A Study Of Avelumab In Combination With Axitinib In Advanced Renal Cell Cancer (JAVELIN Renal 100)

Study Overview
=================
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.

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

Conditions
-----------------
Renal Cell Cancer

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


Participation Criteria
=================
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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose finding phase and dose expansion phase.<br>To test the maximum tolerated dose of avelumab (MSB0010718C) in combination with axitinib (AG-013736) | Drug: Avelumab (MSB0010718C)<br>* Avelumab with two dose levels: 10 mg/kg IV and 5 mg/kg IV every two weeks to find the maximum tolerated dose in combination with axitinib and continue treatment in a dose expansion.<br>Drug: Axitinib (AG-013736)<br>* Axitinib with two dose levels: 5 mg and 3 mg oral BID to find the maximum tolerated dose in combination with avelumab and continue treatment in a dose expansion.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | DLT: greater than or equal to (>=) Grade 3 hematologic/non-hematologic toxicity, Grade 3-4 liver-related laboratory test elevation (alanine aminotransferase, aspartate aminotransferase) with Grade 2 elevation of total bilirubin, non-hematologic Grade 3 laboratory abnormality (required medical intervention to treat participant/led to hospitalization), inability to complete >=75% of first 2 cycles doses of axitinib (from Cycle 1 Day 1 after completion of lead-in period) or 2 infusions of avelumab within DLT observation period due to investigational product related toxicity. | DLT observation period (from the beginning of Cycle 1 up to the end of Cycle 2 [28 days]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With All-causality Treatment Emergent Adverse Events (TEAEs) | Adverse event (AE)=any untoward medical occurrence in participant who received study treatment without regard to causality. TEAE=event between first dose of study treatment and up to 30 days after last dose that were absent before treatment or worsened relative to pretreatment state. Serious AE (SAE)=AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience; persistent or significant disability/incapacity; congenital anomaly. AEs were graded by worst National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 severity grade. Grade 3 event=unacceptable or intolerable event, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 event caused participant to be in imminent danger of death. Grade 5 event=death related to AE. The results reflect data available on cutoff of LPLV (04 Mar 2021). | Baseline up to 30 days after the last dose of study treatment (maximum of 259.7 weeks) | 
| Number of Participants With Treatment-related TEAEs | Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. TEAE=event between first dose of study treatment and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience; persistent or significant disability/incapacity; congenital anomaly. AEs were graded by worst NCI CTCAE v4.03 severity grade. Grade 3 events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 events caused participant to be in imminent danger of death. Grade 5 events=death related to an AE. Treatment-related AEs and SAEs were determined by the investigator. The results reflect data available on cutoff of LPLV (04 Mar 2021). | Baseline up to 30 days after the last dose of study treatment (maximum of 259.7 weeks) | 
| Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE Version 4.03 - Hematology | Laboratory abnormalities (hematology) reported included anemia, platelet count decreased, lymphocyte count decreased, and neutrophil count decreased. Grade 1=mild transient reaction; infusion interruption not indicated; intervention not indicated. Grade 2=therapy or infusion interruption indicated but responds promptly to symptomatic treatment; prophylactic medications indicated for <=24 hours. Grade 3=prolonged; recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae. Grade 4=life threatening consequences; urgent intervention indicated. Grade 5=death. The results reflect data available on cutoff of LPLV (04 Mar 2021). | 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) | 
| Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE Version 4.03 - Chemistry | Laboratory abnormalities (chemistry) reported included creatinine increased, serum amylase increased, lipase increased, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, blood bilirubin increased, creatine kinase increased, hypoglycemia, and hyperglycemia. Grade 1=mild transient reaction; infusion interruption not indicated; intervention not indicated. Grade 2=therapy or infusion interruption indicated but responds promptly to symptomatic treatment; prophylactic medications indicated for <=24 hours. Grade 3=prolonged; recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae. Grade 4=life threatening consequences; urgent intervention indicated. Grade 5=death. The results reflect data available on cutoff of LPLV (04 Mar 2021). | 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) | 
| Change From Baseline in Vital Signs - Sitting Diastolic Blood Pressure | Blood pressure was taken with the participant in the seated position after the participant had been sitting quietly for at least 5 minutes. Baseline was defined as the last assessment prior to the date/time of the first dose of study treatment, which occurred on Day 1 in Lead-in period for participants with lead-in, and occurred on Cycle 1 Day 1 (C1D1) for participants without lead-in. The results reflect data available on cutoff of primary completion date (PCD) (03 Apr 2018). | 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) | 
| Change From Baseline in Vital Signs - Sitting Systolic Blood Pressure | Blood pressure was taken with the participant in the seated position after the participant had been sitting quietly for at least 5 minutes. Baseline was defined as the last assessment prior to the date/time of the first dose of study treatment, which occurred on Day 1 in Lead-in period for participants with lead-in, and occurred on Cycle 1 Day 1 (C1D1) for participants without lead-in. The results reflect data available on cutoff of PCD (03 Apr 2018). | 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) | 
| Change From Baseline in Vital Signs - Pulse Rate | Pulse rate was taken with the participant in the seated position after the participant had been sitting quietly for at least 5 minutes. Baseline was defined as the last assessment prior to the date/time of the first dose of study treatment, which occurred on Day 1 in Lead-in period for participants with lead-in, and occurred on Cycle 1 Day 1 (C1D1) for participants without lead-in. The results reflect data available on cutoff of PCD (03 Apr 2018). | 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) | 
| Number of Participants Achieving Objective Response (OR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Confirmed OR was defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the start date until disease progression or death due to any cause. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR was defined as >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must have been assessed. The results reflect data available on cutoff of PCD (03 Apr 2018). | Cycle 1 Day 1 up to 30 months after the first dose | 
| Number of Participants Achieving Disease Control (DC) Based on RECIST Version 1.1 | DC was defined as OR (CR or PR) or stable disease (SD) per RECIST v1.1 from the start date until the first documentation of objective disease progression or death due to any cause. SD was defined as not qualifying for CR, PR, or progression (PD). PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR was defined as >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must have been assessed. The results reflect data available on cutoff of PCD (03 Apr 2018). | Cycle 1 Day 1 up to 30 months after the first dose | 
| Duration of Response (DR) Based on RECIST Version 1.1 | DR was defined as the time from the first documentation of objective tumor response (CR or PR) that was subsequently confirmed to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR was defined as >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must have been assessed. The results reflect data available on cutoff of PCD (03 Apr 2018). | Cycle 1 Day 1 up to 30 months after the first dose | 
| Progression-free Survival (PFS) | PFS was defined as defined as the time from the start date to the date of the first documentation of objective progression of disease (PD) or death due to any cause, whichever occurred first. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. All target lesions must have been assessed. The results reflect data available on cutoff of PCD (03 Apr 2018). | Cycle 1 Day 1 up to 30 months after the first dose | 
| Time to Tumor Response (TTR) Based on RECIST Version 1.1 | TTR was defined as the time from start date to the first documentation of objective tumor response (CR or PR) that was subsequently confirmed. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR was defined as >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must have been assessed. The results reflect data available on cutoff of PCD (03 Apr 2018). | Cycle 1 Day 1 up to 30 months after the first dose | 
| Overall Survival (OS) | OS was defined as the time from the start date to the date of death due to any cause. The results reflect data available on cutoff of PCD (03 Apr 2018). | Cycle 1 Day 1 up to 30 months after the first dose | 
| Maximum Observed Plasma Concentration (Cmax) for Axitinib When Dosed Alone and in Combination With Avelumab | Cmax for axitinib when dosed alone on Lead-in Day 7 and in combination with avelumab on Cycle 4 Day 1 for Axitinib + Avelumab with Lead-in Arm. The results reflect data available on cutoff of PCD (03 Apr 2018). | Predose, 1, 2, 3, 4, 6, and 8 hours post dose on Lead-in Day 7 and Cycle 4 Day 1 | 
| Time for Cmax (Tmax) for Axitinib When Dosed Alone and in Combination With Avelumab | Tmax for axitinib when dosed alone on Lead-in Day 7 and in combination with avelumab on Cycle 4 Day 1 for Axitinib + Avelumab with Lead-in Arm. The results reflect data available on cutoff of PCD (03 Apr 2018). | Predose, 1, 2, 3, 4, 6, and 8 hours post dose on Lead-in Day 7 and Cycle 4 Day 1 | 
| 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 | AUCtau was defined as area under the plasma concentration time profile from time zero to time tau, the dosing interval at steady state. tau = 12 hrs for Axitinib. AUCtau for Axitinib when dosed alone on Lead-in Day 7 and in combination with avelumab on Cycle 4 Day 1 for Axitinib + Avelumab with Lead-in Arm was reported. The results reflect data available on cutoff of PCD (03 Apr 2018). | Predose, 1, 2, 3, 4, 6, and 8 hours post dose on Lead-in Day 7 and Cycle 4 Day 1 | 
| Terminal Half-Life (t1/2) for Axitinib When Dosed Alone and in Combination With Avelumab | t1/2 was calculated by Log e(2)/kel. kel was the terminal phase rate constant calculated by a linear regression of the log linear concentration time-curve. Only those data points judged to describe the terminal log linear decline were used in the regression. t1/2 for Axitinib when dosed alone on Lead-in Day 7 and in combination with avelumab on Cycle 4 Day 1 for Axitinib + Avelumab with Lead-in Arm was reported. The results reflect data available on cutoff of PCD (03 Apr 2018). | Predose, 1, 2, 3, 4, 6, and 8 hours post dose on Lead-in Day 7 and Cycle 4 Day 1 | 
| Predose Concentration During Multiple Dosing (Ctrough) for Avelumab | Ctrough was directly observed from data. The results reflect data available on cutoff of PCD (03 Apr 2018). | Predose on Day 1 of Cycles 1, 2, 3, 4, 6, 8, 14, 20, 26, 32, 38, 44, and 50 | 
| Cmax for Avelumab | Cmax for avelumab on Cycle 1 Day (C1D1) and C1D4 were reported. The results reflect data available on cutoff of PCD (03 Apr 2018). | Predose, 1 hour, and 168 hours post dose on Cycle 1 Day 1; predose and 1 hour post dose on Cycle 4 Day 1 | 
| Number of Participants With Their Target Programmed Death-Ligand (PD-L1) Status at Baseline | Number of participants with PD-L1 positive (PD-L1 >=1%) status in immune cell (IC), tumor cell (TC), or both IC and TC. The results reflect data available on cutoff of PCD (03 Apr 2018). | Baseline | 
| Number of Participants With Anti-drug Antibody (ADA) Against Avelumab When Combined With Axitinib by Never and Ever Positive Status | Whole blood specimens were collected at the designated times (Day 1 of Cycles 1-4, 6, and 8, then every 12 weeks until Cycle 50, and Follow-up Day 30) to provide serum for evaluation of avelumab immunogenicity. Human serum ADA specimens were analyzed for the presence or absence of anti-avelumab antibodies with quasi-quantitative enzyme-linked immunosorbent assay, following a tiered approach using screening, confirmation and titer/quantitation. ADA serum specimens were screened at tier 1. In the event that there were no positive specimens, no further analyses were to be conducted. If positive specimens were identified, these specimens were further tested with the confirmatory assay to confirm as positive. Number of participants with ADA positive at baseline, ADA never-positive, ADA ever-positive, treatment-boosted ADA, treatment-induced ADA, transient ADA response, or persistent ADA response from baseline up to 2 years. The results reflect data available on cutoff of PCD (03 Apr 2018). | 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) | 

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