Must have recovered to CTCAE v 4 Grade 1 or better from the acute effects of any prior surgery, chemotherapy or radiation therapy. Chronic residual toxicity (i.e., peripheral neuropathy) is permitted. 
• A minimum time period must elapse between the end of a previous treatment and start of study therapy: 
  • 1 week from the completion of radiation therapy for brain metastases;
  • 4 weeks from the completion of chemotherapy or any experimental therapy;
  • 4 weeks from prior major surgery (such as open biopsy or significant traumatic injury).
• Voluntary written consent before any research related procedures or therapy.

• Known active CNS disease.
• If patient has history of brain metastases, the brain lesions must have been treated with radiation and/or surgery.
• Patients should be neurologically stable and requiring ≤ 10mg oral prednisone equivalence of steroids per day.
• Any toxicity from immune-related toxicity from prior immune therapy that would preclude further treatment with anti-PD-1/PDL-1 inhibitor or ongoing IR toxicity ≥ Grade 2.
• Requiring > 10 mg prednisone equivalence of steroids per day for immune-related toxicity.
• Inability or unwilling to swallow study drug.
• Any gastrointestinal condition causing malabsorption or obstruction (e.g., celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome).
• Currently using hormone replacement therapy (oral or patch) or/and phytoestrogen supplements (i.e., black cohosh).
• Known hypersensitivity to exemestane or its excipients.
• Any serious underlying medical condition that, in the opinion of the enrolling physician, would impair the ability of the patient to receive protocol treatment.
• Prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year disease-free interval.
• Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort as these may significantly reduce the availability of exemestane.

• Adult patients, 18 years or older.
• Previous participation in an Astex-sponsored ASTX727 clinical trial (including, but not limited to studies ASTX727-01, ASTX727-02, and ASTX727-04) in which the subject was treated with ASTX727 and was still on active treatment with ASTX727 at the time of study completion as determined by Astex. 
• Subject is considered to be benefitting from ASTX727 treatment in the opinion of the treating investigator at the time of parent study completion (subjects must not be withdrawn from the parent study until eligibility for this study is confirmed). 
• Subject is able to understand and comply with the study procedures and understands the risks involved in the study. 
• Subject provides written informed consent before undergoing any study-specific procedure.
• Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice 2 highly effective contraceptive methods of birth control and must agree not to become pregnant for 6 months after completing treatment; men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures and must agree not to father a child while receiving ASTX727 and for at least 3 months after completing ASTX727 treatment.

• Any subject who, in the opinion of the investigator, may have other conditions, organ dysfunction, or for whom safety data from parent study participation suggests the risks of continuing treatment with ASTX727 may outweigh the benefits.

• 18 years of age or older.
• Able to read, write and understand English.
• Undergoing chemotherapy, radiation therapy, CAR-T, or bone marrow transplant for a cancer diagnosis within the previous 3 years or have metastatic cancer.
• A mean score of at least 1.1 on the Cancer and Treatment Distress (CTxD) or at least one item rated at a 3 (often true) or 4 (nearly all the time).
• A minimum score of 3 on the PC-PTSD-5.
• Denial of suicidal ideation or intent, with no evidence of psychotic behavior.
• Participants must be willing and able to travel to Mayo Clinic outside of normally scheduled visits to participate in the study.

• Individuals under 18 years of age.

• Age > 22 years (minimum age approved for use).
• Polypoid (0-Is) and non-polypoid (0-IIa, 0-IIb and 0-IIc) lateral spreading lesions according to Paris classification.
• Colorectal lesions situated between 5 and 15 cm from the dentate line.
• Colorectal mucosal lesions ranging from 1.5 to 7 cm in maximum diameter.
• Colorectal subepithelial lesions < 2 cm in size.
• Absence of uncorrectable bleeding disorder or coagulopathy (platelet count > 50,000 and INR < 1.5).
• Ability to give informed consent.

