• Ability to comprehend and willingness to sign a written ICF for the study.
• Male and female participants at least 18 years of age at the time of signing the ICF; a legally minor participant from Japan needs written parental consent.
• Histologically or cytologically confirmed cholangiocarcinoma that is previously untreated and considered unresectable and/or metastatic (Stage IV per the AJCC Cancer Staging Manual [AJCC 2002]).
• Radiographically measurable or evaluable disease by CT or MRI per RECIST v1.1 criteria (Eisenhauer et al 2009).
• ECOG performance status 0 to 1.
• Documented FGFR2 rearrangement.

• Received prior anticancer systemic therapy for unresectable and/or metastatic disease (not including adjuvant/neo-adjuvant treatment completed at least 6 months prior to enrollment, and participants that have received treatment for locally advanced disease with trans-arterial chemoembolization or selective internal radiation therapy, if clear evidence of radiological progression is observed before enrollment).
• Child-Pugh B and C.
• Toxicities related to prior therapy(ies) must be CTCAE v5.0 ≤ Grade 1 at the time of screening.
• Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor embolization), other than the therapies being tested in this study.
• The participant must not be a candidate for potentially curative surgery.
• Current evidence of clinically significant corneal (including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and keratoconjunctivitis) or retinal disorder (including but not limited to central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, retinal detachment) as confirmed by ophthalmologic examination
• Radiation therapy administered within 4 weeks of enrollment/randomization/first dose of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Evidence of fibrosis within a radiation field from prior radiotherapy is permitted with medical monitor approval. A 2-week washout is permitted for palliative radiation to non-CNS disease.
• Known CNS metastases or history of uncontrolled seizures. Participants with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period, and they are on stable or decreasing dose of corticosteroids for at least 1 week.
• Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• Participants with laboratory values at screening defined below:
• Hematology
  • Platelets | ≤ 75/100 × 109/L (transfusion allowed with 2-week washout period);
  • Hemoglobin | ≤ 9.0 g/dL (transfusion allowed with 2-week washout period);
  • ANC | ≤ 1.5 × 109/L.
• Hepatic 
  • ALT | > 2.5 × ULN (> 5 × ULN if related to underlying disease or the presence of liver metastases);
  • AST | > 2.5 × ULN (> 5 × ULN if related to underlying disease or the presence of liver metastases);
  • Total bilirubin | ≥ 1.5 × ULN (≥ 2.5 × ULN if Gilbert syndrome).
  • NOTE: Participants with biliary drainage to improve liver function tests to meet above criteria are allowed.
• Renal 
  • < 60 mL/min based on Cockcroft-Gault formula.
• Chemistry 
  • Serum phosphate | > ULN;
  • Serum calcium | Outside of normal range or serum albumin-corrected calcium outside of the normal range when serum albumin is outside of the normal range.
• History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues (exception: commonly observed calcifications in soft tissues, such as the skin, kidney, tendons or vessels due to injury, disease, and aging, in the absence of systemic mineral imbalance).
• Gastrointestinal conditions/disorders that may raise gastric and/or small intestinal pH that could interfere with absorption, metabolism, or excretion of pemigatinib.
• Inability of the participant to swallow and retain oral medication
• Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study treatment administration, New York Heart Association Class III and IV congestive heart failure, and uncontrolled arrhythmia (participants with pacemaker or with atrial fibrillation and well controlled heart rate are allowed).
• History or presence of an abnormal ECG, which, in the investigator's opinion, is clinically meaningful. A screening QTcF interval > 480 milliseconds is excluded. For participants with an interventricular conduction delay (QRS interval >120 ms), the JTc interval may be used in place of the QTc with sponsor approval (the JTc must be ≤ 340 milliseconds if JTc is used in place of the QTc).
• Chronic or current active infectious disease requiring systemic antibiotics or antifungal or antiviral treatment within 2 weeks prior to enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed). Note: HIV-positive participants are allowed if all of the following criteria are met: CD4+ count > 300/uL, undetecable viral load, receiving antiretroviral therapy that does not interact with study drug, and no HIV/AIDS-associated opportunistic infection in the last 12 months. 
• Current use of prohibited medication.
• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment. Note: Moderate CYP3A4 inhibitors are not prohibited.
• Known hypersensitivity or severe reaction to pemigatinib, gemcitabine, cisplatin, or their excipients (refer to the IB and commercially available product information sheets).
• Inability or unlikeliness of the participant to comply with the dose schedule and study evaluations in the opinion of the investigator.
• Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.
• For NA, EU, and ROW participants, women who are pregnant or breastfeeding or participants expecting to conceive or father children within the projected duration of the study, starting with the screening visit through completion of safety follow-up or through 90 days from the date of last dose of pemigatinib and 6 months after the last dose of gemcitabine and/or cisplatin for male participants.
• For Japanese participants, pregnant or breastfeeding women or participants expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after last dose of pemigatinib (men; based on the spermatogenetic cycle) and 30 days after last dose of pemigatinib (women; based on menstrual cycle) and 6 months after the last dose of gemcitabine and/or cisplatin (men and women). Female participants who are breastfeeding and wish to enroll must discontinue breastfeeding before receiving study drug and must not resume breastfeeding until at least 30 days after last dose of study treatment, which exceeds 5 times the half-life of pemigatinib.
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
• Inability of the participant (or parent, guardian, or legally authorized representative) to comprehend or unwilling to sign the ICF.
• Any contraindication to gemcitabine or cisplatin as per each SmPC or product insert.
• History of hypovitaminosis D requiring supraphysiologic doses (e.g., 50,000UI/weekly) to replenish the deficiency. Participants receiving vitamin D supplements are allowed.

