Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02133742
Other study ID # A4061079
Secondary ID KN-035
Status Completed
Phase Phase 1
First received
Last updated
Start date September 16, 2014
Est. completion date July 3, 2019

Study information

Verified date July 2021
Source Pfizer
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Recruitment information / eligibility

Status Completed
Enrollment 52
Est. completion date July 3, 2019
Est. primary completion date March 31, 2017
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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 Design


Related Conditions & MeSH terms


Intervention

Drug:
Axitinib
Axitinib at starting dose of 5 mg and 3 mg BID.
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.

Locations

Country Name City State
United States Beth Israel Deaconess Medical Center Boston Massachusetts
United States Brigham & Women's Hospital Boston Massachusetts
United States Dana-Farber Cancer Institute Boston Massachusetts
United States Massachusetts General Hospital Boston Massachusetts
United States Roswell Park Cancer Institute Buffalo New York
United States Investigational Drug Services Columbus Ohio
United States James Cancer Hospital Columbus Ohio
United States Martha Morehouse Medical Plaza Columbus Ohio
United States The Ohio State University Brain and Spine Hospital Columbus Ohio
United States Texas Oncology - Baylor Charles A. Sammons Cancer Center Dallas Texas
United States Karmanos Cancer Institute Detroit Michigan
United States Henry-Joyce Cancer Clinic Nashville Tennessee
United States Vanderbilt Oncology Pharmacy Nashville Tennessee
United States Attn. Alicia Sammarco, RPh, NYU Investigational Pharmacy New York New York
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 H. Lee Moffitt Cancer Center & Research Institute, Inc. Tampa Florida
United States Georgetown University Medical Center Washington District of Columbia

Sponsors (2)

Lead Sponsor Collaborator
Pfizer Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 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)
Secondary 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)
Secondary 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)
Secondary 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
Secondary 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
Secondary 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
Secondary 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)
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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)
Secondary 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)
Secondary 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)
Secondary 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)
Secondary 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)
Secondary 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)
See also
  Status Clinical Trial Phase
Active, not recruiting NCT04987203 - Study to Compare Tivozanib in Combination With Nivolumab to Tivozanib Monotherapy in Subjects With Renal Cell Carcinoma Phase 3
Recruiting NCT06391879 - Establishment of a Multidimensional Prediction Model for the Natural Course of VHL Disease-related Renal Cell Carcinoma
Completed NCT02526017 - Study of Cabiralizumab in Combination With Nivolumab in Patients With Selected Advanced Cancers Phase 1
Recruiting NCT05059444 - ORACLE: Observation of ResiduAl Cancer With Liquid Biopsy Evaluation
Terminated NCT03655613 - APL-501 or Nivolumab in Combination With APL-101 in Locally Advanced or Metastatic HCC and RCC Phase 1/Phase 2
Active, not recruiting NCT03170960 - Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors Phase 1/Phase 2
Withdrawn NCT05418387 - A Social Support Intervention to Improve Treatment Among Hispanic Kidney and Liver Cancer Patients in Arizona N/A
Recruiting NCT04623502 - An Investigation of Kidney and Urothelial Tumor Metabolism in Patients Undergoing Surgical Resection and/or Biopsy N/A
Completed NCT02853344 - Study of Pembrolizumab (MK-3475) Monotherapy in Locally Advanced/Metastatic Renal Cell Carcinoma (MK-3475-427/KEYNOTE-427) Phase 2
Terminated NCT04088500 - A Study of Combination Nivolumab and Ipilimumab Retreatment in Patients With Advanced Renal Cell Carcinoma Phase 2
Completed NCT05070637 - Circulating Tumor Cell Reducing No-touch Nephrectomy N/A
Active, not recruiting NCT03634540 - A Trial of Belzutifan (PT2977, MK-6482) in Combination With Cabozantinib in Patients With Clear Cell Renal Cell Carcinoma (ccRCC) (MK-6482-003) Phase 2
Not yet recruiting NCT06049030 - A Study of HS-10516 in Patients With Advanced Clear Cell Renal Cell Carcinoma Phase 1
Completed NCT03652077 - A Safety and Tolerability Study of INCAGN02390 in Select Advanced Malignancies Phase 1
Completed NCT01358721 - Phase I Biomarker Study (BMS-936558) Phase 1
Active, not recruiting NCT04503148 - Anesthesia and Cancer Study: Renal Cell Carcinoma N/A
Completed NCT02386826 - INC280 Combined With Bevacizumab in Patients With Glioblastoma Multiforme Phase 1
Not yet recruiting NCT05808608 - A Study of AK104 Plus Axitinib in Advanced/Metastatic Special Pathological Subtypes of Renal Cell Carcinoma Phase 1/Phase 2
Withdrawn NCT03323710 - Study of Propranolol Plus Sunitinib in First-line Treatment of Metastatic Renal Cell Carcinoma Phase 2
Not yet recruiting NCT02787915 - DC1s-CTL Cellular Therapy for Renal Cell Carcinoma Phase 1/Phase 2