• Inability to receive general anesthesia.
• Presence of medical conditions for which a transanal approach is contraindicated (e.g., anal stricture, radiation proctopathy).
• Excavated (0-III) colorectal lesions according to Paris classification.
• Suboptimal colon preparation.
• Clinical discretion of the provider.

• Biopsy-proven histological diagnosis of localized prostate cancer (pT2 or specimen confined pT3).
• Having undergone radical prostatectomy (open or laparoscopic) with bilateral pelvic lymph node dissection.
• Negative surgical margins on final specimen.
• Men that decline adjuvant therapy.
• Detectable serum PSA of 0.1 ng/mL or >.
• 24 months or less since radical prostatectomy at time of study screening.

• Unable or unwilling to provide informed consent.
• Treated prior to surgery with any form of hormone, antiandrogen, or androgen deprivation therapy.
• Treated prior to surgery with any form of chemotherapy or radiotherapy.
• Medical conditions/history that precludes subjects from following a fasting regimen including, but not limited to:
  • Diabetes Mellitus.
• On hormone therapy (Casodex, GnRH agonist/antagonist).

• All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated.
• Laboratory values used to assess eligibility must be no older than 7 days at the start of therapy.
• Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility.
• If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are > 7 days old, then laboratory evaluations must be re-checked within 48 hours prior to initiating therapy. If the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.
• A pre- and post-operative brain MRI with and without contrast, and a baseline spine MRI with contrast, must be obtained prior to enrollment. The requirement for post-operative MRI is waived for patients who undergo biopsy only.
• Patients must be ≥ 3 years and ≤ 21 years of age at the time of enrollment.
• Patients must have eligibility confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1:
  • Newly diagnosed high-grade glioma with BRAFV600-mutation;
  • Positive or negative results for H3 K27M by immunohistochemistry (IHC)
  • Histologically confirmed high-grade glioma (WHO Grade III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG), glioblastoma (GB), and high-grade astrocytoma, NOS.
• Patients must have had histologic verification of a high-grade glioma diagnosis. CSF cytology by lumbar puncture must be done if clinically indicated and determined to be safe prior to study enrollment. If cytology proves positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible.
• A pre- and post-operative brain MRI with and without contrast and a baseline spine MRI with contrast must be obtained prior to enrollment. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is positive, the patient would be considered to have metastatic disease and would be ineligible.
• Patients must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. See https://www.cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials under Standard Sections for Protocols.
• Adequate Bone Marrow Function defined as:
  • Peripheral absolute neutrophil count (ANC) ≥ 1000/µL;
  • Platelet count ≥ 100,000/µL (transfusion independent);
  • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions).
• Adequate Renal Function defined as:
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m^2; or
  • A serum creatinine based on age/gender as follows:
  • 3 to < 6 years | Male 0.8 | Female 0.8;
  • 6 to < 10 years | Male 1.0 | Female 1.0;
  • 10 to < 13 years | Male 1.2 | Female 1.2;
  • 13 to < 16 years | Male 1.5 | Female 1.4;
  • ≥ 16 years | Male 1.7 | Female 1.4.
  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR32 utilizing child length and stature data published by the CDC.
  • Adequate Liver Function defined as:
    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age; and
    • SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
• Central Nervous System Function defined as:
  • Patients with a seizure disorder may be enrolled if their seizures are well controlled while on non-enzyme inducing anticonvulsants permitted on this study.
• Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (Day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.

