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

• ClinicalTrials.gov Identifier: NCT02684006
• Recruitment Status: Active, not recruiting
• First Posted: February 17, 2016
• Last Update Posted: December 22, 2023
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: January 25, 2016
• First Posted Date: February 17, 2016
• Last Update Posted Date: December 22, 2023
• Actual Study Start Date: March 23, 2016
• Actual Primary Completion Date: August 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 21, 2020)

• Progression Free Survival (PFS) in PD-L1 positive patients [ Time Frame: From randomization up to 40 months. ]
  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.
• Overall Survival in PD-L1 positive patients [ Time Frame: Every 3 months up to 8 years ]
  OS is the time from date of randomization to date of death due to any cause.

Original Primary Outcome Measures (submitted: February 11, 2016)

Progression Free Survival (PFS) [ Time Frame: From randomization up to 30 months. ]

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.

Current Secondary Outcome Measures (submitted: February 21, 2020)

• Overall Survival (OS) in unselected patients [ Time Frame: Every 3 months up to 8 years ]
  OS is the time from date of randomization to date of death due to any cause.
• Number of participants with Objective Response (OR) [ Time Frame: Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 40 months from randomization ]
  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)
• Disease Control (DC) [ Time Frame: Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 40 months from randomization ]
  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.
• Time to Tumor Response (TTR) [ Time Frame: Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 40 months from randomization ]
  TRR is the time from randomization to first documentation of objective tumor response (CR or PR).
• Duration of response (DR) [ Time Frame: Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 40 months from randomization ]
  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
• Progression Free Survival (PFS) by Investigator assessment [ Time Frame: 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) 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.
• Trough plasma concentration (Ctrough) of avelumab [ Time Frame: Pre-dose ]
  Ctrough is defined as the concentration at the end of avelumab dosage interval
• Trough plasma concentration (Ctrough) of axitinib [ Time Frame: Pre-dose ]
  Ctrough is defined as the concentration at the end of axitinib dosage interval
• Maximum plasma concentration (Cmax) of axitinib [ Time Frame: 2 hours post-dose ]
  Cmax defined as the maximum plasma concentration of axitinib
• Anti-Drug Antibody (ADA) levels of avelumab/Neutralizing antibodies titers for MSB0010718C [ Time Frame: Pre-dose ]
  Immunogenicity assessment of avelumab
• Tumor tissue biomarker status [ Time Frame: Baseline ]
  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
• Overall Survival (OS) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  OS in biomarker-negative and biomarker-positive subgroups.
• Change From Baseline in FACT-Kidney Symptom Index (FKSI)-19 [ Time Frame: Every 6 weeks up to 8 years ]
  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.
• Change from Baseline in European Quality of Life Questionnaire (EQ-5D) - Health State Profile [ Time Frame: Every 6 weeks up to 8 years ]
  EQ-5D Health State Profile: participant rated questionnaire to assess health-related quality of life in terms of a single index value.
• Progression Free Survival (PFS) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  PFS as measure of clinical outcome in biomarker-negative and biomarker-positive subgroups.
• Objective Response (OR) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  OR in biomarker-negative and biomarker-positive subgroups
• Disease Control (DC) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  DC in biomarker-negative and biomarker-positive subgroups
• Time To Response (TTR) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  TTR in biomarker-negative and biomarker-positive subgroups.
• Duration of Response (DR) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  DR in biomarker-negative and biomarker-positive subgroups.
• Change from Baseline in European Quality of Life Questionnaire (EQ-5D) - Visual Analogic Scale [ Time Frame: Every 6 weeks up to 8 years ]
  EQ-5D Visual Analogic Scale:patients rated their overall health status from 0 (worst imaginable heath state) to 100 (best imaginable heath state).
• Time to treatment discontinuation/failure due to toxicity (TTF) [ Time Frame: From Cycle 1 Day 1, every 6 weeks up to the End of Treatment ]
  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
• Treatment discontinuation/failure due to toxicity [ Time Frame: From Cycle 1 Day 1, every 6 weeks up to the End of Treatment ]
  Treatment discontinuation is the percentage of patients who discontinue the treatment due to an adverse event or death due to study treatment toxicity
• PFS on next-line therapy (PFS2) [ Time Frame: From randomization up to 8 years. ]
  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.
• Progression Free Survival (PFS) in unselected patients [ Time Frame: From randomization up to 40 months. ]
  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.

Original Secondary Outcome Measures (submitted: February 11, 2016)

