A Phase 2 Study to Evaluate the Efficacy and Safety of Belzutifan (MK-6482, formerly PT2977) Monotherapy in Participants with Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), or von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Advanced Solid Tumors With HIF-2a related Genetic Alterations
- Conditions
- angiomatosis cerebelli et retinae-associated tumorsVon Hippel Lindau-disease associated tumors1002911210027655
- Registration Number
- NL-OMON53900
- Lead Sponsor
- Merck Sharp & Dohme (MSD)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Pending
- Sex
- Not specified
- Target Recruitment
- 5
The below mentioned inclusion criteria are the most important ones. A complete
list of specific inlcusion criteria can be found in the protocol.
Cohort A1: (PPGL)
1. Has documented histopathological diagnosis (local report) of
pheochromocytoma or paraganglioma.
2. Has locally advanced or metastatic disease that is not amenable to surgery
or curative intent treatment.
3. Adequately controlled blood pressure defined as BP <=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: (pNET)
4. Has documented histopathological or cytopathological diagnosis (local
report) of well-differentiated, low or intermediate grade (G1 or G2 pNET per
2017 WHO classification and grading) pNET.
5. Has locally advanced disease or metastatic disease that is:
a. Not amenable for surgery, radiation, locoregional therapies or combination
modality of such treatments with curative intent.
b. Experienced disease progression on or after at least 1 line of prior
systemic therapy that includes an approved targeted agent such as everolimus
(mTOR inhibitor) or sunitinib (anti-VEGF targeted agent). Participants who have
received >3 prior systemic therapies will be capped to <=20% of the cohort.
6. Has disease progression within the past 12 months from Screening.
7. Has measurable disease per RECIST 1.1 by CT or MRI as assessed by local site
investigator/radiology assessment and verified by BICR.
a. Irradiated lesions or lesions treated with locoregional therapies should not
be used as target lesions unless they clearly demonstrate growth since
completion of radiation.
b. Metastatic lesions situated in the brain are not considered measurable and
should be considered nontarget lesions. (This criterion does not apply to
Cohort B1 participants)
c. 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. See also Exclusion Criterion
2. For Cohort B1 tumor specific requirements refer inclusion criteria #16 and
#17
8. Is male or female, 12 years of age inclusive (>=40 kg for adolescents [12-17
years of age]), at the time of providing the informed consent. Only adult
participants (>=18 years of age) are eligible to participate for Cohort B1.
9. 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:
• 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
• Must agree to use contraception unless confirmed to be azoospermic
(vasectomized or secondary to medical cause [Appendix 5]) as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive
method when having penile-vaginal intercourse with a WOCBP who is not currently
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to
remain abstinent from penile-vaginal intercourse or
The below mentioned exclusion criteria are the most important ones. A complete
list of specific inlcusion criteria can be found in the protocol.
1. Is unable to swallow orally administered medication or has a disorder that
might affect the absorption of belzutifan.
2. Has a history of a second malignancy, unless potentially curative treatment
has been completed with no evidence of malignancy for 2 years with some
exceptions, refer to the protocol
3. Has known CNS metastases and/or carcinomatous meningitis.
4. Has any of the following:
o A pulse oximeter reading <92% at rest, or
o Requires intermittent supplemental oxygen, or
o Requires chronic supplemental oxygen.
5. Has clinically significant cardiac disease, including unstable angina, acute
myocardial infarction, or arterial bypass (CABG) or 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
BP>150/90 mm Hg despite optimal antihypertensive medications within 2 weeks
prior to the first dose of study treatment.
6. Has a known psychiatric or substance abuse disorder that would interfere
with cooperation with the requirements of the study.
7. Has had major surgery <=4 weeks prior to first dose of study intervention.
Note: Adequate wound healing after major surgery must be assessed clinically,
independent of time elapsed for eligibility.
8. 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.
Note: Refer to exclusion criterion#2g for Cohort B1 participants.
9. Has received prior locoregional therapies or radiation within the past 4
weeks of first dose of study intervention.
10. Has received prior treatment with PRRT/radionuclide therapy (such as
177Lu-Dotatate) or other radiopharmaceutical therapy within the past 12 weeks
from Screening for participants with pNET.
Note: Refer to exclusion criterion#2g for Cohort B1 participants.
11. Has received MIBG therapy or other radiopharmaceutical therapy within the
past 12 weeks from Screening for participants with PPGL.
Note: Refer to exclusion criterion#2g for Cohort B1 participants.
12. Has received prior treatment with any HIF-2a inhibitor (including
belzutifan).
13. Has a known hypersensitivity to the study treatment and/or any of its
excipients.
14. Has toxicities from prior locoregional or systemic or any other therapies
that is not recovered to CTCAE <=Grade 1 (with the exception of alopecia).
15. Has received colony-stimulating factors (eg, G-CSF, GM-CSF, or recombinant
EPO) <=28 days prior to the first dose of study intervention.
16. Is currently receiving strong) inhibitors of CYP3A4 that cannot be
discontinued for the duration of the study. Note: Topical preparations are
acceptable.
17. Is currently receiving either strong or moderate inducers of CYP3A4 that
cannot be discontinued for the duration of the study.
18. 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.
19. Has
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>- Primary Objectives: To evaluate the ORR of belzutifan per RECIST 1.1 by<br /><br>blinded independent central review (BICR).<br /><br>Primary Endpoints: Objective Response (OR): a confirmed complete response (CR)<br /><br>or partial response (PR)<br /><br><br /><br>- Primary Objectives: Cohort B1: To evaluate the ORR of belzutifan per RECIST<br /><br>1.1 by BICR in VHL disease associated PPGL.<br /><br>Primary Endpoints: OR.<br /><br><br /><br>- Primary Objectives: Cohort B1: To evaluate the ORR of belzutifan per RECIST<br /><br>1.1 by BICR in VHL disease associated pNET.<br /><br>Primary Endpoints: OR.<br /><br><br /><br>- Primary Objectives: Cohort B1: To evaluate the ORR of belzutifan per RECIST<br /><br>1.1 by BICR in VHL disease associated RCC among China/Japan participants<br /><br>Primary Endpoints: OR.</p><br>
- Secondary Outcome Measures
Name Time Method