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Avelumab

Axitinib

Antineoplastic Agents, Immunological

Protein Kinase Inhibitors

Enzyme Inhibitors

To test the maximum tolerated dose of avelumab (MSB0010718C) in combination with axitinib (AG-013736)

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.

Avelumab (MSB0010718C)

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.

Axitinib (AG-013736)

Pfizer CT.gov Call Center

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.

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

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

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.

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.

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

Ctrough was directly observed from data. The results reflect data available on cutoff of PCD (03 Apr 2018).

Cmax for avelumab on Cycle 1 Day (C1D1) and C1D4 were reported. The results reflect data available on cutoff of PCD (03 Apr 2018).

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).

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).

Pfizer

Same event may appear as both an adverse event (AE) and serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.

Participants received 5 mg axitinib tablets orally twice daily for 7 days in lead-in period (7 days) followed by 10 milligram/ kilogram (mg/kg) avelumab intravenously every 2 weeks along with 5 mg axitinib tablets orally twice daily, on Day 1 of each treatment cycle (duration of each cycle=14 days) in treatment period (up to maximum of 255.4 weeks).

Axitinib + Avelumab With Lead-in

Participants received 10 mg/kg avelumab intravenously every 2 weeks along with 5 mg axitinib tablets orally twice daily, on Day 1 of each treatment cycle (duration of each cycle=14 days) in treatment period (up to maximum of 240.1 weeks).

Axitinib + Avelumab

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Full analysis set (FAS) included all participants who received at least 1 dose of study drug.

Pfizer ClinicalTrials.gov Call Center

DLT evaluable analysis set: First 6 enrolled participants who received at least 1 dose of avelumab and axitinib, and either experienced DLT during DLT observation period or completed it. Data for this endpoint was only planned to be collected and analyzed for "Axitinib + Avelumab with Lead-in" arm.

Number of Participants With Dose Limiting Toxicities (DLTs)

Participants with TEAEs

Participants with Grade >=3 TEAEs

Participants with SAEs

The population for this outcome measure included all enrolled participants who received at least 1 dose of avelumab or axitinib.

Number of Participants With All-causality Treatment Emergent Adverse Events (TEAEs)

Participants with treatment-related TEAEs

Participants with Grade >=3 treatment-related TEAEs

Participants with treatment-related SAEs

Number of Participants With Treatment-related TEAEs

Participants with Grade >=1 anemia

Participants with Grade >=3 anemia

Participants with Grade >=1 platelet count decreased

Participants with Grade >=3 platelet count decreased

Participants with Grade >=1 lymphocyte count decreased

Participants with Grade >=3 lymphocyte count decreased

Participants with Grade >=1 neutrophil count decreased

Participants with Grade >=3 neutrophil count decreased

Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE Version 4.03 - Hematology

Participants with Grade >=1 creatinine increased

Participants with Grade >=3 creatinine increased

Participants with Grade >=1 serum amylase increased

Participants with Grade >=3 serum amylase increased

Participants with Grade >=1 lipase increased

Participants with Grade >=3 lipase increased

Participants with Grade >=1 ALT increased

Participants with Grade >=3 ALT increased

Participants with Grade >=1 AST increased

Participants with Grade >=3 AST increased

Participants with Grade >=1 blood bilirubin increased

Participants with Grade >=3 blood bilirubin increased

Participants with Grade >=1 creatine kinase increased

Participants with Grade >=3 creatine kinase increased

Participants with Grade >=1 hypoglycemia

Participants with Grade >=3 hypoglycemia

Participants with Grade >=1 hyperglycemia

Participants with Grade >=3 hyperglycemia

Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE Version 4.03 - Chemistry

Lead-in Day 7

C1D1

C1D8

C2D1

C2D8

C3D1

C4D1

C5D1

C6D1

C7D1

C8D1

C9D1

C10D1

C11D1

C12D1

C13D1

C14D1

C15D1

C16D1

C17D1

C18D1

C19D1

C20D1

C21D1

C22D1

C23D1

C24D1

C25D1

C26D1

C27D1

C28D1

C29D1

C30D1

C31D1

C32D1

C33D1

C34D1

C35D1

C36D1

C37D1

C38D1

C39D1

C40D1

C41D1

C42D1

C43D1

C44D1

C45D1

C46D1

C47D1

C48D1

C49D1

C50D1

C51D1

C52D1

C53D1

C54D1

C55D1

C56D1

C57D1

C58D1

C59D1

C60D1

C61D1

C62D1

End of Treatment

Follow-up Day 30

Follow-up Day 60

Follow-up Day 90

The population for this outcome measure included all enrolled participants who received at least 1 dose of avelumab or axitinib (ie, safety analysis set). Number of Participants Analyzed represents the total number of participants in the safety analysis set. Number Analyzed in each row represents the number of participants in the safety analysis set with at least 1 baseline and 1 post-baseline assessments at the visit.

Change From Baseline in Vital Signs - Sitting Diastolic Blood Pressure

Change From Baseline in Vital Signs - Sitting Systolic Blood Pressure

Lean-in Day 7

Change From Baseline in Vital Signs - Pulse Rate

The population for this outcome measure included all participants who received at least 1 dose of study drug (axitinib or avelumab) and all participants who were randomized independent of whether they had received a dose of study drug.

Number of Participants Achieving Objective Response (OR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Number of Participants Achieving Disease Control (DC) Based on RECIST Version 1.1

The population for this outcome measure included all participants who received at least 1 dose of study drug (axitinib or avelumab), all participants who were randomized independent of whether they had received a dose of study drug, and all participants who had achieved confirmed CR or PR.

Duration of Response (DR) Based on RECIST Version 1.1

Progression-free Survival (PFS)

Time to Tumor Response (TTR) Based on RECIST Version 1.1

Overall Survival (OS)

Cycle 4 Day 1

The population for this outcome measure included all enrolled participants who received at least 1 dose of avelumab or axitinib and who had at least 1 of the pharmacokinetic (PK) parameters of interest of either study drug.

Maximum Observed Plasma Concentration (Cmax) for Axitinib When Dosed Alone and in Combination With Avelumab

Time for Cmax (Tmax) for Axitinib When Dosed Alone and in Combination With Avelumab

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

Terminal Half-Life (t1/2) for Axitinib When Dosed Alone and in Combination With Avelumab

Cycle 1 Day 1 (C1D1)

Participants received 10 mg/kg avelumab intravenously every 2 weeks along with 5 mg axitinib tablets orally twice daily, on Day 1 of each treatment cycle (duration of each cycle=14 days) in treatment period (up to maximum of 255.4 weeks).

All Participants

Predose Concentration During Multiple Dosing (Ctrough) for Avelumab

Spots Global Cancer Trial Database for cancer, renal cell cancer, kidney disease, kidney neoplasms, axitinib