• Patients with intrinsic brainstem or primary spinal cord tumors will be excluded.
• Patients with metastatic disease (defined as neuraxis dissemination either by imaging or by cytology) will be excluded.
• Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the treatment of HGG other than surgical intervention and/or corticosteroids.
• Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK inhibitor, or an ERK inhibitor.
• Patients with a history of a malignancy with confirmed activating RAS mutation.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, and their excipients.
• Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease, or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.
• Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs.
• History of Hepatitis B Virus, or Hepatitis C Virus infection (patients with laboratory evidence of cleared Hepatitis B Virus and/or Hepatitis C Virus may be enrolled).
• History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
  • Recent myocardial infarction (within the last 6 months);
  • Uncontrolled congestive heart failure;
  • Unstable angina (within last 6 months);
  • Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to the first dose of study treatment;
  • Coronary angioplasty or stenting (within last 6 months);
  • Intra-cardiac defibrillators;
  • Abnormal cardiac valve morphology (≥ Grade 2) documented by echocardiogram.
• Patients with a history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension).
• Patients with presence of interstitial lung disease or pneumonitis.
• Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants for the duration of the study and for 4 months following discontinuation of study therapy.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential (male or female) are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months following discontinuation of study therapy. Male patients (including those who have had a vasectomy) taking dabrafenib and trametinib combination therapy must use a condom during intercourse while on study and for 16 weeks after stopping treatment, and should not father a child during these periods. Women of childbearing potential should use. effective non-hormonal contraception during therapy and for 4 weeks following discontinuation of dabrafenib and at least 4 months following the last dose of trametinib in patients taking combination therapy.  Women should be advised that dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, FDA, and NCI requirements for human studies must be met.

Eligibility last updated 9/28/21. Questions regarding updates should be directed to the study team contact.

• Between the ages of 18-50 years old.
• Are of moderate to high fitness level and participate in regular physical activity.
• Must have a body mass index (BMI) less than 31 kg/m^2.
• Must be able to provide clear informed written consent.

• History of chronic respiratory, cardiovascular, metabolic disease or neural/cognitive disorders.
• Anemia (< 12 g/dl for males, < 11 g/dl for females).
• Migraines.
• Active smoker (smoke within the past 6 years), or have more than 5 pack-years of smoking history
• Females who are pregnant or trying to become pregnant.

Task 1 Specific:

• History of pneumothorax, functionally limiting barotraumas or any inability to equalize tympanic pressure (e.g., during diving, swimming or flying).
• Current dental abscesses or jaw pain consistent with severe dental caries.
• Prior allergies or serious side effects from vasoconstrictors such as Afrin™ (oxymetazoline hydrochloride) utilized for sinus decongestion.
• Hyperbaric exposure within the last 24 hours (for chamber visits).

• Aged ≥ 12 years.
• At least 1 symptomatic stone event (passage or procedural intervention) within 3 years prior to enrollment or a symptomatic stone event within 5 years if the patient also has new stone formation detected on imaging during the last 5 years. Symptomatic stone defined as any of the following:
  • Stone passage;
  • Procedural intervention;
  • Radiographically or ultrasonographically confirmed stone with any of the following:
    • Gross hematuria;
    • Renal colic or atypical abdominal pain attributed to the stone, as determined by a treating provider;
    • A clinical pattern of intermittent symptoms consistent with intermittent obstruction at the ureteropelvic junction, as determined by a treating provider.
• Low 24‐hr urine volume 1. ≥18 years old: <1.8 L/day 2. <18 years old: <20 ml/Kg/day up to 1.8L/day.
• Able to provide informed consent (parental permission for children).
• Owning and willing to use a smartphone or other device (e.g., tablet) compatible with the study‐provided wireless enabled "smart" bottle.

