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    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2018-000125-30
    A.3Full 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.3.1Title 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.3.2Name 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.4.1Sponsor's protocol code numberPT2977-202/MK-6482-004
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03401788
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPeloton Therapeutics, Inc., a Wholly-Owned Subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPeloton Therapeutics, Inc., a Wholly-Owned Subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPeloton Therapeutics, Inc., a Wholly-Owned Subsidiary of Merck & Co., Inc.
    B.5.2Functional name of contact pointMedical Monitor
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive, P.O. Box 100, Whitehouse Station
    B.5.3.2Town/ cityNew Jersey
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number0034917081250
    B.5.5Fax number0034917081301
    B.5.6E-mailoscar.juan@pivotalcr.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePT2977 (MK-6482)
    D.3.2Product code PT2977 (MK-6482)
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet obtained
    D.3.9.1CAS number 1672688-24-4
    D.3.9.2Current sponsor codePT2977 (MK-6482)
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Von Hippel-Lindau Disease-Associated Renal Cell Carcinoma
    E.1.1.1Medical condition in easily understood language
    Von Hippel-Lindau Disease-Associated Kidney Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10047716
    E.1.2Term Von Hippel-Lindau disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of PT2977 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).
    E.2.2Secondary 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 pharmacokinetics (PK) of PT2977
    Exploratory:
    • To evaluate changes in pharmacodynamic (PD) markers (e.g., serum erythropoietin [EPO])
    • To evaluate molecular features associated with predictors of clinical benefit from treatment with PT2977
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Has the ability to understand and willingness to sign a written 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 participants are eligible to participate if they agree to the following during the intervention period and for at least 5 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 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 participants 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 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 (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 participant 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.4Principal 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 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.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At least 36 weeks after enrollment of the last patient
    E.5.2Secondary 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 (e.g., serumEPO)
    • Changes in the molecular features associated with clinical benefit from treatment with PT2977 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Denmark
    France
    United Kingdom
    United States
    E.8.7Trial 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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 13
    F.4.2.2In the whole clinical trial 61
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-08-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-30
    P. End of Trial
    P.End of Trial StatusOngoing
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