E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Renal Cell Carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Confirmed diagnosis of locally advanced/metastatic Renal Cell Carcinoma with clear cell component |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10038395 |
E.1.2 | Term | Renal carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10050076 |
E.1.2 | Term | Metastatic renal carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 compare the 120 mg once daily (QD) dose and 200 mg QD dose of MK-6482 with respect to objective response rate (ORR) based on Response Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR) |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the 120 mg QD dose and 200 mg QD dose of MK-6482 with respect to progression-free survival (PFS) as assessed by BICR according to RECIST 1.1 2. To evaluate the 120 mg QD dose and 200 mg QD dose of MK-6482 with respect to duration of response (DOR) as assessed by BICR according to RECIST 1.1 3. To evaluate the 120 mg QD dose and 200 mg QD dose of MK-6482 with respect to clinical benefit rate (CBR) as assessed by BICR according to RECIST 1.1 4. To evaluate the 120 mg QD dose and 200 mg QD dose of MK-6482 with respect to overall survival (OS) 5. To evaluate the safety and tolerability of the 120 mg QD dose compared with the 200 mg QD dose of MK-6482 6. To evaluate the pharmacokinetics (PK) of the 120 mg QD dose and 200 mg QD dose of MK-6482 administered orally as monotherapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A participant will be eligible for inclusion in the study if the participant: 1. Must have a histologically confirmed diagnosis of locally advanced/metastatic RCC with clear cell component (with or without sarcomatoid features) 2. Has measurable disease per RECIST 1.1 as assessed by BICR. 3. 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. 4. Has experienced disease progression on or after having received first-line systemic treatment for locally advanced or metastatic RCC with prior anti-PD-1/L1 + anti-CTLA4 combination or anti-PD-1/L1 + VEGF-targeted TKI combination. - PD-1/L1 checkpoint inhibitor-based combination regimens (with either VEGFtargeted TKI or anti-CTLA-4) treatment progression is defined by meeting ALL of the following criteria: o Has received at least 2 doses of an anti-PD-1/L1 mAb. o Has demonstrated radiographic disease progression during or after an anti-PD- 1/L1 mAb as assessed by investigator. - If the participant has received >1 prior regimen, there must have been demonstrated radiographic disease progression after the most recently received regimen. 5. Has received no more than 3 prior systemic regimens for locally advanced or metastatic RCC. 6. Is male or female, who is at least 18 years of age at the time of signing the informed consent. 7. Has a KPS score of at least 70% [Karnofsky, D. A., et al 1948] assessed within 10 days prior to the first dose of study intervention. 8. 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) 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. • 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. 9. 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), 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 • 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. 10. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the main study without participating in FBR. 11. Has adequate organ function, all screening laboratory tests should be performed within 10 days prior to the first dose of study intervention. |
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E.4 | Principal exclusion criteria |
The participant must be excluded from the study if the participant: 1. A WOCBP who has a positive urine pregnancy test within 24 hours prior to randomization (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 2. Has any of the following: - Hypoxia as defined by a pulse oximeter reading <92% at rest, or - Requires intermittent supplemental oxygen, or - Requires chronic supplemental oxygen. 3. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. 4. Has known CNS metastases and/or carcinomatous meningitis. 5. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction ≤6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted. 6. Has moderate to severe hepatic impairment (Child-Pugh B or C). 7. Received colony-stimulating factors (eg, G-CSF, GM-CSF or recombinant EPO) ≤28 days prior to the first dose of study intervention. 8. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study. 9. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption). 10. Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (MK-6482) formulations. 11. Has received prior treatment with MK-6482 or another HIF-2α inhibitor. 12. Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) ≤2 weeks before randomization. 13. Has received any type of systemic anticancer antibody (including investigational antibody) ≤4 weeks before randomization. 14. Has received prior radiotherapy ≤2 weeks prior to first dose of study intervention. Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is required for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. 15. Has had major surgery ≤3 weeks prior to first dose of study intervention. 16. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (eg, bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. 17. Is currently participating in a study of an investigational agent or is currently using an investigational device. 18. Has an active infection requiring systemic therapy. 19. Has active TB. 20. Has a diagnosis of immunodeficiency. 21. Has a known history of HIV infection. 22. Has a known history of HBV (defined as HBsAg reactive) or known active HCV (defined as HCV RNA [qualitative] is detected) infection. 23. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 48 months |
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E.5.2 | Secondary end point(s) |
1. Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) 2. Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) 3. Clinical Benefit Rate (CBR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) 4. Overall Survival (OS) 5. Number of Participants Who Experience One or More Adverse Events (AEs) 6. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) 7. Maximum Plasma Concentration (Cmax) of MK-6482 8. Trough Plasma Concentration (Ctrough) of MK-6482 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 48 months 2. Up to approximately 48 months 3. Up to approximately 48 months 4. Up to approximately 48 months 5. Up to approximately 48 months 6. Up to approximately 48 months 7. Weeks 1 and 3 on Day 1: predose and 1, 2, and 4 hours. Week 5 on Day 1: predose only. 8. Weeks 1 and 3 on Day 1: predose and 1, 2, and 4 hours. Week 5 on Day 1: predose only.
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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 | 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 | Yes |
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 | Information not present in EudraCT |
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 | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 |
Israel |
New Zealand |
Russian Federation |
United States |
Belgium |
Ireland |
Netherlands |
United Kingdom |
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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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Last participant’s last study-related telephone call or visit. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
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 |