A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101)

Study Overview
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Brief Summary
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This is a phase 3 randomized trial evaluating the anti-tumor activity and safety of avelumab in combination with axitinib and of sunitinib monotherapy, administered as first-line treatment, in patients with advanced renal cell carcinoma

Official Title
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A PHASE 3, MULTINATIONAL, RANDOMIZED, OPEN-LABEL, PARALLEL-ARM STUDY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH AXITINIB (INLYTA(REGISTERED)) VERSUS SUNITINIB (SUTENT(REGISTERED)) MONOTHERAPY IN THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED RENAL CELL CARCINOMA

Conditions
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Renal Cell Cancer

Intervention / Treatment
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* Drug: Avelumab (MSB0010718C)
* Drug: Axitinib (AG-013736)
* Drug: Sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced or metastatic RCC with clear cell component Availability of a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from a de novo tumor biopsy during screening (biopsied tumor lesion should not be a RECIST target lesion). Alternatively, a recently obtained archival FFPE tumor tissue block (not cut slides) from a primary or metastatic tumor resection or biopsy can be provided if the following criteria are met: 1) the biopsy or resection was performed within 1 year of randomization AND 2) the patient has not received any intervening systemic anti-cancer treatment from the time the tissue was obtained and randomization onto the current study. If an FFPE tissue block cannot be provided as per documented regulations then, 15 unstained slides (10 minimum) will be acceptable Availability of an archival FFPE tumor tissue from primary tumor resection specimen (if not provided per above). If an FFPE tissue block cannot be providedas per documented regulations 15 unstained slides (10 minimum) will be acceptable At least one measureable lesion as defined by RECIST version 1.1 that has not been previously irradiated Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Adequate bone marrow function, renal and liver functions Exclusion Criteria: Prior systemic therapy directed at advanced or metastatic RCC Prior adjuvant or neoadjuvant therapy for RCC if disease progression or relapse has occurred during or within 12 months after the last dose of treatment. Prior immunotherapy with IL-2, IFN-α, or anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways Prior therapy with axitinib and/or sunitinib as well as any prior therapies with other VEGF pathway inhibitors Newly dignosed or active brain metastasis Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partially controlled asthma Global Initiative for Asthma 2011) Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant pericardial effusion, cerebrovascular accident, transient ischemic attack Any of the following in the previous 6 months: deep vein thrombosis or symptomatic pulmonary embolism Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avelumab in combination with axitinib<br>Avelumab administered at 10 mg/kg IV every two weeks in combination with axitinib, 5 mg PO BID. | Drug: Avelumab (MSB0010718C)<br>* IV treatment Avelumab administered at 10 mg/kg IV every two weeks<br>Drug: Axitinib (AG-013736)<br>* Oral treatment Axitinib given 5 mg PO BID<br>* Other names: Inlyta;|
| Active Comparator: Sunitinib<br>Sunitinib given at 50 mg PO QD on schedule 4/2 | Drug: Sunitinib<br>* Oral treatment Sunitinib given at 50 mg PO QD on schedule 4/2<br>* Other names: Sutent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) in PD-L1 positive patients | Progression Free Survival (PFS) is the time from randomization to date of first documentation of objective progression of disease assessed by BICR (by RECIST version 1.1) or death due to any cause. | From randomization up to 40 months. | 
| Overall Survival in PD-L1 positive patients | OS is the time from date of randomization to date of death due to any cause. | Every 3 months up to 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in unselected patients | OS is the time from date of randomization to date of death due to any cause. | Every 3 months up to 8 years | 
| Number of participants with Objective Response (OR) | Number of participants with objective response (ie, confirmed complete or partial response according to RECIST Version 1.1 recorded from randomization until disease progression assessed by BICR or death due to any cause) | Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 40 months from randomization | 
