MK6482-015 - A Phase 2 Study to Evaluate the Efficacy and Safety of Belzutifan (MK-6482, Formerly PT2977) Monotherapy in Participants With Advanced Pheochromocytoma/Paraganglioma (PPGL) or Pancreatic Neuroendocrine Tumor (pNET)

Studio Clinico

Patologia: Tumori neuroendocrini

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: No

Fase di studio: II

Linee di trattamento: Prima/N linee

Criteri di inclusione: 

Cohort A1: Pheochromocytoma/Paraganglioma (PPGL)
• 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. Locoregional therapies or adjuvant/neoadjuvant therapies are not considered a line of prior systemic therapy.
• Has locally advanced or metastatic disease that is not amenable to surgery or curative intent treatment.
• Has adequately controlled blood pressure defined as blood pressure ≤150/90 mm Hg (≤135/85 mm Hg for adolescents) and with no change in antihypertensive medications (for participants with concomitant hypertension) for at least 2 weeks prior to start of study treatment.

Cohort A2: Pancreatic Neuroendocrine Tumor (pNET)
• Has documented histopathological or cytopathological diagnosis (local report) of well-differentiated, low, or intermediate grade (G1 or G2 pNET per 2017 World Health Organization (WHO) classification and grading) pNET.
• Has locally advanced disease or metastatic disease that is:
1. Not amenable for surgery, radiation, locoregional therapies or combination modality of such treatments with curative intent.
2. Experienced disease progression on or after at least 1 line of prior systemic therapy that includes an approved targeted agent such as everolimus or sunitinib. Participants who have received >3 prior systemic therapies will be capped to ≤20% of the cohort.
Note: Chemoembolization/radiofrequency ablation/locoregional therapies, neoadjuvant/adjuvant treatments, or somatostatin analog monotherapy or interferon monotherapy will not count as 1 line of prior systemic therapy.

Cohorts A1 and A2
• Has disease progression within the past 12 months from screening.
• Has measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by computed tomography (CT) or magnetic resonance imaging (MRI) as assessed by local site investigator/radiology assessment and verified in real time by blinded independent central review (BICR). BICR must confirm the presence of radiologically measurable disease per RECIST 1.1 for the participant to be eligible for the study.
1. Irradiated lesions or lesions treated with locoregional therapies should not be used as target lesions unless they clearly demonstrate growth since completion of radiation.
2. Metastatic lesions situated in the brain are not considered measurable and should be considered nontarget lesions.
3. Only lesions of the primary indication for the cohort may be evaluated for measurability; other neoplastic lesions will be documented by the investigator and this information provided to the independent reviewers to ensure that such lesions are not included in the RECIST assessment.
4. Participants who are adolescents (12-17 years of age) need to have a body weight of 40 kilograms (kg) or more.
• Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of study intervention:
1. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR
2. Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a woman/women of childbearing potential (WOCBP) who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
1. Is not a WOCBP OR
2. Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), for at least 30 days after the last dose of study intervention.
• Submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (not previously irradiated). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue if the lesion is accessible and a biopsy is not clinically contraindicated.
Note: If participant has only 1 measurable lesion per RECIST 1.1, the biopsy specimen should be obtained from a nontarget lesion or archival tissue. Bone biopsies should not be submitted.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 7 days of treatment initiation.
• Has adequate organ function.

Criteri di esclusione: 

• Is unable to swallow orally administered medication or has a disorder that might affect the absorption of belzutifan.
• Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years with the following exceptions:
Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers.
• Participants with history of Von-Hippel Lindau (VHL) disease (germline VHL mutation documented by a local test report or with clinical diagnosis) will be permitted provided concurrent lesions (other than PPGL for Cohort A1 and pNET for Cohort A2) are localized without immediate need for intervention.
• Prior history of surgical resection(s) for concurrent localized VHL disease-associated tumors is allowed provided there is no history of metastatic disease from concurrent tumors; history of systemic therapy for concurrent tumors will be exclusionary.
• Participants with history of other genetic syndromes (such as those with succinate dehydrogenase subunit genes (SDHx) germline mutation or multiple endocrine neoplasia/MEN) will be allowed provided concurrent tumors (outside of the organ affected in Cohort A1 and Cohort A2, respectively) are localized and do not require immediate intervention; history of metastatic disease in concurrent tumors or history of systemic therapy for concurrent tumors will be exclusionary.
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction, or arterial bypass (CABG) or percutaneous transluminal coronary angioplasty (PTCA) ≤6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Concurrent uncontrolled hypertension defined as blood pressure >150/90 mm mercury (Hg) despite optimal antihypertensive medications within 2 weeks prior to the first dose of study treatment.
Note: Medically controlled arrhythmia stable on medication is permitted.
• Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
• Has had major surgery ≤4 weeks prior to first dose of study intervention.
• Has received prior treatment (except somatostatin analogs) with chemotherapy, targeted therapy, or other investigational therapy within the past 4 weeks of study entry, or prior biologics or immunotherapy within the past 6 weeks of study entry.
• Has received prior locoregional therapies or radiation within the past 4 weeks of study entry.
• Has received prior treatment with Peptide Receptor Radionuclide Therapy (PRRT)/radionuclide therapy (such as 177Lu-Dotatate) or other radiopharmaceutical therapy within the past 12 weeks from screening for participants with pNET.
• Has received meta-iodobenzylguanidine (MIBG) therapy or other radiopharmaceutical therapy within the past 12 weeks from screening for participants with PPGL.
• Has received prior treatment with any HIF-2α inhibitor (including belzutifan).
• Has a known hypersensitivity to the study treatment and/or any of its excipients.
• Has toxicities from prior locoregional or systemic or any other therapies that is not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) ≤Grade 1 (with the exception of alopecia).
• Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), or recombinant Erythropoietin (EPO) ≤28 days prior to the first dose of study intervention.
• Is currently receiving strong (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) inhibitors of Cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study.
• Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study.
• Is currently enrolled in and receiving study therapy, was enrolled in a study of an investigational agent, and received study therapy or used an investigational device within 4 weeks (28 days) of the first dose of study intervention.
• Has an active infection requiring systemic therapy.
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has a known history of hepatitis B or known active hepatitis C (HCV) infection.
• For Cohort A2, has a tumor histology consistent with poorly differentiated pNET, neuroendocrine carcinoma, or neuroendocrine tumor (NET) of nonpancreatic origin.
1. Poorly differentiated or high grade pancreatic pNET or pancreatic neuroendocrine carcinoma; mixed adenoneuroendocrine carcinoma of the pancreas or concurrent pancreatic ductal adenocarcinoma will not be allowed.
2. Neuroendocrine tumor of nonpancreatic origin such as gastrointestinal, lung/thoracic, unknown primary, or other organs (including adenocarcinoid/goblet cell carcinoid/small cell carcinoma/large cell carcinoma). Note: Neuroendocrine carcinoma of any origin is exclusionary.
• For Cohort A2, participants who have uncontrolled symptoms from functional pNETs at study entry.

Trattamento sperimentale: 

MK-6482 (Belzutifan) Monotherapy

Trattamento di controllo: 

NA

Centri partecipanti

Nord Italia

Sud Italia e isole

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2020-005028-13

Data di inserimento: 10.05.2022

Data di aggiornamento: 27.03.2023

Promotore

Merck Sharp & Dohme LLC

CRO

/

Principal Investigator ITALIA

Istituto Europeo di Oncologia - IEO (Oncologia Medica Gastrointestinale e Tumori Neuroendocrini)

Riferimento: Dr.ssa Francesca Spada

Telefono: 0257489258

Email: francesca.spada@ieo.it

Localita: Milano