• Overall Survival (OS) [ Time Frame: Every 3 months up to 5 years ]
  OS is the time from date of randomization to date of death due to any cause.
• Number of participants with Objective Response (OR) [ Time Frame: Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 30 mos from randomization ]
  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)
• Disease Control (DC) [ Time Frame: Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 30 mos from randomization ]
  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.
• Time to Tumor Response (TTR) [ Time Frame: Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 30 mos from randomization ]
  TRR is the time from randomization to first documentation of objective tumor response (CR or PR).
• Duration of response (DR) [ Time Frame: Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 30 mos from randomization ]
  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
• Progression Free Survival (PFS) by Investigator assessment [ Time Frame: Every 6 weeks up to 18 months from patient enrollment in the study, then every 12 weeks up to 30 mos from randomization ]
  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.
• Trough plasma concentration (Ctrough) of avelumab [ Time Frame: Pre-dose ]
  Ctrough is defined as the concentration at the end of avelumab dosage interval
• Trough plasma concentration (Ctrough) of axitinib [ Time Frame: Pre-dose ]
  Ctrough is defined as the concentration at the end of axitinib dosage interval
• Maximum plasma concentration (Cmax) of axitinib [ Time Frame: 2 hours post-dose ]
  Cmax defined as the maximum plasma concentration of axitinib
• Anti-Drug Antibody (ADA) levels of avelumab/Neutralizing antibodies titers for MSB0010718C [ Time Frame: Pre-dose ]
  Immunogenicity assessment of avelumab
• Tumor tissue biomarker status [ Time Frame: Baseline ]
  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
• Overall Survival (OS) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  OS in biomarker-negative and biomarker-positive subgroups.
• Change From Baseline in FACT-Kidney Symptom Index (FKSI)-19 [ Time Frame: Every 6 weeks up to 3 years ]
  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.
• Change from Baseline in European Quality of Life Questionnaire (EQ-5D) - Health State Profile [ Time Frame: Every 6 weeks up to 3 years ]
  EQ-5D Health State Profile: participant rated questionnaire to assess health-related quality of life in terms of a single index value.
• Progression Free Survival (PFS) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  PFS as measure of clinical outcome in biomarker-negative and biomarker-positive subgroups.
• Objective Response (OR) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  OR in biomarker-negative and biomarker-positive subgroups
• Disease Control (DC) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  DC in biomarker-negative and biomarker-positive subgroups
• Time To Response (TTR) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  TTR in biomarker-negative and biomarker-positive subgroups.
• Duration of Response (DR) in biomarker-positive and biomarker-negative subgroups [ Time Frame: Baseline ]
  DR in biomarker-negative and biomarker-positive subgroups.
• Change from Baseline in European Quality of Life Questionnaire (EQ-5D) - Visual Analogic Scale [ Time Frame: Every 6 weeks up to 3 years ]
  EQ-5D Visual Analogic Scale:patients rated their overall health status from 0 (worst imaginable heath state) to 100 (best imaginable heath state).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101)
• Official Title: 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
• Brief Summary: 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
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Renal Cell Cancer

Intervention

• Drug: Avelumab (MSB0010718C)
  IV treatment Avelumab administered at 10 mg/kg IV every two weeks
• Drug: Axitinib (AG-013736)
  Oral treatment Axitinib given 5 mg PO BID
  Other Name: Inlyta
• Drug: Sunitinib
  Oral treatment Sunitinib given at 50 mg PO QD on schedule 4/2
  Other Name: Sutent

Study Arms

• Experimental: Avelumab in combination with axitinib
  Avelumab administered at 10 mg/kg IV every two weeks in combination with axitinib, 5 mg PO BID.
  Interventions:

  • Drug: Avelumab (MSB0010718C)
  • Drug: Axitinib (AG-013736)
• Active Comparator: Sunitinib
  Sunitinib given at 50 mg PO QD on schedule 4/2
  Intervention: Drug: Sunitinib

Publications *

• Rini BI, Moslehi JJ, Bonaca M, Schmidinger M, Albiges L, Choueiri TK, Motzer RJ, Atkins MB, Haanen J, Mariani M, Wang J, Hariharan S, Larkin J. Prospective Cardiovascular Surveillance of Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Cancer: Data From the Phase III JAVELIN Renal 101 Trial. J Clin Oncol. 2022 Jun 10;40(17):1929-1938. doi: 10.1200/JCO.21.01806. Epub 2022 Mar 3.
• Masters JC, Khandelwal A, di Pietro A, Dai H, Brar S. Model-informed drug development supporting the approval of the avelumab flat-dose regimen in patients with advanced renal cell carcinoma. CPT Pharmacometrics Syst Pharmacol. 2022 Apr;11(4):458-468. doi: 10.1002/psp4.12771. Epub 2022 Feb 27.
• Rini BI, Atkins MB, Choueiri TK, Thomaidou D, Rosbrook B, Thakur M, Hutson TE. Time to Resolution of Axitinib-Related Adverse Events After Treatment Interruption in Patients With Advanced Renal Cell Carcinoma. Clin Genitourin Cancer. 2021 Oct;19(5):e306-e312. doi: 10.1016/j.clgc.2021.03.019. Epub 2021 Apr 5.
• Choueiri TK, Larkin J, Pal S, Motzer RJ, Rini BI, Venugopal B, Alekseev B, Miyake H, Gravis G, Bilen MA, Hariharan S, Chudnovsky A, Ching KA, Mu XJ, Mariani M, Robbins PB, Huang B, di Pietro A, Albiges L. Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial. ESMO Open. 2021 Jun;6(3):100101. doi: 10.1016/j.esmoop.2021.100101. Epub 2021 Apr 23. Erratum In: ESMO Open. 2021 Aug;6(4):100177.
• Motzer RJ, Robbins PB, Powles T, Albiges L, Haanen JB, Larkin J, Mu XJ, Ching KA, Uemura M, Pal SK, Alekseev B, Gravis G, Campbell MT, Penkov K, Lee JL, Hariharan S, Wang X, Zhang W, Wang J, Chudnovsky A, di Pietro A, Donahue AC, Choueiri TK. Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nat Med. 2020 Nov;26(11):1733-1741. doi: 10.1038/s41591-020-1044-8. Epub 2020 Sep 7.
• Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. doi: 10.1016/j.annonc.2020.04.010. Epub 2020 Apr 25.
• Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. doi: 10.1056/NEJMoa1816047. Epub 2019 Feb 16.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 11, 2021): 888
• Original Estimated Enrollment (submitted: February 11, 2016): 583
• Estimated Study Completion Date: May 21, 2024
• Actual Primary Completion Date: August 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, New Zealand, Romania, Russian Federation, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02684006
• Other Study ID Numbers: B9991003; 2015-002429-20 ( EudraCT Number ); JAVELIN RENAL 101 ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: December 2023