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Cohort A1: Pheochromocytoma/Paraganglioma (PPGL) |
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Has documented histopathological diagnosis (local report) of pheochromocytoma or paraganglioma Note: Participants are allowed to receive therapy in first line where a satisfactory treatment option does not exist and if participants are not candidates for systemic chemotherapy or have refused such therapy. There is no limit on number of prior systemic therapies |
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Locoregional therapies or adjuvant/neoadjuvant therapies are not considered a line of prior |
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systemic therapy |
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Has locally advanced or metastatic disease that is not amenable to surgery or curative |
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intent treatment |
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Has adequately controlled blood pressure defined as blood pressure ≤150/90 mm Hg |
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Cohort A2: Pancreatic Neuroendocrine Tumor (pNET) |
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(≤135/85 mm Hg for adolescents) and with no change in antihypertensive medications |
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(for participants with concomitant hypertension) for at least 2 weeks prior to start |
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Has locally advanced disease or metastatic disease that is |
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of study treatment |
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Has documented histopathological or cytopathological diagnosis (local report) of |
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Note: Chemoembolization/radiofrequency ablation/locoregional therapies |
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well-differentiated, low, or intermediate grade (G1 or G2 pNET per 2017 World Health |
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Organization (WHO) classification and grading) pNET |
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Not amenable for surgery, radiation, locoregional therapies or combination |
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modality of such treatments with curative intent |
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Experienced disease progression on or after at least 1 line of prior systemic |
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therapy that includes an approved targeted agent such as everolimus or sunitinib |
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Participants who have received >3 prior systemic therapies will be capped to ≤20% |
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of the cohort |
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neoadjuvant/adjuvant treatments, or somatostatin analog monotherapy or interferon |
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intervention |
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monotherapy will not count as 1 line of prior systemic therapy |
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Cohorts A1, A2 and PPGL/pNET participants from Cohort D |
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Has disease progression within the past 12 months from Screening |
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Has measurable disease per RECIST 1.1 by computed tomography (CT) or magnetic |
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resonance imaging (MRI) as assessed by local site investigator/radiology assessment |
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and verified by BICR |
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Irradiated lesions or lesions treated with locoregional therapies should not be |
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used as target lesions unless they clearly demonstrate growth since completion of |
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radiation |
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Has adequate organ function |
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Metastatic lesions situated in the brain are not considered measurable and should |
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be considered nontarget lesions |
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Only lesions of the primary indication for the cohort may be evaluated for |
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measurability; other neoplastic lesions will be documented by the investigator |
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and this information provided to the independent reviewers to ensure that such |
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lesions are not included in the RECIST assessment |
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Cohort B1: von Hippel-Lindau (VHL) Disease-Associated Tumors |
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Participants who are adolescents (12-17 years of age) need to have a body weight |
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Have a diagnosis of VHL disease as determined by a germline test (documented germline |
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of 40 kilograms (kg) or more |
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VHL gene alteration) locally and/or clinical diagnosis |
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Male participants are eligible to participate if they agree to the following during |
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Have at least 1 measurable PPGL or pNET per RECIST 1.1 by CT or MRI as assessed by |
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the intervention period and for at least 7 days after the last dose of study |
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local site investigator/radiology assessment and verified by BICR |
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Participants from China or Japan defined as participants of Chinese or Japanese origin |
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Be abstinent from heterosexual intercourse as their preferred and usual lifestyle |
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residing in mainland China or Japan respectively at the time of Screening, must have |
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(abstinent on a long-term and persistent basis) and agree to remain abstinent OR |
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at least 1 measurable RCC or PPGL or pNET per RECIST 1.1 as assessed by local site |
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Must agree to use contraception unless confirmed to be azoospermic (vasectomized |
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investigator/radiology assessment and verified by BICR |
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or secondary to medical cause as detailed below |
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Must be ≥18 years of age |
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i. Agree to use a male condom plus partner use of an additional contraceptive method |
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For Cohort B1 participants with PPGL |
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when having penile-vaginal intercourse with a woman/women of childbearing potential |
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Must not have pheochromocytoma >5 cm or paraganglioma >4 cm that requires immediate |
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(WOCBP) who is not currently pregnant. Note: Men with a pregnant or breastfeeding |
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surgery |
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partner must agree to remain abstinent from penile-vaginal intercourse or use a male |
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Have adequately controlled blood pressure defined as blood pressure ≤150/90 mm Hg and |
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condom during each episode of penile-vaginal penetration |
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with no change in antihypertensive medications (for participants with concomitant |
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A female participant is eligible to participate if she is not pregnant or |
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hypertension) for at least 2 weeks prior to start of study treatment |
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breastfeeding, and at least one of the following conditions applies |
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Must not have Metastatic or locally advanced, unresectable PPGL |
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Presence of concomitant VHL disease-associated tumors is permitted as long as they do |
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Is a WOCBP and using a contraceptive method that is highly effective (with a |
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not require immediate surgery or intervention |
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failure rate of <1% per year), or be abstinent from heterosexual intercourse as |
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For Cohort B1 participants with pNET |
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their preferred and usual lifestyle (abstinent on a long-term and persistent |
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Must not have lesion(s) located in the head of the pancreas must be >2 cm that |
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basis), for at least 30 days after the last dose of study intervention |
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requires immediate surgery |
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Submit an archival tumor tissue sample or newly obtained core or excisional biopsy of |
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Must not have lesion(s) located in the body or tail of the pancreas must be >3 cm that |
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a tumor lesion (not previously irradiated). Formalin-fixed, paraffin embedded (FFPE) |
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requires immediate surgery |
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tissue blocks are preferred to slides. Newly obtained biopsies are preferred to |
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Must not have locally advanced, unresectable or metastatic pNET |
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archived tissue if the lesion is accessible and a biopsy is not clinically |
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Presence of concomitant VHL disease-associated tumors is permitted as long as they do |
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contraindicated |
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not require immediate surgery or intervention |
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Note: If participant has only 1 measurable lesion per RECIST 1.1, the biopsy specimen |
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For Cohort B1 participants with renal cell carcinoma (RCC) |
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should be obtained from a nontarget lesion or archival tissue. Bone biopsies should not be |
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Must not have lesion(s) >3 cm that requires immediate surgery |
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submitted |
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Must not have metastatic RCC |
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Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1 |
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Presence of concomitant VHL disease-associated tumors is permitted as long as they do |
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as assessed within 7 days of treatment initiation |
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not require immediate surgery or intervention |
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For Cohort C participants with GIST (wt) |
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Has documented histopathological diagnosis of GIST |
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Local test report documenting the absence of sensitizing mutations in both platelet |
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derived growth factor receptor alpha (PDGFRA) and receptor tyrosine kinase (c-KIT) |
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Has locally advanced or metastatic disease that is not amenable to surgery or curative |
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intent treatment |
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For Cohort D participants with advanced solid tumors with HIF-2α related genetic |
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alterations |
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Local test report documenting germline or somatic mutations in at least one of the |
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HIF-2α related genes |
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Has locally advanced or metastatic solid tumor that is not amenable to surgery or |
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curative intent treatment |
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Has progressed on/after standard therapy for advanced/metastatic disease |
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Is not a WOCBP OR |
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Has a life expectancy of at least 3 months |
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Note: Medically controlled arrhythmia stable on medication is permitted
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Has a known hypersensitivity to the study treatment and/or any of its excipients
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Has an active infection requiring systemic therapy
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Has a known history of human immunodeficiency virus (HIV) infection
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Has a known history of hepatitis B or known active hepatitis C (HCV) infection
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Is unable to swallow orally administered medication or has a disorder that might
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affect the absorption of belzutifan
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Has a history of a second malignancy, unless potentially curative treatment has been
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completed with no evidence of malignancy for 2 years with the following exceptions
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Note: The time requirement does not apply to participants who underwent successful
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definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the
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skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers
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Prior history of surgical resection(s) for concurrent localized VHL disease-associated
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tumors is allowed provided there is no history of metastatic disease from concurrent
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tumors; history of systemic therapy for concurrent tumors will be exclusionary
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Participants with history of other genetic syndromes (such as those with succinate
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dehydrogenase subunit genes (SDHx) germline mutation or multiple endocrine
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neoplasia/MEN) will be allowed provided concurrent tumors (outside of the organ
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Has clinically significant cardiac disease, including unstable angina, acute
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myocardial infarction, or arterial bypass (CABG) or percutaneous transluminal coronary
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angioplasty (PTCA) ≤6 months from Day 1 of study drug administration, or New York
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Heart Association Class III or IV congestive heart failure. Concurrent uncontrolled