- No available autologous iPSC-CL as defined by the manufacturer's release criteria.  (This applies to Part II of the study and applies to the treatment arm only).

- History of symptomatic episodes of cardiac arrythmia requiring cardiac defibrillation or escalation of medications.

- Heart failure with preserved ejection fraction.

- Heart failure due to co-morbid conditions (e.g., amyloidosis, valvular heart disease, refractory anemia).

- QTc greater than 500 ms.

- Stage III or higher chronic kidney disease.

- Decompensated liver cirrhosis.

- History of coronary artery disease.

- Uncontrolled diabetes mellitus.

- Any history of cancer.

- Contraindication for use of amiodarone for up to 3 months (treatment arm only).

- Contraindication for insertion of Insertable Cardiac Monitor.

- Contraindication for placement of LifeVest cardioverter defibrillator.

- Positive serology testing for HIV, Hepatitis B, Hepatitis C or Syphilis.

- Obesity with BMI greater than 30.

- Current alcohol or drug abuse precluding heart transplantation.

- Active infection requiring ongoing treatment.

- Contraindication to anesthesia.

- Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose
additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality of the data
obtained from the study.

- Inability or unwillingness of a participant to give written informed consent or comply with study protocol.

- History of non-compliance.

- Inability to be accompanied around the clock for any part of the first 3 weeks post product administration.

- Uncontrolled depression.

- Denied heart transplant due to social determinants.

- Current participation in another cardiac interventional clinical trial that could confound the results of this study.

- Previous heart transplant.

Eligibility last updated 7/19/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 9/20/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 11/2/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

• Documentation of Disease
  • Confirmation of GCT histology (both seminoma and nonseminoma) on pathologic review at the center of enrollment
  • Tumor may have originated in any primary site
    • In rare circumstances, patients will be allowed to enroll even if a pathologic diagnosis may not have been established
    • This would require a clinical situation consistent with the diagnosis of GCT (testicular, peritoneal, retroperitoneal or mediastinal mass, elevated tumor marker levels {HCG ≥ 500; AFP ≥ 500} and typical pattern of metastases)
• Evidence of Disease
  • Must have evidence of progressive or recurrent GCT (measurable or non-measurable) following one line of cisplatin-based chemotherapy, defined as meeting at least one of the following criteria
    • Tumor biopsy of new or growing or unresectable lesions demonstrating viable non-teratomatous GCT
      • Enrollment in this study for adjuvant treatment after macroscopically complete resection of viable GCT is not allowed
    • In the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for the study
    • Consecutive elevated serum tumor markers (HCG or AFP) that are increasing
      • Increase of an elevated LDH alone does not constitute progressive disease
    • Development of new or enlarging lesions in the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to increase
• Prior Treatment
  • Must have received 3-6 cycles of cisplatin-based chemotherapy as part of first-line (initial) chemotherapy
    • Prior POMBACE, CBOP-BEP, or GAMEC are allowed
    • For patients requiring immediate treatment, 1 cycle of conventional-dose salvage chemotherapy is allowed
      • Therefore, these patients may have received 7 prior cycles of chemotherapy. 6 cycles as part of first-line chemotherapy and 1 cycle of salvage conventional chemotherapy
  • No more than one prior line of chemotherapy for GCT (other than the 1 cycle of salvage chemotherapy as defined in the protocol)
    • Definition of one line of chemotherapy: One line of therapy can in some cases consist of 2 different cisplatin-based treatment combinations, provided there is no disease progression between these two regimens
    • Prior treatment with carboplatin as adjuvant therapy is allowed, provided patients meet other eligibility criteria (e.g., the patient has also received 3-4 cycles of cisplatin-based chemotherapy)
    • Prior treatment with 1-2 cycles of BEP or EP as adjuvant chemotherapy for early stage GCT is allowed, provided the patient also received 3-4 cycles of BEP or EP again at relapse.
      • Patients treated with 3-4 cycles of VIP at relapse following 1-2 cycles of BEP/EP are not eligible as this would be considered more than 1 line of prior therapy
  • No prior treatment with high-dose chemotherapy (defined as treatment utilizing stem cell rescue)
  • No prior treatment with TIP with the exception when given as a bridge to treatment on protocol for patients with rapidly progressive disease who cannot wait to complete the eligibility screening process. Only one cycle is allowed.
  • No concurrent treatment with other cytotoxic drugs or targeted therapies
  • No radiation therapy (other than to the brain) within 14 days of day 1 of protocol chemotherapy except radiation to brain metastases, which must be completed 7 days prior to start of chemotherapy
  • No previous chemotherapy within 17 days prior to enrollment. A minimum of three weeks after the last day of the start of the previous chemotherapy regimen before the first day of chemotherapy on study protocol
  • Must have adequate recovery from prior surgery (eg, healed scar, resumption of diet)
• Age ≥ 14 years (≥ 18 years in Germany)
• ECOG performance status 0 to 2
• Male gender
• Required initial laboratory values
  • Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3
  • Platelet Count ≥ 100,000/mm^3
  • Calculated creatinine clearance ≥ 50 mL/min
  • Bilirubin ≤ 2.0 x upper limits of normal (ULN)
  • AST/ALT ≤ 2.5 x upper limits of normal (ULN)
• No concurrent malignancy other than non-melanoma skin cancer, superficial noninvasive (pTa or pTis) TCC of the bladder, contralateral GCT, or intratubular germ cell neoplasia
  • Patients with a prior malignancy, but at least 2 years since any evidence of disease are allowed
• Negative Serology (antibody test) for the following infectious diseases
  • Human Immunodeficiency Virus (HIV) type 1 and 2
  • Human T-cell Leukemia Virus (HTLV) type 1 and 2 (mandatory in US but optional in Canada and Europe)
  • Hepatitis B surface antigen
  • Hepatitis C antibody
• No late relapse with completely surgically resectable disease
• Patients with late relapses defined as relapse ≥ 2 years from the date of completion of the last chemotherapy regimen whose disease is completely surgically resectable are not eligible
  • Patients with late relapses who have unresectable disease are eligible.
• No large (≥ 2 cm) hemorrhagic or symptomatic brain metastases until local treatment has been administered (radiation therapy or surgery)
  • Treatment may begin ≥ 7 days after completion of local treatment
  • Patients with small (< 2 cm) and asymptomatic brain metastases are allowed and may be treated with radiation therapy and/or surgery concurrently with Arm A or cycles 1 and 2 of Arm B if deemed medically indicated
• Radiation therapy should not be given concurrently with high-dose carboplatin or etoposide
• No secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression

• Adult subject, ≥ 18 years old at the time of informed consent.
• Able and willing to give informed consent and comply with all study visits and procedures.
• Presentation with macula-off RRD with a duration ≥ 24 hours up to 14 days from time of central visual decline to the Baseline (Visit 2) visit, inclusive (based on subject reported date of loss of central vision) in the Study Eye (SE).
• Visual acuity with subject's current corrective lenses or pinhole of 20/100 (line scoring) on the Snellen or ETDRS chart to light perception (LP) in the SE.
• Visual acuity with subject's current corrective lenses or pinhole of 20/200 (line scoring) or better in the fellow eye.
• Determination by Investigator of macula-off status by clinical examination with confirmation by SD-OCT or B-scan ultrasound, if available.
• SOC retinal reattachment surgery by means of a pars plana vitrectomy (with or without scleral buckle) is indicated.
• In the opinion of the Investigator, can safely undergo the IVT injection procedure at Baseline (Visit 2).
• Surgical repair scheduled or anticipated to take place >12 hours after IVT injection or sham (Visit 2) and ≤10 days from Screening (Visit 1).

• Presence of a complex retinal detachment (RD) in the SE, identified by one or more of the following:
  • Giant retinal tear, defined as retinal break ≥ 3 clock hours in extent;
  • Proliferative vitreoretinopathy grade C1 or worse on the Retina Society Terminology Committee Classification System;
  • Presence of tractional detachments as seen in proliferative retinopathies;
  • RRD in the setting of open- or closed-globe trauma;
  • RRD following endophthalmitis or infectious retinitis;
  • Similarly complex RD as determined by the Investigator.
• Use of silicone oil tamponade in the primary RD repair without planned removal by end of study.
• Vitreous hemorrhage or cataract in the SE that prohibits adequate examination for other exclusion criteria, per Investigator's discretion.
• Presence of ocular or periocular infection or intraocular inflammation in either eye.
• Uncontrolled glaucoma, as defined by an IOP > 36 mmHg in either eye, at Screening.
• Any other significant ocular disease in the SE that, in the opinion of the Investigator, would preclude a postoperative (post-op) visual acuity of at least 20/30.
• History of previous ocular surgery in the SE for RD (excluding only barrier laser), endophthalmitis, glaucoma tube shunts, trabeculectomy, or ocular trauma.
• Any systemic condition or ocular condition in either eye that, in the opinion of the Investigator, makes the subject unsuitable for treatment with an investigational agent or that would compromise the safety and tolerability of assessments in the trial.
• History of and/or active:
  • Autoimmune disease in active flare (i.e., not well controlled on current medications) with ocular involvement that, in the opinion of the Investigator, would impact ability to participate in the trial and/or alter the outcome of retinal reattachment surgery;
  • Ocular malignancy;
  • Proliferative diabetic retinopathy or diabetic macular edema or uveitis.
• Currently participating in other clinical trials or use of any other investigational drugs or devices within 12 weeks prior to Visit 1.
• Females who are pregnant or lactating, and women of childbearing potential (WOCBP) or men with female partners of childbearing potential who are not using at least one adequate contraceptive precaution (e.g., intrauterine device, oral contraceptive, barrier method, or other contraception deemed adequate by the Investigator).

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

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

• Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
• Documented treatment failure from most recent prior therapy (e.g. tumor progression, clinical deterioration, or recurrence), and from at least one prior platinum-containing regimen in any treatment setting.
• Known tumor missense HRAS mutation.
• Measurable disease by RECIST v1.1.
• ECOG performance status of 0-1.
• Acceptable liver, renal and hematological function.

• Has disease that is suitable for local therapy administered with curative intent.
• Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g., mucosal melanoma).
• Known additional malignancy that is progressing or requires active treatment (excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
• Ongoing treatment with an anticancer agent not contemplated in this protocol (excluding adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
• Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor (FTI).
• Any use of investigational therapy within 2 weeks of Cycle 1 Day 1 (C1D1) or 5 half-lives (whichever is longer).
• Received treatment for unstable angina within prior year, myocardial infarction within the prior year, cerebro-vascular attack within the prior year, history of New York Heart Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.
• Non-tolerable Grade 2 or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1.
• Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery.
• Active, uncontrolled bacterial, viral or fungal infections requiring systemic therapy, including known history of infection with human immunodeficiency virus or an active infection with hepatitis B or hepatitis C.
• Subjects who have exhibited allergic reactions to tipifarnib or structural compounds similar to tipifarnib or to its excipients.
• Required use of concomitant medications classified as strong inhibitors or inducers of cytochrome P450 3A4 or UDP-glucuronosyltransferase (UGT).
• Concomitant disease or condition that could interfere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subjects in this study.
• Female subjects who are pregnant or lactating

• Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology.
• HRAS wildtype determined by a test
• Will or has received at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC.

• Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g., mucosal melanoma).
• Concomitant disease or condition that could interefere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.

- Karnofsky performance status ≥ 60% (Eastern Cooperative Oncology Group [ECOG] ≤ 2).

- Absolute neutrophil count ≥ 1,500/mcL.

- Platelets ≥ 100,000/mcL.

- Hemoglobin ≥ 10 g/dL.

- Total bilirubin ≤ 2 x institutional upper limit of normal (ULN).

- Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT) ≤ 3 x
institutional ULN.

- Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m^2.

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retro-viral therapy with undetectable viral load within 6 months are eligible for this trial.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial.

- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

- The effects of selinexor (KPT-330) and temozolomide on the developing human fetus are unknown. For this reason and because selective nuclear export inhibitors as well as
deoxyribonucleic acid (DNA) alkylating agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 180 days after the last dose of temozolomide. Should a
woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of study treatment administration.

- Ability to understand and the willingness to sign a written informed consent document.  Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible.

Key

• Written, signed, and dated informed subject/parent consent; and for subjects who are minors, age-appropriate assent (performed according to local regulations).
• Males or females at least 4 years of age.
• Previous participation in Clementia's natural history study (NCT02322255); clinically diagnosed with FOP, with the R206H ACVR1 mutation or other FOP variants reported to be associated with progressive HO (who have not participated in any Clementia-sponsored study); participants in Clementia's Phase 2 studies (NCT02279095 and NCT02979769) who cannot currently receive the chronic/flare-up regimen due to country of residence or those traveling long distances to participate in the Phase 2 studies.
• No flare-up symptoms within the past 4 weeks, including at the time of enrollment.
• Abstinent or using two highly effective forms of birth control.
• Accessible for treatment and follow-up; able to undergo all study procedures including low-dose WBCT (excluding head) without sedation.

Key

• Weight <10 kg.
• Concomitant medications that are strong inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity; or kinase inhibitors such as imatinib.
• Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of chronic pancreatitis.
• Elevated aspartate aminotransferase or alanine aminotransferase >2.5x ULN.
• Fasting triglycerides >400 mg/dL with or without therapy.
• Female subjects who are breastfeeding.
• Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
• Simultaneous participation in another clinical research study (other than palovarotene studies) within 4 weeks prior to Screening; or within five half-lives of the investigational agent, whichever is longer.
• Any reason that, in the opinion of the Investigator, would lead to the inability of the subject and/or family to comply with the protocol.

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

Eligibility last updated 9/15/22. Questions regarding updates should be directed to the study team contact.

PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA

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

PRIOR TO STEP 2 RANDOMIZATION INCLUSION CRITERIA

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

PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA

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

PRIOR TO STEP 2 RANDOMIZATION EXCLUSION CRITERIA

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

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

Eligibility last updated 5/1/23. Questions regarding updates should be directed to the study team contact.

• Baseline measurements and evaluations must be obtained within 6 weeks of randomization to the study. Abnormal PET or CT scans may constitute evaluable disease. Patient must have at least one objective measurable disease parameter. Measurable disease in the liver is required if the liver is the only site of lymphoma. 
• MIPI score must be calculated and entered in Oncology Patient Enrollment Network (OPEN). 
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2. 
• Patients must have untreated histologically confirmed mantle cell lymphoma, with cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescent in situ hybridization (FISH). The diagnosis must be confirmed by formal hematopathology review at the enrolling center.
• Patients being treated with gastric reducing agents proton pump inhibitors must be switched to an alternative drug before starting acalabrutinib. 
  • Absolute neutrophil count (ANC) ≥ 1,000/mcL (obtained with 14 days of randomization). If disease includes marrow involvement or hypersplenism, please reference the below revised ANC requirement: 
    • ANC ≥ 500/mcL. 
  • Platelets ≥ 75,000 mcL (obtained with 14 days of randomization). If disease includes involvement or hypersplenism, please reference the below revised platelet requirement: 
    • Platelets ≥ 25,000/mcL.
  • Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) (obtained with 14 days of randomization). If disease includes hepatic infiltration or is causing biliary obstruction, or if elevated bilirubin is due to Gilbert's disease, please reference the below revised bilirubin requirements: 
    • Bilirubin ≤ 3 x institutional ULN.
  • Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 x institutional ULN (obtained with 14 days of randomization). If disease includes hepatic infiltration or is causing biliary obstruction, or if elevated bilirubin is due to Gilbert's disease, please reference the below revised AST/ALT requirements: 
    • AST/ALT ≤ 5 x institutional ULN.
• Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (aPTT) in the absence of lupus anticoagulant) < 2 x institutional ULN (obtained with 14 days of randomization).
• Patients receiving anticoagulant therapy (other than warfarin or equivalent vitamin K antagonists which are excluded), higher INR/aPTT may be permitted to enroll to this study after discussion with the primary investigator (PI). 
• Creatinine ≤ institutional ULN, OR glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m^2 (obtained with 14 days of randomization). 
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. 
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. 
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. 
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. 
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional classification. To be eligible for this trial, patients should be class 2B or better. 
• Patients must have a QT interval (QTc) ≤ 480 msec obtained within 14 days of randomization. 
• Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and until 12 months after the last dose of study treatment. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has achieved menarche at some point, has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
• Women of childbearing potential and sexually active males must agree to use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for 12 months after treatment ends. 

• Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) 3A inhibitor. 
• Patients may not have received the following within 7 days prior to the first dose of study drug: 
  • Strong and moderate CYP3A inhibitors;
  • Strong and moderate CYP3A inducers.
• Patients are ineligible if they have any of the following:
  • Malabsorption syndrome or disease significantly affecting gastrointestinal function;
  • Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease);
  • Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenia purpura).;
  • Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug;
  • History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug;
  • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infections at study enrollment (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment);
  • History of severe allergic reaction attributed to compounds of similar chemical or biologic composition to rituximab, bendamustine, cytarabine, or acalabrutinib. 
• Patients must be able to fulfill one of the following eligibility requirements pertaining to biospecimen availability for submission following randomization: 
  • Archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the original diagnostic biopsy is available for submission; or
  • If tumor tissue is not available, peripheral blood collected prior to initiation of protocol therapy will be submitted.
    • NOTE: Biospecimens must be submitted within 60 days following randomization to Adaptive Biotechnologies for ClonoSEQ ID molecular marker identification of unique clonal immunoglobulin deoxyribonucleic acid (DNA) sequence. If peripheral blood will be submitted, Adaptive Biotechnologies should be contacted prior to patient randomization for guidance pertaining to collection and submission requirements.

1. Willing and able to provide written informed consent
2. Age ≥ 18 years
3. Diagnostic coronary angiography/left heart catheterization or percutaneous coronary intervention via the transradial approach

1. Presence of a palpable hematoma or clinical concern of hemostasis at the transradial access site in which bleeding risk would be prohibitive
2. Access or attempted access site – including contralateral radial artery, brachial artery, or femoral artery or vein as switching of access could be attributed to arterial injury
3. Planned staged procedure, coronary artery bypass grafting or noncardiac surgery, within 30 days
4. Pregnant or lactating females
5. Contraindication or high risk of bleeding with anticoagulation
   1. bleeding requiring medical attention in the previous 6 months
   2. thrombocytopenia (platelets < 50 x 10^9/L)
   3. any prior intracranial hemorrhage
   4. use of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention
   5. administration of thrombolytic therapy in the preceding 24 hours
   6. use of regular non-steroidal anti-inflammatory medications excluding Aspirin < 100mg/day
   7. ischemic stroke or transient ischemic attack diagnosed in the last 3 months
6. Cardiogenic shock
7. Ventricular arrhythmias refractory to treatment
8. Liver dysfunction (Child-Pugh class B or C)
9. Unexplained anemia with a Hgb below 100 g/L
10. History of medication noncompliance or risk factor for noncompliance
11. Active malignancy
12. Allergy to rivaroxaban
13. Another indication for anticoagulation
14. Strong CYP3A4 and P-glycoprotein inhibitor use which increase rivaroxaban levels (ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, diltiazem, verapamil and conivaptan, carbamazepine, phenytoin, rifampin, St.John’s wort)
15. Life expectancy <30 days
16. Women capable of pregnancy not on birth control
17. Chronic kidney disease with creatinine clearance of less than 30mL/min
18. History of antiphospholipid syndrome, in particular triple positive (lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies)

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

Eligibility last updated 8/22/23. Questions regarding updates should be directed to the study team contact.

• Patient or legal representative voluntarily agreed to participate by signing and dating the written informed consent form after trial has been fully explained.
• Patient 18 years of age or older.
• History of recurrent CDI.
• Current active qualifying CDI episode.
• Females (assigned at birth) must fulfill at least 1 of the following criteria: 
• Postmenopausal, defined as amenorrhea ≥ 1 year; or 
  • Surgically sterile: hysterectomy, bilateral oophorectomy, or tubal ligation; or 
  • Abstinent or willing to use adequate contraception from Screening through the week 24 visit.
• Males (as assigned at birth) must fulfill the following criteria:
  • Abstinent or willing to use adequate contraception from Screening through the Week 24 visit.