• Spinal cord injury.
• Currently undergoing active treatment for cancer except basal cell skin cancer, or patients with a history of cancer who completed their initial therapy <1 year before screening. 
• Known infectious (struvite), monogenic or other causes of stone disease for which therapies are likely to significantly alter course of stone disease:
  • Cystinuria;
  • Primary hyperoxaluria;
  • Primary xanthinuria;
  • Primary hyperparathyroidism;
  • Sarcoidosis;
  • Medullary sponge kidney.
• History or presence of hyponatremia (serum sodium <130 mmol/L) or hypo‐osmolality (serum osmolality <275 mosm/kg).
• Study participants with comorbidities that preclude high fluid intake or prior surgery precluding high fluid intake or leading to GI fluid losses:
  • History of or current Crohn's disease, ulcerative colitis, short gut syndrome (e.g. ileostomy, bowel bypass surgery to treat obesity, small bowel resection), chronic diarrhea, or GI tract ostomy.
  • History of malabsorptive (e.g., Roux‐en‐Y gastric bypass) or restrictive (e.g., sleeve gastrectomy) bariatric surgery procedures.
  • Congestive heart failure:
    • NYHA class II or greater; and/or
    • Hospital admission in the past year for heart failure.
  • Lung disease with a home oxygen requirement.
  • Chronic kidney disease (eGFR <30 ml/min/1.7 m2 over a 3‐month period):
    • For adults (age ≥18), we will use the CKD‐Epi equation which requires the measurement of serum creatinine only;
    • For children (age <18), we will use the bedside Schwartz (CKiD) formula.
  • Nephrotic syndrome (>3.5 grams of protein per 24 hours) g. Cirrhosis with ascites.
• Women who are currently pregnant or planning pregnancy within 2 years.
• Renal transplant recipient.
• Bedridden study participants (ECOG ≥ 3).
• Uncorrected anatomical obstruction of the urinary tract.
• History of recurrent urinary tract infections (> 3 UTI/year proven by urine culture).
• Exclusions due to medication use:
  • Chronic use of lithium'
  • Long‐term glucocorticoid use (> 7.5 mg prednisone daily for > 30 days prior to enrollment)'
  • Intake of narcotic medication on a daily basis for >30 days prior to enrollment'
  • Supplemental Vitamin C (> 1 g daily).
• Individuals with stones that have developed after the initiation of medications that are strongly associated with USD such as carbonic anhydrase inhibitors (acetazolamide, topiramate, zonisamide), high dose vitamin C (> 1 g daily), high dose calcium supplementation (> 1,200 mg daily) AND who have discontinued or plan to discontinue these medications.
• Individuals with stones composed of medications that may crystallize in the urine (guaifenesin, sulfonamides, triamterene, and the protease inhibitors indinavir and nelfinavir) AND who have discontinued or plan to discontinue these medications.
  • Note: Individuals who are on long‐term medications that increase the risk of stone disease, who cannot stop these medications due to other chronic conditions (e.g., HIV) and who may reduce their risk for stone recurrence through increased fluid intake, will be eligible to participate in the trial. Examples of these medications include:
    • Carbonic anhydrase inhibitors (acetazolamide, topiramate, zonisamide);
    • Medications that may crystallize in the urine (guaifenesin, sulfonamides, triamterene, and the protease inhibitors indinavir and nelfinavir).
• Study participants <2 yrs life expectancy.
• Non‐English Speakers.
• History of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH).
• Anatomical urologic abnormalities including ileal conduits, horseshoe kidney, megaureter or solitary kidney.
• Psychiatric conditions impairing compliance with the study.
• Vulnerable population (prisoner and/or cognitive impairment that the investigator feels will impact the study participant's ability to participate in the protocol).
• Individual who will be unable to participate in the protocol in the judgment of the investigator.

• Adolescents between the ages of 14 and 19 years of age.
• Existing or newly diagnosed epilepsy.
• Currently receiving continued care within the Mayo Clinic Pediatric Neurology Department.
• Participants must live within approximately 70 miles of the Mayo Clinic Rochester campus.

• Adolescents with a history of severe intellectual disability based on chart review and/or prior neuropsychological testing (e.g., nonverbal, non-ambulatory).

• Non-Infectious Active Uveitis of the posterior segment of the eye.

• Females who are pregnant, nursing, or planning a pregnancy.
• Confirmed or suspected infectious uveitis.

