E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Von Hippel-Lindau Disease-Associated Renal Cell Carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Von Hippel-Lindau Disease-Associated Kidney Cancer |
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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 |
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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 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). |
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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 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 penilevaginal intercourse or use a male condom during each episode of penilevaginal 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. |
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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 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.
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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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At least 36 weeks after enrollment of the last patient |
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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 (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) |
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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) |
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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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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.8.3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
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 |
Denmark |
France |
United Kingdom |
United States |
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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
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |