Clinical Trials Register

Summary
EudraCT Number:	2018-000125-30
Sponsor's Protocol Code Number:	PT2977-202/MK-6482-004
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-06-12
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2018-000125-30

A.3

Full title of the trial

An Open-Label Phase 2 Study to Evaluate PT2977 for the Treatment of von Hippel-Lindau Disease-Associated Renal Cell Carcinoma

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

An Open-Label Phase 2 study to evaluate the effect of PT2977 for the treatment of von Hippel-Lindau Disease-Associated with kidney cancer

A.3.2

Name or abbreviated title of the trial where available

Phase 2 Study of PT2977 for Treatment of Von Hippel Lindau Disease-Associated Renal Cell Carcinoma

A.4.1

Sponsor's protocol code number

PT2977-202/MK-6482-004

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03401788

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Peloton Therapeutics, Inc., a Wholly-Owned Subsidiary of Merck & Co., Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Peloton Therapeutics, Inc., a Wholly-Owned Subsidiary of Merck & Co., Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Peloton Therapeutics, Inc., a Wholly-Owned Subsidiary of Merck & Co., Inc.
B.5.2	Functional name of contact point	Medical Monitor
B.5.3	Address:
B.5.3.1	Street Address	126 East Lincoln Ave. P.O. Box 2000
B.5.3.2	Town/ city	Rahway, New Jersey
B.5.3.3	Post code	07065
B.5.3.4	Country	United States
B.5.4	Telephone number	0034917081250
B.5.5	Fax number	0034917081301
B.5.6	E-mail	oscar.juan@pivotalcr.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	PT2977/MK-6482/Belzutifan
D.3.2	Product code	PT2977/MK-6482/Belzutifan
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Belzutifan
D.3.9.1	CAS number	1672688-24-4
D.3.9.2	Current sponsor code	PT2977 (MK-6482)
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Von Hippel-Lindau Disease-Associated Renal Cell Carcinoma

E.1.1.1

Medical condition in easily understood language

Von Hippel-Lindau Disease-Associated Kidney Cancer

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	20.0
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of PT2977 (Belzutifan) for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) as measured by overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by an independent review committee (IRC).

E.2.2

Secondary objectives of the trial

To evaluate efficacy of PT2977 for the treatment of VHL disease associated RCC measured as follows: Duration of response (DOR), Time to response (TTR), Progression-free survival (PFS), Time to Surgery (TTS)
•To evaluate efficacy of PT2977 for the treatment of VHL disease associated non-RCC tumors (retinal and CNS hemangioblastomas, pancreatic, adrenal, endolymphatic sac tumor and epididymal cystadenomas.)
•To evaluate safety and tolerability of PT2977
•To assess the PK of PT2977
Exploratory:
• To evaluate changes in PD markers
• To evaluate molecular features associated with predictors of clinical benefit from treatment with PT2977
• To evaluate efficacy of PT2977 for the treatment of VHL disease-associated RCC as measured by ORR and DOR in pts with either partial or complete VHL gene deletion
• To evaluate the Nr of pts who undergo surgical intervention and/or procedures for their RCC and/or non-RCC tumors
• To evaluate the Nr of pts who develop metastatic RCC

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Has the ability to understand and willingness to provide documented informed consent form before the performance of any study-specific procedures
2. 18 years of age or older
3. Has a diagnosis of von Hippel-Lindau disease, based on a germline VHL alteration
4. Has at least 1 measurable solid RCC tumor and no RCC tumor greater than 3.0 cm that requires immediate surgical intervention. The diagnosis of RCC can be radiologic (histologic diagnosis not required). Patients may have VHL disease-associated tumors in other organ systems
5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
6. Has organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1,000/μL, hemoglobin level ≥ 10 g/dL and platelet count ≥ 100,000/μL without transfusion or growth factor support within 2 weeks prior to obtaining the hematology values at screening;
• Serum creatinine level ≤ 2.0 × upper limit of normal (ULN)
• AST and ALT < 2.5 × ULN, total bilirubin < 1.5 × ULN (< 3 × ULN in patients with Gilbert’s disease), and alkaline phosphatase ≤ 2.5 × ULN
7. Male patients 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 2]) as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a 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.
• Male patients must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
• Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
8. A female patient 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 (abstinent on a long term and persistent basis), as described in Appendix [2] during the intervention period and for at least 30 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the patient must be excluded from participation if the serum pregnancy result is positive.
• Additional requirements for pregnancy testing during and after study intervention are located in Appendix [2].
• 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.
9. Able to swallow oral medications and comply with study procedures.

E.4

Principal exclusion criteria

1. Has participated in another clinical trial of an investigational drug (or a medical device) within 30 days of study enrollment
2. Has received prior treatment with PT2977 (Belzutifan) or another HIF-2α inhibitor
3. Has had any systemic anti-cancer therapy (includes anti-VEGF therapy or any systemic investigational anti-cancer agent)
4. Has had radiotherapy within 4 weeks prior to study enrollment
5. Has had surgical procedure for VHL disease or any major surgical procedure completed within 4 weeks prior to study enrollment
6. Has an immediate need for surgical intervention for tumor treatment
7. Has a prior or concomitant non-VHL disease-associated invasive malignancy with the exception of adequately treated basal or squamous cell carcinoma of the skin, cervical carcinoma in situ or any other malignancy from which the patient has remained disease free for more than 2 years
8. Evidence of metastatic disease on screening imaging.
9. Has malabsorption due to prior gastrointestinal (GI) surgery or GI disease
10. Has hypersensitivity to the active pharmaceutical ingredient or any component in the formulation
11. Has an active infection requiring systemic treatment
12. Has had any major cardiovascular event within 6 months prior to study drug administration including but not limited to myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic event, pulmonary embolism, clinically significant ventricular arrhythmias
(e.g. sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) or New York Heart Association Class III or IV heart failure
13. Has any other clinically significant cardiac, respiratory, or other medical or psychiatric condition that might interfere with participation in the trial or interfere with the interpretation of trial results, in the opinion of the investigator or medical monitor
14. If a female patient, intends to breast feed a child while on study drug or within 30 days after administration of the last dose of study drug.
15. A WOCBP who has a positive urine pregnancy test within 24 hours prior to the first dose of study intervention (see Appendix 2). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
16. Adults without legal capacity, under guardianship or curatorship, deprived of their liberty.

E.5 End points

E.5.1

Primary end point(s)

Overall response rate (ORR) in VHL disease-associated RCC tumors, defined as proportion of patients with a best confirmed response of CR or PR as determined by RECIST 1.1 and as assessed by an IRC.

E.5.1.1

Timepoint(s) of evaluation of this end point

At least 36 weeks after enrollment of the last patient

E.5.2

Secondary end point(s)

Secondary Endpoints:
• Duration of response (DOR) in VHL disease-associated RCC tumors, defined as the interval from the first documentation of response, as determined by RECIST 1.1, to the earlier of the first documentation of disease progression or death from any cause, and calculated for patients with a best confirmed response of CR or PR.
• Time to response (TTR) in VHL disease-associated RCC tumors, defined as the interval from the start of study treatment to the first documentation of a response, as determined by RECIST 1.1, and calculated for patients with a best confirmed response of CR or PR.
• Progression-free survival (PFS) in VHL disease-associated RCC tumors, defined as the interval from the start of study treatment until the earlier of the first documentation of disease progression determined by RECIST 1.1 or death from any cause.
• Time to surgery (TTS) for VHL disease-associated RCC tumors, defined as the interval from the start of study treatment to the date of surgery.
• ORR, DOR, TTR, PFS, and TTS for non-RCC tumors associated with VHL disease in individual organ systems.
• Pharmacokinetics will be evaluated.
Exploratory endpoints:
• Changes in PD markers (eg, serumEPO)
• Changes in the molecular features associated with clinical benefit from treatment with PT2977 (Belzutifan) as assessed by blood and tumor samples
Safety:
• Physical examinations
• Vital sign measurements (including pulse oximetry)
• 12-lead electrocardiograms (ECG) with QTc interval determination
• Clinical laboratory measurements
• Concomitant medications
• Incidence, intensity, and relationship of AEs and serious adverse events (SAEs)
• Effects on fertility in males (semen analysis, and measurement of testosterone, follicle-stimulating hormone, luteinizing hormone, and inhibin B levels)

E.5.2.1

Timepoint(s) of evaluation of this end point

•DOR & TTR: screening & within 7 days before the Wk 13, &every 12 wks thereafter. Primary data analysis performed at least 36 weeks after enrollment of the last patient
•PFS: screening & within 7 days before the Wk 13, &every 12 wks thereafter.
•TTS: date of surgey
•PKs; Wk 1 & Wk 3 before (pre-dose), 2 hours (± 15 minutes) postdose, and 5 hours (± 1 hour) post-dose and at the Wk 5, 9, & 13 before study drug administration
•PD: before study drug administration at Wks 1, 3, 5, 9 & 13
•Fresh tissue sample at the time of surgery from consenting patients
•Vital signs, Lab, ECG, AEs & conc. med; screening, pre-post dose, on wk 1 & 3, pre-dose on wk 5, 9, 13, 17, 21, 25 and every 12 wks thereafter
•Fertility tests; acreening, Wk 17 & 13 wks after last treatment (if required)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

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

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

United Kingdom

United States

Denmark

France

E.8.7

Trial has a data monitoring committee

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

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-08-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-30

P. End of Trial
P.	End of Trial Status	Ongoing

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