• Known stool samples testing positive for enteric pathogens (e.g., Salmonella, Shigella, diarrhoeagenic E. coli, Campylobacter, Giardia) within 28 days prior to Screening.
• Inability to ingest capsules (e.g., severe nausea, vomiting, gastroparesis, gastric outlet obstruction, dysphagia and/or history of chronic aspiration).
• Active or suspected ileus, toxic megacolon, or bowel obstruction.
• Historical or current diagnosis of inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, indeterminate colitis, or microscopic colitis).
• Recent diagnosis (< 6 months prior to Screening) of diarrhea-predominant irritable bowel syndrome (post-infection or not related to an enteric infection). Patients with diarrhea-predominant irritable bowel syndrome ≥ 6 months prior to Screening may be randomized following confirmation of eligibility.
• Current diagnosis of chronic diarrheal illness with pre-CDI baseline diarrhea. This includes but is not limited to celiac disease, bile salt diarrhea, chronic pancreatitis, and short gut syndrome.
• Past administration of bezlotoxumab (Zinplava™), or past enrollment in a C. difficile vaccine trial within 12 months prior to Randomization.
• Participation in PRISM3 (CDI-001) or PRISM-EXT (CP101-CDI-E02) or received CP101 at any time in the past.
• Fecal transplant or other live microbiome therapeutics for any condition, regardless of route of administration within 12 months prior to Randomization.
• Initiation of any systemic cancer treatment (e.g., chemotherapy, radiotherapy, biologic, immunotherapy, others) for active malignancy that is planned 8 weeks prior to Randomization or during the 8 weeks following Randomization. Patients on maintenance treatment for malignancy may be randomized following confirmation of eligibility.
  • NOTE: Patients on hormone therapy alone are eligible.
• Known primary or secondary immunodeficiency, including but not limited to, IgA deficiency, common variable immunodeficiency, severe combined immunodeficiency, or human immunodeficiency virus/acquired immune deficiency syndrome.
• History of solid organ transplantation or stem cell transplant.
• Initiation or dose escalation of systemic immunosuppressive agents, at the discretion of the Investigator, for any condition during the 8 weeks prior to Randomization or planned during the 8 weeks following Randomization. Examples may include but are not limited to corticosteroid agents given orally or intravenously, cyclosporine, tacrolimus, or tumor necrosis factor inhibitors. Patients on stable low dose of systemic immunosuppressive agents or short courses (< 2 weeks) may be randomized following confirmation of eligibility.
• Major intra-abdominal surgery (e.g., bowel resection) within the past 60 days prior to Screening (excluding appendectomy or cholecystectomy)and/or planned invasive surgery/hospitalization during the trial.
• History of total colectomy or ileostomy.
• Use of a systemic antibiotic for any condition (other than CDI) during the Screening period, or any anticipated use of a systemic antibiotic for any condition other than CDI during the trial for 8 weeks after Randomization. This includes patients who have a known medical procedure that requires antibiotic prophylaxis (e.g., elective surgical procedure or dental procedure requiring prophylactic antibiotics) scheduled during the trial.
• Active drug, chemical, or alcohol dependency as determined by the Investigator through history or optional toxicology screen.
• Enrollment in any other investigational drug, device, or observational trial within 30 days or 5 half-lives of the last dose, prior to Randomization (Day 1) or at any time during this trial.
• Pregnant, breast-feeding, or planning to become pregnant during the trial.
• Clinically significant abnormal laboratory values including, but not limited to, white blood cell count ≥ 15 × 10^9/L, absolute neutrophil count of < 1 × 10^9 neutrophils/L, or laboratory evidence of acute kidney injury at Investigators discretion, at Screening.
• Screening nasopharyngeal PCR test is positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• Any acute, chronic, or unstable medical comorbidity, psychiatric, social, or other circumstances that, in the opinion of the Investigator, may interfere with trial compliance, completion, or accurate assessment of trial outcomes/safety. Examples include but not limited to acute myocardial infarction, acute stroke, uncompensated congestive heart failure, or decompensated liver disease.
  • NOTE: Trial patients may be screened while an inpatient in an acute care facility/hospital but must be discharged from inpatient medical admission prior to Randomization.
• Life expectancy < 24 weeks.
• Known hypersensitivity to CP101 or any component of its formulation or history of severe adverse reactions or other common drug class effects during prior exposure to similar compounds per the judgment of the investigator.

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

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

• Must be ≥ 18 years of age and, in selected countries, adolescents aged 12 years and greater and weighing ≥ 30 kilogram (kg) at time of randomization.
• Must undergo deoxyribose nucleic acid (DNA)-based human leukocyte antigen (HLA) matching and be 8 of 8 or 7 of 8 HLA-matched (singe allele or antigen mismatch at HLA-A, -B, and -C, and HLA-DRB1 is allowable) unrelated hematopoietic stem cell transplantation (HSCT) from either peripheral blood or bone marrow stem cells for a hematologic malignancy or myeloproliferative disorder.
• For whom a myeloablative conditioning or reduced intensity conditioning (RIC) is planned.
• Allo-HSCT eligible (meeting institutional criteria)-participants planned medical care should include aGvHD prophylaxis with a combination of calcineurin inhibitor (CNI) (cyclosporine [CYS] or tacrolimus [TAC]) and methotrexate (MTX) or CNI and mycophenolate mofetil (MMF). With the exception of antithymocyte globulin (ATG) (antithymocyte globulin-Fresenius [ATG-F] or thymoglobulin), all other therapies, approved or investigational, for GvHD prophylaxis are excluded.
• Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (<=) 2 for participants aged ≥ 18 years at randomization or ≥ 60 percent (%) using the Karnofsky performance status for adolescent subjects aged ≥ 16 years at randomization or the Lansky performance status for adolescent participants aged 12 to ≤ 16 years at randomization.

• Had prior allo- HSCT.
• Planned umbilical cord blood transplant or planned to receive posttransplant cyclophosphamide, in-vivo or ex-vivo T cell-depleted hematopoietic stem cells (HSCs) with the exception of ATG (ATG-F or thymoglobulin).
• Planned allo-HSCT for nonmalignant hematological disorders (example; aplastic anemia, sickle cell anemia, thalassemias, Fanconi anemia or immunodeficiency).

• For Dose escalation: subjects with cervical, ovarian, bladder and colorectal cancer (CRC), head and neck, gastric and hepatocellular cancer naive to immuno-oncology agents; 1st line melanoma and 1st line/2nd line NSCLC; Renal Cell Carcinoma naive to IO; NSCLC progressing while on or after therapy with anti-PD1/anti-PDL-1 and melanoma subjects progressed while-on or after treatment with anti-PD1 or anti-PDL1 with or without anti-CTLA-4.
• For Dose Expansion: all of the above in escalation except for cervical, ovarian, and CRC
• Progressed, or been intolerant to, at least one standard treatment regimen, except for subjects in 1st line cohorts.
• ECOG performance status of 0 or 1
• At least 1 lesion with measurable disease at baseline
• Availability of an existing tumor biopsy sample (and consent to allow pre-treatment tumor biopsy)

• Primary central nervous system (CNS) tumors or solid tumors with CNS metastases as the only site of active disease
• Autoimmune disease
• Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
• Uncontrolled CNS metastases

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

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

INCLUSION CRITERIA FOR SCREENING (STEP 0
•PREREGISTRATION)

