Clinical trial NCT02493751: A Study Of Avelumab In Combination With Axitinib In Advanced Renal Cell Cancer (JAVELIN Renal 100)
Official title: A PHASE 1B, OPEN-LABEL, DOSE-FINDING STUDY TO EVALUATE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AVELUMAB (MSB0010718C) IN COMBINATION WITH AXITINIB (AG-013736) IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED RENAL CELL CANCER
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Cell Cancer
Keywords: Cancer, renal cell cancer, kidney disease, kidney neoplasms, axitinib
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2015-07-09
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Primary purpose: TREATMENT

Brief summary: This is a Phase 1b, open-label, multi-center, multiple-dose trial designed to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of avelumab (MSB0010718C) in combination with axitinib (AG-013736). Once the MTD of avelumab administered in combination with axitinib is estimated (dose finding portion), the dose expansion phase will be opened to further characterize the combination in term of safety profile, anti tumor activity, pharmacokinetics, pharmacodynamics and biomarker modulation.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed advanced RCC with clear cell component
* Primary tumor resected
* Availability of a recent 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 enrollment AND 2) the patient has not received any intervening systemic anti-cancer treatment from the time the tissue was obtained and enrollment onto the current study. If an FFPE tissue block cannot be provided as per documented regulations,, 15 unstained slides (10 minimum) will be acceptable.
* Availability of an archival FFPE tumor tissue block from primary diagnosis specimen (if available and not provided per above). If an FFPE tissue block cannot be provided, 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.
* Age ≥18 years (≥ 20 years in Japan).
* 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 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 as well as any prior therapies with other VEGF pathway inhibitors.
* Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any history of anaphylaxis.
* Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, 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).

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: DLT observation period (from the beginning of Cycle 1 up to the end of Cycle 2 [28 days])
Secondary outcomes:
measure: Number of Participants With All-causality Treatment Emergent Adverse Events (TEAEs)
timeFrame: Baseline up to 30 days after the last dose of study treatment (maximum of 259.7 weeks)
measure: Number of Participants With Treatment-related TEAEs
timeFrame: Baseline up to 30 days after the last dose of study treatment (maximum of 259.7 weeks)
measure: Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE Version 4.03 - Hematology
timeFrame: Baseline up to 30 days after the last dose of study treatment and 1 day before the start day of new anti-cancer drug therapy (maximum of 259.7 weeks)
measure: Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE Version 4.03 - Chemistry
timeFrame: Baseline up to 30 days after the last dose of study treatment and 1 day before the start day of new anti-cancer drug therapy (maximum of 259.7 weeks)
measure: Change From Baseline in Vital Signs - Sitting Diastolic Blood Pressure
timeFrame: Baseline, Day 1 of each cycle, Day 8 of Cycles 1 and 2, end of treatment, Follow-up Days 30, 60, 90 for all participants in the analysis population, and Lead-in Day 7 for participants with lead-in (maximum of 139.6 weeks by PCD)
measure: Change From Baseline in Vital Signs - Sitting Systolic Blood Pressure
timeFrame: Baseline, Day 1 of each cycle, Day 8 of Cycles 1 and 2, end of treatment, Follow-up Days 30, 60, 90 for all participants in the analysis population, and Lead-in Day 7 for participants with lead-in (maximum of 139.6 weeks by PCD)
measure: Change From Baseline in Vital Signs - Pulse Rate