• Subject is male or female.
• Subject is at least 30 years old.
• Subject is female and must be nonpregnant and nonlactating. A woman of childbearing potential must have a documented negative pregnancy test at screening.
  • NOTE: A woman is considered to be of childbearing potential unless she is postmenopausal (amenorrheic for at least 2 years) or documented to be surgically sterile (bilateral tubal ligation or total hysterectomy). A female subject may be admitted to the study on the basis of a negative urine pregnancy test. If the urine bHCG (beta human chorionic gonadotropin) test is positive, a serum bHCG test must be performed. The pregnancy test must be confirmed negative for a subject to be eligible for this study.
• During the study and for 30 days after receiving the last dose of the study drug, females of childbearing potential or males capable of fathering children must agree to use highly effective birth control measures (failure rate <1% when used consistently and correctly) or agree to abstain from sexual intercourse.
• Subject must meet the diagnostic criteria of nOH, as demonstrated by a sustained reduction in BP of ≥ 20 mmHg (systolic) or ≥ 10 mmHg (diastolic) within 3 min of being tilted up to ≥ 60° from a supine position as determined by a tilt-table test.
• Subject must score at least a 4 on the Orthostatic Hypotension Symptom Assessment Question #1 at randomization visit.
• For subjects with PD only: Subject has a diagnosis of PD according to the United Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria (1992).
• For subjects with MSA only: Subject has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (2008).
• For subjects with PAF only: Subject has documented impaired autonomic reflexes, including the Valsalva maneuver performed within 24 months from the date of randomization.
• Subject has plasma NE levels >100 pg/mL after being in seated position for 30 minutes.
• Subject is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.
• Subject is able to communicate well with the investigator and clinic staff, understands the expectations of the study and is able to comply with the study procedures, requirements, and restrictions.

• Subject has a known systemic illness known to produce autonomic neuropathy, including but not limited to amyloidosis and autoimmune neuropathies. Subject has diabetes mellitus and diagnosis of PAF. Subject with diabetes mellitus and either MSA or PD, will be evaluated on a case by case basis by the medical monitor and considered ineligible unless they meet all of the following criteria:
  • Well controlled type-2 DM in treatment with only oral medications and diet;
  • HgbA1C of ≤ 7.5% performed during screening or up to 12 weeks before screening;
  • No clinically evident peripheral neuropathy (e.g., normal sensory examination on peripheral extremities);
  • No known retinopathy (e.g., annual ophthalmic exam is sufficient);
  • No nephropathy (e.g., absence of albuminuria and GFR > 60).
• Subject has a known intolerance to other NRIs or SNRIs.
• Subject currently uses concomitant antihypertensive medication for the treatment of essential hypertension.
• Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, whichever is longer, prior to randomization or requires concomitant use until the follow-up visit.
• Subject has changed dose, frequency, or type of prescribed medication for orthostatic hypotension within 7 days prior to randomization visit.
  •  Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior to randomization.
• Subject has a known or suspected alcohol or substance abuse within the past 12 months (DSM-IV-TR® definition of alcohol or substance abuse).
• Subject has a clinically unstable coronary artery disease, or major cardiovascular or neurological event in the past 6 months.
• Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to randomization.
• Subject has a history of untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the subject.
• Subject has any significant uncontrolled cardiac arrhythmia.
• Subject has a Montreal Cognitive Assessment (MoCA) ≤ 23.
• Subject is unable or unwilling to complete all protocol specified procedures including questionnaires.
• Subject had a myocardial infarction in the past 6 months or has current unstable angina. 
• Subject has known congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).
• Subject has any malignant disease other than carcinoma in situ of the cervix or basal cell carcinoma within the past 2 years prior to screening.
• Subject has a known gastrointestinal (GI) condition, which in the investigator’s judgment, may affect the absorption of study medication (e.g., ulcerative colitis, gastric bypass).
• Subject has psychiatric, neurological, or behavioral disorders that may interfere with the ability of the subject to give informed consent or interfere with the conduct of the study.
• Subject is currently receiving any investigational drug or has received an investigational drug within 30 days of dosing. An investigational drug is defined as nonregulatory agency approved drug (e.g., Food and Drug Administration).
• Subject has a clinically significant abnormal laboratory findings (e.g., alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3.0 x upper limit of normal [ULN]; blood bilirubin [total] > 1.5 x ULN; estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m^2, or any abnormal laboratory value that could interfere with safety of the subject).
• Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal behavior, as outlined by the C-SSRS (Baseline/Screening Version) subject should be assessed by the rater for risk of suicide and the subject’s appropriateness for inclusion in the study.
• Subject has a concurrent disease or condition that, in the opinion of the investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug.
• Subject has known hypersensitivity to TD-9855 (ampreloxetine hydrochloride), or any excipients in the formulation.
• Subject has:
  • confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) documented with coronavirus disease 2019 [COVID-19] positive test result, OR (ii) is suspected of SARS-CoV-2 infection (clinical features without documented test results two weeks after resolution of symptoms and remains asymptomatic until Day 1); OR
  • has been in close contact with a person with known (or suspected) SARS-CoV-2 infection and remains asymptomatic until Day 1.

• Male and female patients aged ≥ 6 years and ≤ 65 years on the day informed consent is obtained.
• Patients diagnosed with TSC based on the clinical diagnostic criteria of International Tuberous Sclerosis Complex Consensus Conference 2012 and presenting visible facial angiofibroma.
• An FA severity score of 2 or 3 on the IGA scale.
• Patients or their legal representatives capable of understanding the explanation of the clinical trial and who give written informed consent for participation.
• Patients or their legal representatives able to maintain patient diaries following the instructions of the investigator or sub-investigator.

• Patients who cannot carry out the treatment plan or follow-up assessment.
• Patients with serious skin lesions such as erosions or ulcers.
• Patients with known hypersensitivity to any component of the study product.
• Patients who have received rapamycin/sirolimus, everolimus, or temsirolimus within 3 months of enrolment.
• Patients who received laser therapy or surgical therapy within 6 months prior to trial enrolment.
• Patients who participated in any other clinical trial within 3 months prior to the day of enrolment.
• Patients judged unsuitable for this clinical trial by the investigator or sub-investigator.
• Pregnant or lactating females.
• Sexually active females of childbearing potential not using adequate contraception and sexually active males not using adequate contraception.
• Patients with immune dysfunction or receiving any form of immunosuppression.
• Patients with severe FA, with a score of 4 on the IGA scale.
• Patients with an FA severity score of less than 2 on the IGA scale.

• Patients 18
  •65 years of age.
• Diagnosed with primary IgAN.
• Currently being treated for IgAN with stable, optimal therapy, including an ACE inhibitor or an ARB or a direct renin-inhibitor.
• Has urine protein greater than or equal to 1 gram/24-hour. 
• Has hematuria (blood cells present in urine).

• Patients less than 18 years or older than 65 years old.
• Has renal disease other than IgAN.
• Has a diagnosis of rapidly progressive glomerulonephritis. 
• Has a diagnosis of Henoch-Schonlein Purpura (IgA Vasculitis).
• Has poor kidney function with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m^2. 
• Has known human immunodeficiency virus (HIV) infection, hepatitis C virus (HCV) infection or hepatitis B virus (HBV) infection.
• Has on-going high blood pressure.
• Treated with systemic corticosteroids or any immunosuppressant agents in the past 12 months .
• Received an organ transplant.

Patient

• Adolescents and young adults age 12 to 21 years at time of consent who have had NYHA Class II or higher heart failure in the preceding two years.
• Actively being followed by a pediatric heart failure specialist with at least one visit in the past year, or actively being followed by a pediatric cardiologist with Heart Failure as an active diagnosis and history of consultation with a pediatric heart failure specialist.
• English speaking.
• Inpatient or outpatient.
• Any etiology of heart failure including but not limited to cardiomyopathy, myocarditis, and congenital heart disease, unless mentioned in Exclusion Criteria.
• May have systolic or diastolic heart failure, or Fontan/single ventricle heart failure.
• May have had advanced cardiac therapies including pacemakers, ICDs, ventricular assist devices, or cardiac transplant as long as other Inclusion Criteria are met.