• Age ≥ 18 and ≤ 70 years.
• Patients must have histologically confirmed mantle cell lymphoma, with cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH. The proliferation rate, using Ki-67 or MIB-1, should also be determined, but is not required until Step 1 registration. Patients may register to Step 0 without a documented Ki-67 index.
• In the opinion of the enrolling physician, patients must be felt to be a candidate for autologous stem cell transplantation.
• Patient may be about to begin, be receiving, or have completed induction therapy within 120 days prior to preregistration to Step 0.  No more than 300 days may have passed between the first day of induction therapy and preregistration to Step 0.
• For patients who have completed induction therapy and have been restaged, restaging evaluation must show status of partial (PR) or complete response (CR). Postinduction patients with evidence of clinical disease progression are not eligible for preregistration.
• Up to two regimens of therapy (conventional chemotherapy, antibody therapy, or an oral regimen) are allowed as long as a continuous response was ongoing throughout therapy. Overall, a partial response needs to have been achieved (using studies at the time of diagnosis as the baseline).
  • NOTE: For example, a patient who started treatment with rituximab/bendamustine and was then switched to R-CHOP (due to insufficient response or excessive toxicity) would be counted as having received 2 regimens.  However, R-CHOP alternating with R-DHAP as a planned induction regimen would count as one regimen.
• Patient does not have any documented history of central nervous system (CNS) involvement by mantle cell lymphoma. This includes no evidence of parenchymal brain, spinal cord, or cerebrospinal fluid involvement. Radiculopathy symptoms from nerve root compression by lymphoma do not constitute CNS involvement.
• Patient must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the original diagnostic biopsy available for submission to Adaptive Biotechnologies for ClonoSEQ® ID molecular marker identification of unique  clonal immunoglobulin DNA sequence.
  • NOTE: If adequate tumor tissue is not available, peripheral blood collected prior to start of treatment with high disease burden (> 5%) is acceptable for molecular marker ID testing.  Adaptive Biotechnologies will forward results within fourteen (14) days of receipt of any stored (e.g., frozen or FFPE) tumor tissue specimen to the submitting institution and to the ECOG-ACRIN Operations Office.
  • NOTE: Patients for whom the molecular marker is identified will have peripheral blood collected after completion of induction (patient’s disease status is PR or CR) and submitted to Adaptive Biotechnologies for minimal residual disease (MRD) assessment.  Adaptive Biotechnologies will forward results within seven (7) days of receipt of fresh peripheral blood specimen to the submitting institution and to the ECOG-ACRIN Operations Office.

Eligibility Criteria for Treatment Assignment (STEP 1)

• Patients must have met eligibility criteria for the screening step 0.
• The proliferation rate, using Ki-67 or MIB-1 immunohistochemistry (≤ 30% versus > 30% versus indeterminate Ki-67 index), must be documented for a baseline tumor biopsy specimen.
• Institution has received results from Adaptive Biotechnologies as defined by one of the following criteria:
  • Patients are MRD Indeterminate : ClonoSEQ® ID molecular marker assessment did not identify any unique clonal immunoglobulin DNA sequence; OR
  • ClonoSEQ® ID molecular marker assessment identified unique clonal immunoglobulin DNA sequence and MRD assessment is completed.
• Patients must have completed induction therapy within 150 days prior to registration to Step 1, AND no more than 300 days may have elapsed from the first dose of induction chemotherapy (C1D1) given, until the last day of induction  chemotherapy administered. For those assigned to Arms A, C, or D, the date of transplant ( Day 0 ) must not be greater than 365 days after the first dose of induction chemotherapy (C1D1) given.
• Patient must have received at least four (4) cycles of induction therapy.
• Up to two regimens of therapy (conventional chemotherapy, antibody therapy, or an oral regimen) are allowed as long as a continuous response was ongoing throughout therapy.
  • NOTE: For example, a patient who started treatment with rituximab/bendamustine and was then switched to R-CHOP (due to insufficient response or excessive toxicity) would be counted as having received 2 regimens.  However, R-CHOP alternating with R-DHAP as a planned induction regimen would count as one regimen.
• Patients must have achieved a radiologic complete or partial remission as defined by the Lugano Criteria.
• In the opinion of the enrolling physician, patients must be felt to be a candidate for autologous stem cell transplantation.
• Patients have an ECOG performance status of 0-2.
• HIV positive patients are not excluded, but to enroll, must meet all of the below criteria:
  • HIV is sensitive to antiretroviral therapy;
  • Must be willing to take effective antiretroviral therapy that has minimal overlapping toxicity and pharmacokinetic interactions with protocol therapy;
  • No history of HIV-related opportunistic disease or AIDS defining conditions within past 12 months other than historic CD4+ T-cell counts below 200 cells/mm3;
  • Expected long-term survival if lymphoma were not present.
• Patient must be disease-free ≥ 3 years of prior malignancies with the exception of adequately treated non-melanoma skin cancer, adequately treated in situ carcinoma, melanoma in situ post wide local excision or Mohs surgery, low grade prostate carcinoma (Gleason grade ≤ 6) managed with observation that has been stable for at least 6 months.
• Women must not be pregnant or breast-feeding due to the potential for congenital abnormalities and of harm to nursing infants due to the treatment regimens used.  
• All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Female of child bearing potential? ______ (Yes or No)
  • Date of blood test or urine study: ___________
• Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for 12 months post rituximab treatment.