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hypertension defined as blood pressure >150/90 mm mercury (Hg) despite optimal
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antihypertensive medications within 2 weeks prior to the first dose of study
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treatment
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Has a known psychiatric or substance abuse disorder that would interfere with
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cooperation with the requirements of the study
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Has had major surgery ≤4 weeks prior to first dose of study intervention
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Has received prior locoregional therapies or radiation within the past 4 weeks of
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Participants with history of VHL disease (germline VHL mutation documented by a local
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Has received prior treatment with Peptide Receptor Radionuclide Therapy
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test report or with clinical diagnosis) will be permitted provided concurrent lesions
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(PRRT)/radionuclide therapy (such as 177Lu-Dotatate) or other radiopharmaceutical
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Has received meta-iodobenzylguanidine (MIBG) therapy or other radiopharmaceutical
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Has received prior treatment with any HIF-2α inhibitor (including belzutifan)
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Has toxicities from prior locoregional or systemic or any other therapies that is not
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Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor
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(G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), or recombinant
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Erythropoietin (EPO) ≤28 days prior to the first dose of study intervention
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Cohort B1 participants with concomitant central nervous system (CNS) hemangioblastoma
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must not require immediate surgery or intervention and must not be at risk of imminent
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neurological complications
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Cohort B1 participants with concomitant retinal angiomas/retinal hemangioblastomas
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(other than the tumor type being assessed such as PPGL for Cohort A1 and pNET for
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must not require immediate intervention
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Cohort A2) are localized without immediate need for intervention. Cohort D
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Cohort B1 participants with any concomitant tumors must not require immediate surgery
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participants with VHL disease will not be eligible
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or intervention
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For Cohort B1 participants, history of any anticancer systemic therapy (including
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discontinued for the duration of the study
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investigational agents) for any VHL disease-associated tumor or history of metastatic
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Is currently enrolled in and receiving study therapy, was enrolled in a study of an
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disease from any VHL disease-associated tumor or other non-VHL disease-related
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investigational agent, and received study therapy or used an investigational device
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tumor(s) will be exclusionary
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within 4 weeks (28 days) of the first dose of study intervention
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Has known CNS metastases and/or carcinomatous meningitis
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affected in Cohort A1, Cohort A2, C and D respectively) are localized and do not
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require immediate intervention; history of metastatic disease in concurrent tumors or
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history of systemic therapy for concurrent tumors will be exclusionary
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For Cohort A2, has a tumor histology consistent with poorly differentiated pNET
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neuroendocrine carcinoma, or neuroendocrine tumor (NET) of nonpancreatic origin
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Poorly differentiated or high grade pancreatic pNET or pancreatic neuroendocrine
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carcinoma; mixed adenoneuroendocrine carcinoma of the pancreas or concurrent
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pancreatic ductal adenocarcinoma will not be allowed
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Neuroendocrine tumor of nonpancreatic origin such as gastrointestinal
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Has any of the following: A pulse oximeter reading <92% at rest, or requires
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lung/thoracic, unknown primary, or other organs (including adenocarcinoid/goblet
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intermittent supplemental oxygen, or requires chronic supplemental oxygen
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cell carcinoid/small cell carcinoma/large cell carcinoma). Note: Neuroendocrine
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carcinoma of any origin is exclusionary
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For Cohort A2, participants who have uncontrolled symptoms from functional pNETs at
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first dose of study intervention
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therapy within the past 12 weeks from Screening for participants with pNET
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therapy within the past 12 weeks from Screening for participants with PPGL
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chemotherapy, targeted therapy, biologics or other investigational therapy within the
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recovered to Common Terminology Criteria for Adverse Events (CTCAE) ≤Grade 1 (with the
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past 4 weeks of first dose of study intervention
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exception of alopecia)
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Has received prior treatment (except somatostatin analogs for pNET participants) with
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Is currently receiving strong inhibitors of Cytochrome P450 3A4 (CYP3A4) that cannot
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be discontinued for the duration of the study
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Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be
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study entry
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Has had an allogenic tissue/solid organ transplant
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For Cohort B1 participants, metastatic disease identified at Screening
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For Cohort C and GIST participants, clinically significant active bleeding (such as
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gastrointestinal [GI] bleeding), perforation, obstruction, and other disease-related
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complications, requiring emergency surgery
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For Cohort D participants, VHL disease is exclusionary
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