E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023400 |
E.1.2 | Term | Kidney cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
1. To evaluate and compare PFS per RECIST 1.1 as assessed by BICR in subjects. treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
2. To evaluate and compare OS in subjects treated with pembrolizumab plus axitinib versus sunitinib monotherapy. |
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E.2.2 | Secondary objectives of the trial |
1. To compare ORR and DCR per RECIST 1.1 as assessed by BICR in subjects treated with a combination of pembrolizumab plus axitinib versus sunitinib monotherapy. DOR will also be evaluated.
2. To evaluate and compare safety and tolerability profiles in subjects treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
3. To compare time to deterioration (TTD) based on the Functional Assessment of Cancer Therapy Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) scale in subjects treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
4. To assess the longitudinal score changes from baseline to 42 weeks as measured by European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 global health status/quality of life scale. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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E.3 | Principal inclusion criteria |
- Be > or = 18 years of age on day of signing informed consent
- Have histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features
- Have locally advanced/metastatic disease (i.e., Stage IV RCC per American Joint Committee on Cancer) or have recurrent disease
- Have measurable disease per RECIST 1.1 as assessed by the investigator /site radiologist. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
- Have received no prior systemic therapy for advanced RCC
- Provide tumor tissue for biomarker analysis
- Demonstrate adequate organ function |
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E.4 | Principal exclusion criteria |
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization
- Has had major surgery within 4 weeks prior to randomization or radiation therapy within 2 weeks prior to randomization, or who has not recovered (i.e., < or = Grade 1 or at baseline) from AEs due to prior treatment
- Has had prior treatment with any anti-PD-1, or PD-L1, or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms. Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, and GITR
- Has received prior therapy with VEGF/VEGFR or mTOR targeting agents
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization
- Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents
- Has a known additional malignancy that has progressed or has required active treatment in the last 3 years
- Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable
- Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
- Has a clinically significant gastrointestinal (GI) abnormality including: Inability to take oral medication, Requirement for IV alimentation, Prior surgical procedures affecting absorption including total gastric resection, Treatment for active peptic ulcer within the past 6 months, Active GI bleeding, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy, Intraluminal metastatic lesion with suspected bleeding, inflammatory bowel disease, ulcerative colitis or other GI condition associated with increased risk of perforation, or history of GI perforation, Malabsorption syndromes, Inflammatory bowel disease
- Has QT interval corrected for heart rate (QTc) > or = 480 msec
- Has a history of any of the following cardiovascular conditions within 12 months of screening: Myocardial infarction, Unstable angina pectoris, Cardiac angioplasty or stenting, Coronary/peripheral artery bypass graft, Class III or IV congestive heart failure per New York Heart Association, Cerebrovascular accident or transient ischemic attack
- Has a history of deep vein thrombosis or pulmonary embolism within 6 months of screening
- Has poorly controlled hypertension defined as systolic blood pressure (SBP) > or = 150 mm Hg and/or diastolic blood pressure (DBP) > or = 90 mm Hg
- Has evidence of inadequate wound healing
- Has active bleeding disorder or other history of significant bleeding episodes within 30 days of randomization
- Has hemoptysis within 6 weeks prior to randomization
- Has current use or anticipated need for treatment with drugs or foods that are known strong cytochrome P450 (CYP3A4/5) inhibitors
- Has current use or anticipated need for treatment with drugs that are known strong CYP3A4/5 inducers
- Has had a prior solid organ transplant
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E.5 End points |
E.5.1 | Primary end point(s) |
- Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR
- Overall Survival (OS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
First Interim Analysis (IA1)
- Timing: To be performed after enrollment completion, when all subjects have an opportunity to have at least 4 scheduled scans, and when approximately 50% of the final required OS events (or 198 deaths) have accrued. It is expected to be 21 months after study start. Approximately 380 PFS events are expected at IA1
- Purpose: Final analysis for PFS and IA1 for OS
Second Interim Analysis (IA2)
- Timing: To be performed when approximately 75% of the final required OS events (or 297 deaths) have accrued, expected to be 29 months after study start
- Purpose: IA2 for OS
Final analysis
- Timing: When approximately 396 deaths have accrued, expected to be 39 months after study start
- Purpose: Final analysis for OS (assuming not declared successful at the IA) |
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E.5.2 | Secondary end point(s) |
- To compare ORR, DOR and DCR per RECIST 1.1 as assessed by BICR
- To evaluate and compare safety and tolerability profiles
- To compare time to deterioration (TTD) based on the Functional Assessment of Cancer Therapy Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) scale
- To assess the longitudinal score changes from baseline to 42 weeks as measured by European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 global health status/quality of life scale
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS (primary testing), OS, ORR: 21 months (IA1)
- OS, ORR: 29 months (IA2)
- OS, ORR: 39 months (FA)
- The safety endpoint will be evaluated at each IA and at the Final Analysis while the QoL endpoints will be evaluated at Final Analysis
- In addition, the DMC will review safety periodically (every 4 months in the first year and frequency may be reduced after one year if no unexpected safety signals occur)
- The multiplicity adjustment for these safety reviews will be described in the DMC charter |
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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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
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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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 59 |
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 |
Brazil |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Ireland |
Italy |
Japan |
Korea, Republic of |
Poland |
Russian Federation |
Spain |
Taiwan |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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The study will be concluded after the clinical cutoff for the final OS analysis has been achieved |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |