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JOURNAL ONKOLOGIE – STUDIE

Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)

Rekrutierend

NCT-Nummer:
NCT04924075

Studienbeginn:
August 2021

Letztes Update:
25.04.2024

Wirkstoff:
Belzutifan

Indikation (Clinical Trials):
Neuroendocrine Tumors, Pheochromocytoma, Adenoma, Islet Cell, Paraganglioma, Von Hippel-Lindau Disease, Neoplasms, Gastrointestinal Stromal Tumors

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
Phase 2

Sponsor:
Merck Sharp & Dohme LLC

Collaborator:
-

Studienleiter

Medical Director
Study Director
Merck Sharp & Dohme LLC

Kontakt

Studienlocations
(3 von 68)

Klinikum der Ludwig-Maximilians-Universitaet Muenchen-Department of Internal Medicine IV, Division (
80336 München
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +4989440052221» Ansprechpartner anzeigen
Comprehensive Cancer Center Mainfranken-Div. of Endocrinology and Diabetes ( Site 0500)
97080 Würzburg
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +49-(0)931-20 13 90 21» Ansprechpartner anzeigen
Charité Universitaetsmedizin Berlin - Campus Mitte-Department of Endocrinology and Metabolism ( Site
10117 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +4930450614303» Ansprechpartner anzeigen
Johns Hopkins Hospital-Sidney Kimmel Comprehensive Cancer Center - Developmental Therapeutics ( Site
21287 Baltimore
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 410-502-5140» Ansprechpartner anzeigen
Penn Medicine: University of Pennsylvania Health System-Heme/Onc ( Site 0127)
19104 Philadelphia
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 215-615-1725» Ansprechpartner anzeigen
Peking University First Hospital-Urology ( Site 1900)
100034 Beijing
ChinaAktiv, nicht rekrutierend» Google-Maps
Sun Yat-sen University Cancer Center ( Site 1905)
510060 Guangzhou
ChinaAktiv, nicht rekrutierend» Google-Maps
Renji Hospital Shanghai Jiao Tong University School of Medicine ( Site 1904)
Shanghai
ChinaAktiv, nicht rekrutierend» Google-Maps
CHU Strasbourg-Hautepierre-Medecine Interne, Endocrinologie et Nutrition ( Site 0402)
67098 Strasbourg
FranceRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +(0)3 88 12 75 93» Ansprechpartner anzeigen
Semmelweis University-Belgyógyászati és Onkológiai Klinika Hematológia Osztály ( Site 0600)
1083 Budapest
HungaryRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +3614591500» Ansprechpartner anzeigen
Sheba Medical Center-Institute of Endocrinology, Diabetes and Metabolism ( Site 1400)
5262100 Ramat Gan
IsraelRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +972506844706» Ansprechpartner anzeigen
University of Naples Federico II-Dipartimento di Medicina Clinica e Chirurgia ( Site 0704)
80100 Naples
ItalyAbgeschlossen» Google-Maps
Istituto Europeo di Oncologia IRCCS-Divisione di Oncologia Medica Gastrointestinale e Tumori Neuroe
20141 Milano
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +390257489258» Ansprechpartner anzeigen
Hokkaido University Hospital ( Site 1800)
060-8648 Sapporo
JapanAktiv, nicht rekrutierend» Google-Maps
Yokohama City University Hospital-Department of Urology ( Site 1804)
236-0004 Yokohama
JapanAktiv, nicht rekrutierend» Google-Maps
Kochi Medical School Hospital ( Site 1807)
783-8505 Nankoku
JapanAktiv, nicht rekrutierend» Google-Maps
National Cancer Center Hospital ( Site 1802)
104-0045 Chuo-ku
JapanAktiv, nicht rekrutierend» Google-Maps
Kyoto University Hospital ( Site 1806)
Kyoto
JapanAktiv, nicht rekrutierend» Google-Maps
Tokyo Women's Medical University Adachi Medical Center ( Site 1803)
123-8558 Tokyo
JapanAktiv, nicht rekrutierend» Google-Maps
GBUZ Republican Clinical Oncological Dispensary ( Site 0804)
450054 Ufa
Russian FederationSchwebend» Google-Maps
Saint Petersburg State University-Clinic of advanced medical technologies n. a. Nicolay I. Pirogov (
190020 Saint Petersburg
Russian FederationAbgeschlossen» Google-Maps
Saint-Petersburg City Clinical Oncology Dispensary-Department of chemotherapy ( Site 0803)
198255 Saint Petersburg
Russian FederationSchwebend» Google-Maps
Fed State Budgetary Inst N.N. Blokhin Med Center of Oncology MHRF ( Site 0801)
115478 Moscow
Russian FederationSchwebend» Google-Maps
Endocrinology Research Center of Rosmedtechnologies-Surgery ( Site 0809)
117036 Moscow
Russian FederationAbgeschlossen» Google-Maps
MD Anderson Cancer Center-Oncology ( Site 1102)
28033 Madrid
SpainAbgeschlossen» Google-Maps
Karolinska Universitetssjukhuset Solna ( Site 1202)
171 76 Stockholm
SwedenAbgeschlossen» Google-Maps
Sahlgrenska Universitetssjukhuset-Department of Oncology CTU Clinical Trial Unit ( Site 1204)
413 45 Gothenburg
SwedenRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +46313421000» Ansprechpartner anzeigen
Royal Free Hospital ( Site 1302)
NW32QG London
United KingdomAktiv, nicht rekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Brief Summary:

This is a study to evaluate the efficacy and safety of belzutifan monotherapy in participants

with advanced pheochromocytoma/paraganglioma (PPGL), pancreatic neuroendocrine tumor (pNET),

von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor

(wt GIST), or Advanced Solid Tumors With hypoxia inducible factor-2 alpha (HIF-2α) related

genetic alterations. The primary objective of the study is to evaluate the objective response

rate (ORR) of belzutifan per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST

1.1) by blinded independent central review (BICR).

Ein-/Ausschlusskriterien

Inclusion Criteria:

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, A2 and PPGL/pNET participants from Cohort D

- Has disease progression within the past 12 months from Screening.

- Has measurable disease per RECIST 1.1 by computed tomography (CT) or magnetic

resonance imaging (MRI) as assessed by local site investigator/radiology assessment

and verified by BICR.

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.

Cohort B1: von Hippel-Lindau (VHL) Disease-Associated Tumors

- Have a diagnosis of VHL disease as determined by a germline test (documented germline

VHL gene alteration) locally and/or clinical diagnosis.

- Have at least 1 measurable PPGL or pNET per RECIST 1.1 by CT or MRI as assessed by

local site investigator/radiology assessment and verified by BICR.

- Participants from China or Japan defined as participants of Chinese or Japanese origin

residing in mainland China or Japan respectively at the time of Screening, must have

at least 1 measurable RCC or PPGL or pNET per RECIST 1.1 as assessed by local site

investigator/radiology assessment and verified by BICR.

- Must be ≥18 years of age.

For Cohort B1 participants with PPGL

- Must not have pheochromocytoma >5 cm or paraganglioma >4 cm that requires immediate

surgery.

- Have adequately controlled blood pressure defined as blood pressure ≤150/90 mm Hg and

with no change in antihypertensive medications (for participants with concomitant

hypertension) for at least 2 weeks prior to start of study treatment.

- Must not have Metastatic or locally advanced, unresectable PPGL.

- Presence of concomitant VHL disease-associated tumors is permitted as long as they do

not require immediate surgery or intervention.

For Cohort B1 participants with pNET:

- Must not have lesion(s) located in the head of the pancreas must be >2 cm that

requires immediate surgery.

- Must not have lesion(s) located in the body or tail of the pancreas must be >3 cm that

requires immediate surgery.

- Must not have locally advanced, unresectable or metastatic pNET.

- Presence of concomitant VHL disease-associated tumors is permitted as long as they do

not require immediate surgery or intervention.

For Cohort B1 participants with renal cell carcinoma (RCC):

- Must not have lesion(s) >3 cm that requires immediate surgery.

- Must not have metastatic RCC.

- Presence of concomitant VHL disease-associated tumors is permitted as long as they do

not require immediate surgery or intervention.

For Cohort C participants with GIST (wt):

- Has documented histopathological diagnosis of GIST.

- Local test report documenting the absence of sensitizing mutations in both platelet

derived growth factor receptor alpha (PDGFRA) and receptor tyrosine kinase (c-KIT).

