A Dose Finding Study To Evaluate Safety, Drug Interaction, Tumor Markers Of Axitinib In Combination With MK-3475 In Adult Patients With Previously Untreated Advanced Renal Cell Cancer

A PHASE 1B, OPEN LABEL, DOSE FINDING STUDY TO EVALUATE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AXITINIB (AG-013736) IN COMBINATION WITH PEMBROLIZUMAB (MK-3475) IN PATIENTS WITH ADVANCED RENAL CELL CANCER

Despite substantial improvements of patients outcome in advanced RCC, durable and complete response is uncommon. The majority of patients eventually develop resistance and exhibit disease progression. Combining a PD-1 inhibitor, which has shown single-agent efficacy with axitinib may provide additional clinical benefit compared to axitinib alone.

Study Overview

• Status: Completed
• Conditions: Renal Cell Carcinoma
• Intervention / Treatment: Drug: Axitinib; Drug: MK-3475

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute, Inc.
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • New York, New York, United States, 10016
      • NYU Langone
    • New York, New York, United States, 10016
      • Attn. Alicia Sammarco, RPh, NYU Investigational Pharmacy
  • Ohio
    • Columbus, Ohio, United States, 43221
      • Martha Morehouse Medical Plaza
    • Columbus, Ohio, United States, 43210
      • Investigational Drug Services
    • Columbus, Ohio, United States, 43210
      • James Cancer Hospital
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Brain and Spine Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Henry-Joyce Cancer Clinic
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Oncology Pharmacy
  • Texas
    • Dallas, Texas, United States, 75246
      • Texas Oncology - Baylor Charles A. Sammons Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed advanced RCC with predominantly clear-cell subtype with primary tumor resected
• At least one measureable lesion as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
• Eastern Cooperative Oncology Group performance status 0 or 1
• Controlled hypertension

Exclusion Criteria:

• Prior treatment with systemic therapy for advanced RCC
• Prior adjuvant or neoadjuvant therapy if disease progression or relapse has occurred during or within 12 months after the last dose of treatment
• Prior treatment with any agent specifically targeting T-cell co-stimulation or checkpoint pathways
• Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis
• Diagnosis of any non-RCC malignancy occurring within 2 years prior to the date of randomization except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix or low grade prostate cancer with no plans for treatment intervention
• In past 12 months: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack
• In past 6 months: deep vein thrombosis or pulmonary embolism