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

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

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

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

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

Eligibility last updated 5/1/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

• Allogeneic HSCT patients surviving ≥ 1 year post-HSCT
• Diagnosis of both malignant and non-malignant conditions as HSCT indications
• HSCT survivors receiving any type of conditioning chemo/radiotherapy for HSCT
• Ability to provide written and verbal informed consent
• Age ≥ 18 years
• Adequate blood counts; i.e., platelets > 50,000 per microliter; HB > 9/dL, and ANC > 1000 per microliter

Exclusion Criteria

• HSCT survivor with human immunodeficiency virus (HIV) infection
• HSCT survivor with active hepatitis B or C HSCT survivor on any TKI for either Philadelphia chromosome positive cancers or for GVHD treatments or for any other indication (e.g., imatinib for GIST, sorafenib for FLT3+ AML etc.)
• HSCT survivor with any post-transplant maintenance chemotherapy
• Post-transplant relapse of cancer
• Active progressive CHRONIC chronic or overlap GVHD (per the NIH chronic GVHD criteria)
• Presence of uncontrolled psychiatric disorder
• Patient unable to give informed consent
• Extremely poor overall prognosis (< 6 months as deemed by the primary transplant physician)
• HSCT survivors with confirmed drug addiction
• HSCT survivors with active coronary artery disease (CAD) [including angina] or active congestive heart failure (CHF)
• International HSCT survivors in whom loss to follow-up would be a concern as deemed by primary transplant physician
• Known hypersensitivity or allergy to dasatinib, or quercetin
• Presence of uncontrolled lupus
• Presence of uncontrolled pleural/pericardial effusions or ascites
• Presence of active new cancer (solid or hematologic) except non-melanoma skin cancers
• Presence of progeroid syndromes in family
• Invasive fungal or viral infection not responding to appropriate antifungal or antiviral therapies.
• Creatinine clearance < 60 mL/min/1.73 m^2 based on the Cockcroft-Gault
• Inability to tolerate oral medications
• Total bilirubin >2 x upper limit normal (unless deemed to be due to Gilbert's syndrome); AST/ALT >2.5 x ULN
• Active progressive ACUTE graft-versus-host disease
• Active progressive OVERLAP graft-versus-host disease
• Patients taking medications that are sensitive substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus or sirolimus). If antifungals are absolutely necessary from infectious disease perspective, then they will be allowed only if the levels are therapeutic. Levels will be checked at baseline and also at day +4 post intervention.
• Patients taking H2-antagonists or proton pump inhibitors
• Patients on therapeutic doses of anticoagulants (e.g. warfarin, heparin, low molecular weight heparin, factor Xa inhibitors etc.)
• On antiplatelet agents (e.g., full dose aspirin, clopidogrel etc.). Baby aspirin if absolutely necessary from cardiac perspective will be allowed.
• On any quinolone antibiotic therapy for treatment or for prevention of infections.
• QTc > 450 msec. Common drugs that are well known in prolonging QTc include azithromycin, citalopram, escitalopram, fluconazole, and pentamidine. Baselines EKG will be obtained in each patient and if QTc > 450 msec, then they will be excluded from the trial.

• Adult Employee and Community Health (ECH) patients seen at the Mayo Clinic Rochester practices.
• Patients suffering from one or more cutaneous warts as diagnosed by the examining physician at baseline visit on typical diagnostic characteristics.
• Able to provide consent.
• Both recalcitrant and non-recalcitrant warts will be included.

• Patients with prior use of home or office-based destructive treatments for this wart(s) in the last 1 month with SA or cryotherapy.
• Immunoadjuvant therapy for warts in the last 4 months (e.g Candida).
• History of vitamin D injection of warts ever.
• High-dose vitamin D supplementation (> 4,000 IU daily or equivalent) in the preceding 3 months.
• Pregnancy or lactation.
• Facial or genital warts.
• Lesions not felt by the examining clinician to be a wart (e.g., corns or calluses).
• Immunosuppression (to include immunosuppressive medications or conditions as judged by the physician evaluating the patient at the baseline visit).
• Allergy to sesame oil.

• Histological or cytologically confirmed adenocarcinoma of the pancreas that has not been previously treated in the metastatic setting.
• Initial diagnosis of metastatic disease must have occurred ≤ 6 weeks prior to screening.
• Subject has one or more metastatic tumours measurable by computed tomography (CT) scan (or magnetic resonance imaging (MRI), if the subject is allergic to CT contrast media) according to RECIST Version 1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Subject has adequate biological parameters as demonstrated by the following blood counts:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3 without the use of hemopoietic growth factors within the last 7 days prior to randomisation;
  • Platelet count ≥100,000/^;
  • Haemoglobin (Hgb) ≥ 9 g/dL obtained ≤ 14 days prior to randomisation.
• Adequate hepatic function as evidenced by:
  • Serum total bilirubin ≤ 1.5 x ULN (biliary drainage is allowed for biliary obstruction); and
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) (≤ 5 x ULN is acceptable if liver metastases are present).
• Adequate renal function as evidenced by creatinine clearance ≥ 30 mL/min.
• Adequate coagulation studies (obtained ≤ 14 days prior to randomisation) as demonstrated by prothrombin time and partial thromboplastin time within normal limits (≤ 1.5 x ULN ).

• Prior treatment of pancreatic cancer in the metastatic setting with surgery, radiotherapy, chemotherapy or investigational therapy.
• Prior treatment of pancreatic adenocarcinoma with chemotherapy in the adjuvant setting, except those where at least 12 months have elapsed since completion of the last dose and no persistent treatment-related toxicities are present.
• Subject has only localised advanced disease.
• Documented serum albumin < 3 g/dL.
• Known history of central nervous system (CNS) metastases.
• Clinically significant gastrointestinal disorder.
• History of any second malignancy in the last 2 years.
• Concurrent illnesses that would be a relative contraindication to trial participation.
• Use of strong inhibitors or inducers of CYP3A, CYP2C8 and UGT1A1.
• Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma.