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
- Registration Number
- NCT02133742
- Lead Sponsor
- Pfizer
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 52
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Dose finding phase and dose expansion phase MK-3475 To test the maximum tolerated dose of MK-3475 at 2 mg/kg every three weeks intravenous infusion in combination with approved axitinib dose Dose finding phase and dose expansion phase Axitinib To test the maximum tolerated dose of MK-3475 at 2 mg/kg every three weeks intravenous infusion in combination with approved axitinib dose
- Primary Outcome Measures
Name Time Method Number of Participants With Dose-Limiting Toxicities (DLT): Dose Finding Phase Cycle 1 Day 1 to Cycle 2 Day 21 (up to 42 days) 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.
- Secondary Outcome Measures
Name Time Method 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 Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Baseline up to 28 days after last dose of study drug (approximately up to 1552 days) 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.
Number of Participants With Laboratory Test Abnormalities: Urinalysis Baseline up to a maximum of 1083 days 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.
Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) Baseline up to 28 days after last dose of study drug (approximately up to 1552 days) 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.
Number of Participants With Adverse Events (AEs) According to Severity of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03 Baseline up to 28 days after last dose of study drug (approximately up to 1552 days) 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.
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 Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Hematology Baseline up to a maximum of 1083 days 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.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs Baseline up to a maximum of 1083 days Vital signs included blood pressure, pulse rate and weight. Change from baseline values were considered to be clinically significant based on investigator's judgement.
Number of Participants With Eastern Cooperative Oncology Group [ECOG] Performance Status Score Baseline up to Cycle 43 (up to 1083 days) 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.
Objective Response Rate Baseline until disease progression or death due to any cause, up to a maximum of 1083 days 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.
Number of Participants With Programmed Death-Ligand 1 (PD-L1) Tumor Proportion Score Baseline up to Cycle 43 (up to 1083 days) 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%.
Number of Participants With Vascular Endothelial Growth Factor A (VEGF-A) Tumor Proportion Score Baseline up to Cycle 64 (up to 1344 days) 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).
Concentration of Vascular Endothelial Growth Factor A (VEGF-A) in Serum Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days) 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).
Concentration of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in Serum Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days) 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).
Duration of Response (DR) Baseline until disease progression or death due to any cause, up to a maximum of 1083 days 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.
Time to Response (TTR) Baseline until disease progression or death due to any cause, up to a maximum of 1083 days 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.
Progression-Free Survival (PFS) Baseline until disease progression or death due to any cause, up to a maximum of 1083 days 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.
Overall Survival (OS) Baseline until disease progression or death due to any cause, up to a maximum of 1552 days 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.
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 Apparent Oral Clearance (CL/F) 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 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).
Apparent Volume of Distribution (Vz/F) 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 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.
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) 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)
Trial Locations
- Locations (19)
Brigham & Women's Hospital
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
James Cancer Hospital
🇺🇸Columbus, Ohio, United States
NYU Langone
🇺🇸New York, New York, United States
NYU Langone Medical Center
🇺🇸New York, New York, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
H. Lee Moffitt Cancer Center & Research Institute, Inc.
🇺🇸Tampa, Florida, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Attn. Alicia Sammarco, RPh, NYU Investigational Pharmacy
🇺🇸New York, New York, United States
Investigational Drug Services
🇺🇸Columbus, Ohio, United States
The Ohio State University Brain and Spine Hospital
🇺🇸Columbus, Ohio, United States
Martha Morehouse Medical Plaza
🇺🇸Columbus, Ohio, United States
Henry-Joyce Cancer Clinic
🇺🇸Nashville, Tennessee, United States
Texas Oncology - Baylor Charles A. Sammons Cancer Center
🇺🇸Dallas, Texas, United States
Vanderbilt Oncology Pharmacy
🇺🇸Nashville, Tennessee, United States