| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023400 |
| E.1.2 | Term | Kidney cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 PFS rate per RECIST 1.1 as assessed by BICR at 12, 18, and 24 months based on data adequacy; to evaluate OS rates at 12, 18, and 24 months based on data adequacy.
3. 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| 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 ie, newly diagnosed 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. 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, received 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 systemic anti-cancer therapy for RCC (e.g., VEGF/VEGFR, chemotherapy or mTOR-targeting agents).
- Has a diagnosis of immunodeficiency OR is receiving a systemic steroid therapy exceeding physiologic corticosteroid dose or any other form of immunosuppressive therapy within 7 days prior to randomization
- Has an active autoimmune disease requiring systemic treatment within the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) 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 radiologically stable
- Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
- Has a clinically significant gastrointestinal (GI) abnormality including: a) Malabsorption, total gastric resection, or any other condition that might affect the absorption of orally taken medication. b) Active GI bleeding, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy c) Intraluminal metastatic lesion with suspected bleeding, inflammatory bowel disease, ulcerative colitis or other GI condition associated with increased risk of perforation
- 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 randomization: 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 (within 7 days of randomization) or anticipated need for treatment with drugs or foods that are known strong cytochrome P450 (CYP3A4/5) inhibitors
- Has current use (within 7 days of randomization) or anticipated need for treatment with drugs that are known strong CYP3A4/5 inducers: including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort; or drugs that are known with proarrhythmic potential
- 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) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
First Interim Analysis (IA1)
Performed after enrollment completion, once a 7-mo minimum follow up has been achieved and a minimum of 305 PFS events have accrued.
Expected to be 22 mo after the first sbj randomized. Approximately 48% of final required OS events (or 195 deaths) are expected at that time.
Purpose: First IA for PFS and OS.
Second Interim Analysis (IA2)
Performed when approximately 74% of the final required OS events (or 299 deaths) have accrued, expected to be 31 mo after study start. At IA2, approximately 487 PFS events are expected.
Purpose: Final analysis for PFS and IA2 for OS.
Final analysis (event-driven trial)
When approximately 404 deaths have accrued, expected to be 43 mo after study start.
Purpose: Final analysis for OS (if not declared successful at IA) |
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| E.5.2 | Secondary end point(s) |
•Objective Response Rate (ORR) – RECIST 1.1 by BICR
Objective response rate is defined as the proportion of the subjects in the analysis population who have a CR or PR per RECIST 1.1.
•Duration of Response (DOR) - RECIST 1.1 by BICR
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented evidence of CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death due to any cause, whichever occurs first. See Section 8.6.1 for the censoring rules.
•Disease Control Rate (DCR) - RECIST 1.1 by BICR
Disease control rate is defined as the percentage of subjects who have achieved CR, PR, or SD of ≥ 6 months based on assessments by BICR per RECIST 1.1.
•Safety endpoints: The following safety parameters will be analyzed:
AEs and SAEs graded per NCI CTCAE, Version 4.0 criteria with time to onset/recovery, causality and outcome; changes in laboratory values, vital signs since baseline, treatment discontinuations and reason for discontinuation, death and cause of death, etc. Concomitant medications will be collected with time and reasons for use.
•Health-Related Quality of Life Endpoints: FKSI-DRS, EORTC-QLQ-C30, and EuroQol EQ-5D-3L questionnaires.
As of end of January 2020. PRO data will no longer be collected. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Imaging after randomization will be performed at Week 12 (84 days ±7 days), then Q6W (42 days ±7 days) through Week 54, then Q12W (84 days ±7 days) thereafter until PD is BICR verified or further confirmed by the investigator. Imaging visit window may be ± 14 days after Week 104. Unscheduled imaging can be performed as clinically indicated. The
timing of imaging assessments should follow calendar days from randomization and should not be adjusted for dose delays or cycle starts.
Safety and Health-Related Quality of Life assessments are cycle based.
The DMC has responsibility for assessment of overall risk: benefit. 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). |
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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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Ukraine |
| Taiwan |
| Brazil |
| Canada |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United Kingdom |
| United States |
| Czechia |
| France |
| Germany |
| Hungary |
| Ireland |
| Poland |
| Spain |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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