timeFrame: Baseline, Day 1 of each cycle, Day 8 of Cycles 1 and 2, end of treatment, Follow-up Days 30, 60, 90 for all participants in the analysis population, and Lead-in Day 7 for participants with lead-in (maximum of 139.6 weeks by PCD)
measure: Number of Participants Achieving Objective Response (OR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Cycle 1 Day 1 up to 30 months after the first dose
measure: Number of Participants Achieving Disease Control (DC) Based on RECIST Version 1.1
timeFrame: Cycle 1 Day 1 up to 30 months after the first dose
measure: Duration of Response (DR) Based on RECIST Version 1.1
timeFrame: Cycle 1 Day 1 up to 30 months after the first dose
measure: Progression-free Survival (PFS)
timeFrame: Cycle 1 Day 1 up to 30 months after the first dose
measure: Time to Tumor Response (TTR) Based on RECIST Version 1.1
timeFrame: Cycle 1 Day 1 up to 30 months after the first dose
measure: Overall Survival (OS)
timeFrame: Cycle 1 Day 1 up to 30 months after the first dose
measure: Maximum Observed Plasma Concentration (Cmax) for Axitinib When Dosed Alone and in Combination With Avelumab
timeFrame: Predose, 1, 2, 3, 4, 6, and 8 hours post dose on Lead-in Day 7 and Cycle 4 Day 1
measure: Time for Cmax (Tmax) for Axitinib When Dosed Alone and in Combination With Avelumab
timeFrame: Predose, 1, 2, 3, 4, 6, and 8 hours post dose on Lead-in Day 7 and Cycle 4 Day 1
measure: Area Under the Plasma Concentration Time Profile From Time Zero to the Next Dose at Steady State (AUCtau) for Axitinib When Dosed Alone and in Combination With Avelumab
timeFrame: Predose, 1, 2, 3, 4, 6, and 8 hours post dose on Lead-in Day 7 and Cycle 4 Day 1
measure: Terminal Half-Life (t1/2) for Axitinib When Dosed Alone and in Combination With Avelumab
timeFrame: Predose, 1, 2, 3, 4, 6, and 8 hours post dose on Lead-in Day 7 and Cycle 4 Day 1
measure: Predose Concentration During Multiple Dosing (Ctrough) for Avelumab
timeFrame: Predose on Day 1 of Cycles 1, 2, 3, 4, 6, 8, 14, 20, 26, 32, 38, 44, and 50
measure: Cmax for Avelumab
timeFrame: Predose, 1 hour, and 168 hours post dose on Cycle 1 Day 1; predose and 1 hour post dose on Cycle 4 Day 1
measure: Number of Participants With Their Target Programmed Death-Ligand (PD-L1) Status at Baseline
timeFrame: Baseline
measure: Number of Participants With Anti-drug Antibody (ADA) Against Avelumab When Combined With Axitinib by Never and Ever Positive Status
timeFrame: Pre-dose on Day 1 of Cycles 1-4, 6, 8, then every 12 weeks thereafter until Cycle 50, and on Follow-up Day 30 (maximum of 2 years)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Scottsdale Healthcare Hospitals d/b/a HonorHealth
state: Arizona
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Laura & Isaac Perlmutter Cancer Center At NYU Langone
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Nashville
country: United States
facility: Henry Joyce Cancer Clinic
state: Tennessee
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Hospital
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Institute
state: Utah
city: Chuo-ku, Niigata
country: Japan
facility: Niigata University Medical & Dental Hospital
state: Niigata
city: Osakasayama
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Shinjuku-ku
country: Japan
facility: Keio University Hospital
state: Tokyo
city: London
country: United Kingdom
facility: Mount Vernon Cancer Center, East and North Herts. NHS Trust
state: Middlesex
city: Carshalton
country: United Kingdom
facility: St Helier Hospital
state: Surrey
city: London
country: United Kingdom
facility: St. Bartholomew's Hospital
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: Choueiri TK, Larkin J, Oya M, Thistlethwaite F, Martignoni M, Nathan P, Powles T, McDermott D, Robbins PB, Chism DD, Cho D, Atkins MB, Gordon MS, Gupta S, Uemura H, Tomita Y, Compagnoni A, Fowst C, di Pietro A, Rini BI. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018 Apr;19(4):451-460. doi: 10.1016/S1470-2045(18)30107-4. Epub 2018 Mar 9.