- Has locally advanced or metastatic disease that is not amenable to surgery or curative

intent treatment.

For Cohort D participants with advanced solid tumors with HIF-2α related genetic

alterations:

- Local test report documenting germline or somatic mutations in at least one of the

HIF-2α related genes.

- Has locally advanced or metastatic solid tumor that is not amenable to surgery or

curative intent treatment.

- Has progressed on/after standard therapy for advanced/metastatic disease.

- 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:

i. 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.

- Has a life expectancy of at least 3 months.

Exclusion Criteria:

- 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 VHL disease (germline VHL mutation documented by a local

test report or with clinical diagnosis) will be permitted provided concurrent lesions

(other than the tumor type being assessed such as PPGL for Cohort A1 and pNET for

Cohort A2) are localized without immediate need for intervention. Cohort D

participants with VHL disease will not be eligible.

- 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, Cohort A2, C and D 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.

- Cohort B1 participants with concomitant central nervous system (CNS) hemangioblastoma

must not require immediate surgery or intervention and must not be at risk of imminent

neurological complications.

- Cohort B1 participants with concomitant retinal angiomas/retinal hemangioblastomas

must not require immediate intervention.

- Cohort B1 participants with any concomitant tumors must not require immediate surgery

or intervention.

- For Cohort B1 participants, history of any anticancer systemic therapy (including

investigational agents) for any VHL disease-associated tumor or history of metastatic

disease from any VHL disease-associated tumor or other non-VHL disease-related

tumor(s) will be exclusionary.

- Has known 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 any of the following: A pulse oximeter reading <92% at rest, or requires

intermittent supplemental oxygen, or requires chronic supplemental oxygen.

- 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 for pNET participants) with

chemotherapy, targeted therapy, biologics or other investigational therapy within the

past 4 weeks of first dose of study intervention.

- Has received prior locoregional therapies or radiation within the past 4 weeks of

first dose of study intervention.

- 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 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 inhibitors of Cytochrome P450 3A4 (CYP3A4) that cannot

be discontinued for the duration of the study.

- Is currently receiving either strong or moderate 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.

- Has had an allogenic tissue/solid organ transplant.

- For Cohort B1 participants, metastatic disease identified at Screening.

- For Cohort C and GIST participants, clinically significant active bleeding (such as

gastrointestinal [GI] bleeding), perforation, obstruction, and other disease-related

complications, requiring emergency surgery.

- For Cohort D participants, VHL disease is exclusionary.

Studien-Rationale

Primary outcome:

1. Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) (Time Frame - Up to approximately 5.5 years):
ORR is the percentage of participants with complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions) until progressive disease (PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progression) or death due to any cause, whichever occurs first.



Secondary outcome:

1. Duration of Response (DOR) as Assessed by BICR (Time Frame - Up to approximately 5.5 years):
DOR is the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.

2. Time to Response (TTR) as Assessed by BICR (Time Frame - Up to approximately 5.5 years):
TTR is defined as the time from first dose of belzutifan to first documented evidence of CR or PR.

3. Disease Control Rate (DCR) as Assessed by BICR (Time Frame - Up to approximately 5.5 years):
Disease control is a confirmed CR, PR, or stable disease (SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study).

4. Progressive Free Survival (PFS) as Assessed by BICR (Time Frame - Up to approximately 5.5 years):
PFS is the time from first dose of belzutifan to the first documented PD or death from any cause, whichever occurs first.

5. Overall Survival (OS) (Time Frame - Up to approximately 5.5 years):
OS is the time from first dose of belzutifan until death from any cause.

6. Number of Participants Experiencing Adverse Events (AEs) (Time Frame - Up to approximately 5.5 years):
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.

7. Number of Participants Discontinuing Study Drug due to an AE (Time Frame - Up to approximately 5.5 years):
An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinue study treatment due to an AE will be presented.

8. Time to Surgery (TTS) (Time Frame - Up to approximately 5.5 years):
TTS is defined as the time from the first dose of belzutifan to the first documented surgical intervention or tumor reduction procedure.

Geprüfte Regime

  • Belzutifan (MK-6482 / WELIREG™ / ):
    Belzutifan, 120 mg, oral, once daily (QD) until progressive disease or discontinuation.

Quelle: ClinicalTrials.gov


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"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)"

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