| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pheochromocytoma/Paraganglioma or Pancreatic Neuroendocrine Tumor or von Hippel-Lindau (VHL) Disease-Associated Tumors or Gastrointestinal Stromal Tumor (wt GIST), or Advanced Solid Tumors with HIF-2α related Genetic Alterations |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pheochromocytoma, Paraganglioma or Pancreatic Neuroendocrine Tumors or von Hippel-Lindau (VHL) Disease or Gastrointestinal Stromal Tumor or Advanced Solid Tumors with HIF-2α related GeneticAlterations |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034876 |
| E.1.2 | Term | Pheochromocytoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073860 |
| E.1.2 | Term | Paraganglioma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067518 |
| E.1.2 | Term | Pancreatic neuroendocrine tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062427 |
| E.1.2 | Term | Gastrointestinal stromal tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10047716 |
| E.1.2 | Term | Von Hippel-Lindau disease |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. 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).
2. Cohort B1: To evaluate the ORR of belzutifan per RECIST 1.1 by BICR in VHL disease-associated PPGL
3. Cohort B1: To evaluate the ORR of belzutifan per RECIST 1.1 by BICR in VHL disease-associated pNET
4. Cohort B1: To evaluate the ORR of belzutifan per RECIST 1.1 by BICR in VHL disease-associated RCC among China/Japan participants
|
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the duration of response (DOR) of belzutifan in participants with a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 by BICR
2. To evaluate the time to response (TTR) of belzutifan in participants with a confirmed CR or PR per RECIST 1.1 by BICR
3. To evaluate disease control rate (DCR) of belzutifan per RECIST 1.1 by BICR
4. To evaluate progression-free survival (PFS) per RECIST 1.1 by BICR in participants receiving belzutifan
5. To evaluate the overall survival (OS) of participants receiving belzutifan
6. To evaluate the safety of belzutifan
7. Cohort B1: To evaluate the tumor specific DOR, TTR, DCR, PFS of belzutifan per RECIST 1.1 by BICR and time to surgery (TTS) in VHL disease-associated a.) PPGL, b.) pNET
8. Cohort B1: To evaluate the DOR, TTR, DCR, and PFS of belzutifan per RECIST 1.1 by BICR and TTS in VHL disease-associated RCC among China/Japan participants |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 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: 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 (antiVEGF 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
(Cohorts A1, A2 and PPGL/pNET participants from Cohort D)
7. Has measurable disease per RECIST v1.1 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
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) 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
• Contraceptive use by men should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies
10. A female participant is eligible to participate if she is not pregnant or
breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using a contraceptive method that is highly effective
(with a failure rate of <1% per year), with low user dependency, or be
abstinent from heterosexual intercourse as their preferred and usual
lifestyle, during the intervention period and for at least 30 days after
the last dose of study intervention
• A WOCBP must have a negative highly sensitive pregnancy test within
24 hours for urine or 72 hours for serum before the first dose of study
intervention
• If a urine test cannot be confirmed as negative, a serum pregnancy
test is required
• The investigator is responsible for review of medical history, menstrual
history, and recent sexual activity to decrease the risk for inclusion of a
woman with an early undetected pregnancy
• Contraceptive use by women should be consistent with local
regulations regarding the methods of contraception for those
participating in clinical studies
11. The participant (or legally acceptable representative) has provided
documented informed consent for the study.
12. Submit an archival tumor tissue sample or newly obtained core or
excisional biopsy of a tumor lesion (not previously irradiated). 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
13. Has an ECOG performance status of either 0 or 1, as assessed within
7 days of treatment initiation
14. Has adequate organ function
- Life expectancy of at least 3 months
For Cohort B1, Cohort C and Cohort D specific inclusion criteria see
details in the protocol section 5.1. |
|
| E.4 | Principal exclusion criteria |
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 the following exceptions:
a) Participants with history of VHL disease 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
b) 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
c) Participants with history of other genetic syndromes will be allowed provided concurrent tumors (outside of the organ affected in Cohort A1 and 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.
d. Refer to exclusion criterion protocol section 5.2 for Cohort B1 participants
3. Has known CNS metastases and/or carcinomatous meningitis
4. Has any of the following:
• A pulse oximeter reading <92% at rest, or
• Requires intermittent supplemental oxygen, or
• Requires chronic supplemental oxygen
5. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction, or 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
8. Has received prior treatment (except somatostatin analogs for pNET participants) with chemotherapy, targeted therapy, biologics or other inv. therapy within the past 4 weeks of first dose of study intervention.
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 or other radiopharmaceutical therapy within the past 12 weeks from screening for participants with pNET
11. Has received MIBG therapy or other radiopharmaceutical therapy within the past 12 weeks from screening for participants with PPGL
12. Has received prior treatment with any HIF-2α inhibitor
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
15. Has received colony-stimulating factors ≤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
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 inv. agent and received study therapy or used an investigational device within 4 weeks of the first dose of study intervention
19. Has an active infection requiring systemic therapy
20. Has a known history of HIV infection
21. Has known active hepatitis B or known active HCV infection
22. Participant has resting ECG indicating uncontrolled cardiac conditions, as judged by the investigator, or participant has congenital long QT syndrome
23. For Cohort A2, has a tumor histology consistent with poorly differentiated pNET, neuroendocrine carcinoma, or NET of nonpancreatic origin
24. For Cohort A2, participants who have uncontrolled symptoms from functional pNETs at study entry
25. In the judgment of the investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study
26. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not the best interest of the participant to participate,
in the opinion of the treating investigator
27. Has had an allogenic tissue/solid organ transplant.
28. For Cohort B1 participants, metastatic disease identified at Screening.
29. For Cohort C and GIST participants, clinically significant active
bleeding, perforation, obstruction, and other disease-related
complications, requiring emergency surgery.
30. For Cohort D participants, VHL disease is exclusionary. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Objective Response (OR): a confirmed complete response (CR) or partial response (PR)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 5 years |
|
| E.5.2 | Secondary end point(s) |
1. Duration of response: 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, defined as the time from first dose of belzutifan to first documented evidence of CR or PR
3. Disease control: a confirmed CR, PR, or stable disease (SD)
4. Progression-free survival: the time from first dose of belzutifan to the first documented progressive disease (PD) or death from any cause, whichever occurs first
5. Overall survival: the time from first dose of belzutifan until death from any cause
6. Number of Participants Who Experienced One or More Adverse Events (AEs)
7. Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE)
8. Time to Surgery: TTS is defined as the time from the first dose of belzutifan to the first documented surgical intervention or tumor reduction procedure |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 5 years
2. Up to approximately 5 years
3. Up to approximately 5 years
4. Up to approximately 5 years
5. Up to approximately 5 years
6. Up to approximately 5 years
7. Up to approximately 5 years
8. Up to approximately 5 years |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| China |
| Israel |
| Japan |
| New Zealand |
| Singapore |
| United States |
| Russian Federation |
| Turkey |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS
For purposes of analysis and reporting, the overall study ends when the
Sponsor receives the last laboratory test result or at the time of final contact with the last participant, whichever comes last. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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