| Disease Control (DC) | DC is defined as complete response (CR), partial response (PR), or stable disease (SD) according to the RECIST v.1.1 recorded from randomization until disease progression assessed by BICR or death due to any cause. | Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 40 months from randomization | 
| Time to Tumor Response (TTR) | TRR is the time from randomization to first documentation of objective tumor response (CR or PR). | Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 40 months from randomization | 
| Duration of response (DR) | DR is the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression assessed by BICR or death due to any cause | Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 40 months from randomization | 
| Progression Free Survival (PFS) by Investigator assessment | Progression Free Survival (PFS) is the time from randomization to date of first documentation of objective progression of disease assessed by the Investigator (by RECIST version 1.1) or death due to any cause. | Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 40 months from randomization | 
| Trough plasma concentration (Ctrough) of avelumab | Ctrough is defined as the concentration at the end of avelumab dosage interval | Pre-dose | 
| Trough plasma concentration (Ctrough) of axitinib | Ctrough is defined as the concentration at the end of axitinib dosage interval | Pre-dose | 
| Maximum plasma concentration (Cmax) of axitinib | Cmax defined as the maximum plasma concentration of axitinib | 2 hours post-dose | 
| Anti-Drug Antibody (ADA) levels of avelumab/Neutralizing antibodies titers for MSB0010718C | Immunogenicity assessment of avelumab | Pre-dose | 
| Tumor tissue biomarker status | Biomarker status defined as positive or negative based on a pre-specified scoring algorithm involving, for example, PD-L1 expression and/or quantitation of tumor infiltrating CD8+T lymphocytes as assessed by IHC | Baseline | 
| Overall Survival (OS) in biomarker-positive and biomarker-negative subgroups | OS in biomarker-negative and biomarker-positive subgroups. | Baseline | 
| Change From Baseline in FACT-Kidney Symptom Index (FKSI)-19 | The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains- Disease Related Symptoms (physical and emotional), Treatment related side effects and Functional and Well-Being . A negative change from Baseline represents a worsening of condition. | Every 6 weeks up to 8 years | 
| Change from Baseline in European Quality of Life Questionnaire (EQ-5D) - Health State Profile | EQ-5D Health State Profile: participant rated questionnaire to assess health-related quality of life in terms of a single index value. | Every 6 weeks up to 8 years | 
| Progression Free Survival (PFS) in biomarker-positive and biomarker-negative subgroups | PFS as measure of clinical outcome in biomarker-negative and biomarker-positive subgroups. | Baseline | 
| Objective Response (OR) in biomarker-positive and biomarker-negative subgroups | OR in biomarker-negative and biomarker-positive subgroups | Baseline | 
| Disease Control (DC) in biomarker-positive and biomarker-negative subgroups | DC in biomarker-negative and biomarker-positive subgroups | Baseline | 
| Time To Response (TTR) in biomarker-positive and biomarker-negative subgroups | TTR in biomarker-negative and biomarker-positive subgroups. | Baseline | 
| Duration of Response (DR) in biomarker-positive and biomarker-negative subgroups | DR in biomarker-negative and biomarker-positive subgroups. | Baseline | 
| Change from Baseline in European Quality of Life Questionnaire (EQ-5D) - Visual Analogic Scale | EQ-5D Visual Analogic Scale:patients rated their overall health status from 0 (worst imaginable heath state) to 100 (best imaginable heath state). | Every 6 weeks up to 8 years | 
| Time to treatment discontinuation/failure due to toxicity (TTF) | TTF is defined as the time from Cycle 1 Day 1 to the date of the first documentation of discontinuation due to an adverse event or death due to study treatment toxicity | From Cycle 1 Day 1, every 6 weeks up to the End of Treatment | 
| Treatment discontinuation/failure due to toxicity | Treatment discontinuation is the percentage of patients who discontinue the treatment due to an adverse event or death due to study treatment toxicity | From Cycle 1 Day 1, every 6 weeks up to the End of Treatment | 
| PFS on next-line therapy (PFS2) | PFS2 is defined as the time from randomization to discontinuation of next line treatment, second objective disease progression, or death from any cause, whichever occurs first. | From randomization up to 8 years. | 
| Progression Free Survival (PFS) in unselected patients | Progression Free Survival (PFS) is the time from randomization to date of first documentation of objective progression of disease assessed by BICR (by RECIST version 1.1) or death due to any cause. | From randomization up to 40 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, renal cell cancer, kidney disease, kidney neoplasms, axitinib, sunitinib