Caregiver

• Parent(s)/guardian(s)/caregiver(s) of participating adolescent/young adult subjects with heart failure.
• Age 18 or older.
• English speaking.
• Significant co-morbidities that may greatly impact their ability to distinguish symptoms of heart failure, such as: muscular dystrophy, active malignancy, or primary non-cardiac organ failure (e.g., renal failure with uremic cardiomyopathy).
• Clinical condition that would interfere with their ability to participate in a focus group or interview (e.g., severe developmental delay or other cognitive impairment).

Patient

• Significant co-morbidities that may greatly impact their ability to distinguish symptoms of heart failure, such as: muscular dystrophy, active malignancy, or primary non-cardiac organ failure (e.g., renal failure with uremic cardiomyopathy).
• Clinical condition that would interfere with their ability to participate in a focus group or interview (e.g., severe developmental delay or other cognitive impairment).

Caregiver

• Clinical condition that would interfere with their ability to participate in a focus group or interview (e.g., severe developmental delay or other cognitive impairment).

   

• Subject and/or legally authorized representative is willing and able to provide consent prior to study participation.
• Subject is ≥ 18 years of age.
• Subject is undergoing or a candidate for routine SOC monitoring per the collection sites’ CMV management protocol.
• Subject meets one of the following two criteria:
  • Subject is a kidney, liver, lung, or heart transplant recipient; or
  • Subject is an allogeneic or autologous HSCTR.
• Subject is serotype D+/R-, D-/R+ or D+/R+.
• Subject has a positive CMV result of equal to or above the LLOQ (≥LLOQ) within 10 days prior to enrollment with no intervening negative CMV result below the LLOQ (<LLOQ) and/or TND by SOC viral load testing.

• Subject already participated in this study.
• Subject is unsuitable for study participation based on the PI’s decision (e.g., unlikely to comply with study procedure(s), significant medical complication).
• Subject is participating in another investigational study that the PI believes might interfere with the subject’s participation in this study.

• The subject is of legal age to participate in the study per the laws of their respective geography. 
• Underwent a prior catheter ablation procedure for non-valvular AF between 90 and 180 days prior to randomization (sequential) or is planning to have clinically indicated catheter ablation within 10 days of randomization (concomitant). 
• The subject has a calculated CHA2DS2-VASc score of 2 or greater for males or 3 or greater for females. 
• The subject is deemed to be suitable for the defined protocol pharmacologic regimen. 
• The subject is able to undergo TEE examinations. 
• The subject or legal representative is able to understand and is willing to provide written informed consent to participate in the trial. 
• The subject is able and willing to return for required follow-up visits and examinations.

• The subject is currently enrolled in another investigational study that would directly interfere with the current study, except when the subject is participating in a mandatory governmental registry, or a purely observational registry with no associated treatments. Each instance must be brought to the attention of the sponsor to determine eligibility, regardless of type of co-enrollment being proposed. 
• The subject requires long-term anticoagulation therapy for reasons other than AF-related stroke risk reduction, for example due to an underlying hypercoagulable state (i.e., even if the device is implanted, the subjects would not be eligible to discontinue OAC due to other medical conditions requiring chronic OAC therapy). 
• The subject is deemed by the treating physician to be unsuitable for chronic anticoagulation and/or aspirin therapy due to bleeding risk, allergy, or other reasons. 
• The subject had or is planning to have any cardiac or major non-cardiac interventional or surgical procedure (excluding non-valvular AF ablation and cardioversion) within 30 days prior to or 60 days after randomization [including, but not limited to: percutaneous coronary intervention (PCI), other cardiac ablation (VT ablation, etc.), etc.]. 
• The subject had a stroke or transient ischemic attack (TIA) within the 60 days prior to randomization. 
• The subject had a prior major bleeding event per ISTH definition within the 14 days prior to randomization. Lack of resolution of related clinical sequelae, or planned and pending interventions to resolve bleeding/bleeding source, are a further exclusion regardless of timing of the bleeding event. 
• The subject has had a myocardial infarction (MI) documented in the clinical record as either a non-ST elevation MI (NSTEMI) or as an ST-elevation MI (STEMI), with or without intervention, within 90 days prior to randomization.
• The subject has a history of atrial septal repair or has an ASD/PFO device. 
• The subject has an implanted mechanical valve prosthesis in any position. 
• The subject is of childbearing potential and is, or plans to become pregnant during the time of the study (method of assessment upon study physician's discretion).
• The subject has a documented life expectancy of less than two years.
• The subject has a cardiac tumor. 
• The subject has signs/symptoms of acute or chronic pericarditis. 
• There is evidence of tamponade physiology. 
• Contraindications (anatomical or medical) to percutaneous catheterization procedures. 
• The subject has documented NYHA Class IV heart failure. 
• The subject has documented surgical closure of the left atrial appendage. 
• The subject has an active infection.

• Patients that are undergoing liver tumor treatment with microwave ablation therapy.

• Pregnant women.
• The liver tumor cannot be easily identified on a contrast-enhanced CT scan.
• There are contraindications to the use of contrast required in the study.
• Treatment of 4 or more liver tumors.

• Age 18 years or older at the time of enrollment on Segment A.
• Patients with acute leukemia or chronic myelogenous leukemia with no circulating blasts and with less than 5% blasts in the bone marrow.
• Patients with myelodysplasia with no circulating blasts and with less than 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with <5% vs. 5-10% blasts in this disease).
• Patients with relapsed chronic lymphocytic leukemia with chemosensitive disease at time of transplantation.
• Patients with lymphoma with chemosensitive disease at the time of transplantation.
• Planned reduced intensity conditioning regimen.
• Patients must have a related or unrelated peripheral blood stem cell donor as follows:
  • Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing, and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation.
  • Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and –DRB1 at high resolution using DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem cells and meet NMDP criteria for donation.
• Cardiac function: Left ventricular ejection fraction at least 45%.
• Estimated creatinine clearance acceptable per institutional guidelines.
• Pulmonary function: DLCO corrected for hemoglobin at least 40% and FEV1 predicted at least 50%.
• Liver function acceptable per institutional guidelines.
• Karnofsky Performance Score at least 60%.
• Female patients (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two (2) effective methods of contraception at the same time, or agree to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 12 months post-transplant (see Section 2.6.4 for definition of postmenopausal).
• Male patients (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following: practice effective barrier contraception (see Section 2.6.4 for list of barrier methods), or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant.
• Plans for the use of post-transplant maintenance therapy must be disclosed upon enrollment and must be used irrespective of the outcome of the randomization.
• Voluntary written consent obtained prior to the performance of any study-related procedure that is not a part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

• Prior allogeneic transplant.
• Active CNS involvement by malignant cells.
• Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, including CMML.
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
• Presence of clinically significant fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated.
• Patients seropositive for human immunodeficiency virus (HIV) with detectable viral load. HIV+ patients with an undetectable viral load on antiviral therapy are eligible.
• Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
• Female patients who are pregnant (as per institutional practice) or lactating.
• Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Patients with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously must be reviewed and approved by the Protocol Officer or Chairs.
• Planned use of ATG or alemtuzumab in conditioning regimen.

• Congenital hemophilia A; FVIII ≤ 5% or congenital hemophilia B; FIX ≤ 5%.
• Birth date on or after January 1, 2010.
• Care established at one of the participating HTCs.
• Co-enrollment in the ATHNdataset.
• Parent or authorized guardian can provide informed consent.

• Patients who are referred to the HTC with no record of bleed and factor utilization data.