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose finding phase and dose expansion phase; To test the maximum tolerated dose of MK-3475 at 2 mg/kg every three weeks intravenous infusion in combination with approved axitinib dose	Drug: Axitinib; Axitinib at starting dose of 5 mg and 3 mg BID.; Drug: MK-3475; MK-3475 with two dose levels: 2 mg/kg every three weeks to find the maximum tolerated dose and continue treatment in a dose expansion phase.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-Limiting Toxicities (DLT): Dose Finding Phase	DLT was defined as any of the following adverse events (AEs) occurring in the first two cycles of treatment which were attributable to one or both the study drugs: 1) Grade 4 neutropenia, 2) Febrile neutropenia lasting greater than (>) 1 hour, 3) Grade greater than or equal to (>=) 3 neutropenia with infection, 4) Grade >=3 thrombocytopenia with bleeding, 4) Grade 4 thrombocytopenia, 5) Any grade >=3 non-hematologic: non-laboratory toxicities despite maximum supportive therapy or hypertension despite maximal medical therapy, 6) Grade >=3 non-hematologic toxicities resulted in hospitalisation or medical intervention 7) Inability to complete at least 75 percent (%) of axitinib dosing or 2 infusions of pembrolizumab within the DLT observation period (up to 42 days) due to treatment related toxicity. Severity of AEs was graded according to NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	Cycle 1 Day 1 to Cycle 2 Day 21 (up to 42 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant and jeopardized the participants or required treatment to prevent other AE outcomes for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs are events which occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.	Baseline up to 28 days after last dose of study drug (approximately up to 1552 days)
Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant and jeopardized the participants or required treatment to prevent other AE outcomes for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs are events which occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator.	Baseline up to 28 days after last dose of study drug (approximately up to 1552 days)
Number of Participants With Adverse Events (AEs) According to Severity of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant and jeopardized the participants or required treatment to prevent other AE outcomes for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs were graded according to the Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA) as Grade 3: Severe, Grade 4: Life threatening, Grade 5: Death related to AE. Participants were counted once according to the maximum grade observed.	Baseline up to 28 days after last dose of study drug (approximately up to 1552 days)
Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Hematology	Laboratory parameters included hematological and biochemistry parameters. Biochemistry parameters included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin (total), creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia. Hematology parameters included anemia, haemoglobin increased, lymphocyte count increased, lymphopenia, neutrophils (absolute), platelets and white blood cells. Test abnormalities were graded by NCI CTCAE version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Only categories with at least 1 participant with abnormality are reported in this outcome measure.	Baseline up to a maximum of 1083 days
Number of Participants With Laboratory Test Abnormalities: Urinalysis	Urinalysis parameter included urine protein, urine blood/hemoglobin and urine glucose. Test abnormalities was defined as deviation from normal range. Normal range of 24-hour urine protein test: less than 150 mg of protein per day, urine glucose: 0 to 0.8 mmol/L (millimoles per liter), urine protein: 0 to 20 mg/dL (milligrams per deciliter). Urine blood/hemoglobin abnormality was defined as presence and absence of blood/hemoglobin in urine of participants.	Baseline up to a maximum of 1083 days
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Vital signs included blood pressure, pulse rate and weight. Change from baseline values were considered to be clinically significant based on investigator's judgement.	Baseline up to a maximum of 1083 days
Number of Participants With Eastern Cooperative Oncology Group [ECOG] Performance Status Score	ECOG performance status was used to assess how disease affect the daily living abilities of a participant. It was measured on a scale ranging from 0 to 4, where 0=fully active (able to carry on all pre-disease activities without restriction); 1=restricted in physically strenuous activity but ambulatory (able to carry out light/sedentary work); 2=ambulatory and capable of all self-care but unable to carry out any work activities (for more than 50% of waking hours); 3=capable of limited self-care, confined to bed or chair (for >50% of waking hours); 4=completely disabled, not capable of any self-care, totally confined to bed or chair. Higher scores signified =more functional impairment of a participant.	Baseline up to Cycle 43 (up to 1083 days)
Objective Response Rate	Objective response rate was defined as percentage of participants with confirmed complete response (CR) or confirmed partial response (PR), as assessed by response evaluation criteria in solid tumors (RECIST) version 1.1. Confirmed responses were those that persist on repeated imaging for at least 4 weeks after initial documentation of response. CR was defined as disappearance of all target lesions and the reduction in short axis of any pathological lymph nodes to <10 mm. PR was defined as a 30% or more decrease in the sum of longest dimensions of the target lesions, taking as reference the baseline sum of longest dimensions.	Baseline until disease progression or death due to any cause, up to a maximum of 1083 days
Duration of Response (DR)	DR:date of first documentation of objective tumour response(OR) confirmed to date of first documentation of PD/death due to any cause,whichever occurred first.PD per RECIST 1.1:>=20%increase in sum of longest dimensions(LD) of target lesions,reference to smallest sum of LD recorded since treatment started/appearance of 1 or more new lesions/increase of at least 5mm addition to relative increase of 20%.DR calculated only for participants with confirmed OR.Participants lacking evaluation of tumour response after date of first study drug dose was censored on date of first dose unless death occurred prior to 18 weeks.If participants had at least 1 on-study assessment,PFS was censored on date of last evaluable tumour disease assessment documenting absence of PD for participants who were alive and progression free at time of analysis/had documentation of PD/death after>=2 consecutive missed tumour assessments/given anti-tumour treatment other than study drug prior to documented PD/death.	Baseline until disease progression or death due to any cause, up to a maximum of 1083 days
Time to Response (TTR)	TTR was defined as the time from first dose of study treatment to the first documentation of objective tumor response (CR or PR) that was subsequently confirmed.	Baseline until disease progression or death due to any cause, up to a maximum of 1083 days
Progression-Free Survival (PFS)	PFS: time from date of first dose of study drug to the date of first documented PD or death on study due to any cause. PD as per RECIST v1.1 defined as at least a 20% increase in sum of longest dimensions of target lesions, reference to smallest sum of longest dimensions recorded since treatment started, or appearance of 1 or more new lesions or increase of at least 5 mm in addition to relative increase of 20%. Participants lacking an evaluation of tumor response after date of first study drug dose had event time censored on date of first dose unless death occurred prior to 18 weeks. If participants had at least 1 on-study assessment, PFS data was censored on date of last evaluable tumor disease assessment documenting absence of PD for participants who were alive and progression free at the time of analysis or had documentation of PD or had death after >=2 consecutive missed tumor assessments or were given anti-tumor treatment other than study drug prior to documented PD or death.	Baseline until disease progression or death due to any cause, up to a maximum of 1083 days
Overall Survival (OS)	OS was defined as the time from the first dose of study drug to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive.	Baseline until disease progression or death due to any cause, up to a maximum of 1552 days
Maximum Observed Plasma Concentration (Cmax) of Axitinib		Dose Finding Phase:Pre-dose,1,2,3,4,6,8 hours (hrs) post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1;Dose Expansion Phase:Pre dose,1,2,3,4,6,8 hrs post dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib		Dose Finding Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1; Dose Expansion Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC 0-12) of Axitinib		Dose Finding Phase:Pre-dose, 1, 2, 3, 4,6,8, 12 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1; Dose Expansion Phase:Pre-dose, 1,2,3,4,6,8,12 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1
Apparent Oral Clearance (CL/F) of Axitinib	Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes).	Dose Finding Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1; Dose Expansion Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1
Apparent Volume of Distribution (Vz/F) of Axitinib	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.	Dose Finding Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1; Dose Expansion Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1
Number of Participants With Positive Anti-Drug Antibodies (ADA) of Pembrolizumab (MK-3475)		Day 1 of Cycle 1 up to Day 21 of Cycle 56 (up to 1176 days)
Number of Participants With Programmed Death-Ligand 1 (PD-L1) Tumor Proportion Score	PD-L1- tumor proportion score was defined as the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. Participants with positive or negative scores were reported. PD-L1 negative: if tumor proportion score was less than 1%; PD-L1 positive: if the tumor proportion score greater than or equal to 1%.	Baseline up to Cycle 43 (up to 1083 days)
Number of Participants With Vascular Endothelial Growth Factor A (VEGF-A) Tumor Proportion Score	Vascular Endothelial Growth Factor (VEGF) promotes cancer progression by inducing angiogenesis via VEGF receptors, signals directly through receptors VEGFR-1 and VEGFR-2. Change in biomarkers related to VEGFR signal transduction pathways after axitinib treatment was assessed. Plasma VEGF concentration evaluations were performed using samples from peripheral blood plasma, bone marrow aspirate, bone marrow (Core) biopsy and bone marrow clot. The VEGFR, axitinib and mechanistic target of rapamycin inhibitor everolimus are used individually in subsequent lines of therapy for advanced clear cell renal cell carcinoma (ccRCC).	Baseline up to Cycle 64 (up to 1344 days)
Concentration of Vascular Endothelial Growth Factor A (VEGF-A) in Serum	Vascular endothelial growth factor (VEGF) promotes cancer progression by inducing angiogenesis via VEGF receptors, signals directly through receptors VEGFR-1 and VEGFR-2. Change in biomarkers related to VEGFR signal transduction pathways after axitinib treatment was assessed. Mononuclear (MNC) cell VEGF receptor expression and phosphorylation was assessed by in situ western blot analysis. VEGFR-1 and VEGFR-2 evaluations were performed using samples from peripheral blood plasma, bone marrow aspirate, bone marrow (Core) biopsy and bone marrow clot. The VEGFR, axitinib and mechanistic target of rapamycin inhibitor everolimus are used individually in subsequent lines of therapy for advanced clear cell renal cell carcinoma (ccRCC).	Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days)
Concentration of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in Serum	Vascular endothelial growth factor (VEGF) promotes cancer progression by inducing angiogenesis via VEGF receptors, signals directly through receptors VEGFR-1 and VEGFR-2. Change in biomarkers related to VEGFR signal transduction pathways after axitinib treatment was assessed. Mononuclear (MNC) cell VEGF receptor expression and phosphorylation was assessed by in situ western blot analysis. VEGFR-1 and VEGFR-2 evaluations were performed using samples from peripheral blood plasma, bone marrow aspirate, bone marrow (Core) biopsy and bone marrow clot. The VEGFR, axitinib and mechanistic target of rapamycin inhibitor everolimus are used individually in subsequent lines of therapy for advanced clear cell renal cell carcinoma (ccRCC).	Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days)
Concentration of Interleukin 8 (IL-8) in Serum		Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days)

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, Vaishampayan U, George S, Tarazi JC, Duggan W, Perini R, Thakur M, Fernandez KC, Choueiri TK. Axitinib plus pembrolizumab in patients with advanced renal-cell carcinoma: Long-term efficacy and safety from a phase Ib trial. Eur J Cancer. 2021 Mar;145:1-10. doi: 10.1016/j.ejca.2020.12.009. Epub 2021 Jan 4.
• Martini JF, Plimack ER, Choueiri TK, McDermott DF, Puzanov I, Fishman MN, Cho DC, Vaishampayan U, Rosbrook B, Fernandez KC, Tarazi JC, George S, Atkins MB. Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma. Clin Cancer Res. 2020 Nov 1;26(21):5598-5608. doi: 10.1158/1078-0432.CCR-20-1408. Epub 2020 Aug 18.
• Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, Vaishampayan U, George S, Olencki TE, Tarazi JC, Rosbrook B, Fernandez KC, Lechuga M, Choueiri TK. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018 Mar;19(3):405-415. doi: 10.1016/S1470-2045(18)30081-0. Epub 2018 Feb 10.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2014
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): July 3, 2019

Study Registration Dates

• First Submitted: May 6, 2014
• First Submitted That Met QC Criteria: May 6, 2014
• First Posted (Estimate): May 8, 2014

Study Record Updates

• Last Update Posted (Actual): July 28, 2021
• Last Update Submitted That Met QC Criteria: July 26, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Axitinib and MK-3475; patients with advanced Renal Cell Cancer.
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Pembrolizumab; Axitinib
• Other Study ID Numbers: A4061079; KN-035 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD 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.