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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02133742
Recruitment Status : Active, not recruiting
First Posted : May 8, 2014
Results First Posted : June 21, 2019
Last Update Posted : June 21, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Renal Cell Carcinoma Drug: Axitinib Drug: MK-3475 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 16, 2014
Actual Primary Completion Date : March 31, 2017
Estimated Study Completion Date : June 26, 2019

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Number of Participants With Dose-Limiting Toxicities (DLT): Dose Finding Phase [ Time Frame: 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 :
  1. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline, up to 28 days after last dose of study drug (up to 1111 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.

  2. Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline, up to 28 days after last dose of study drug (up to 1111 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.

  3. Number of Participants With Adverse Events (AEs) According to Severity of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03 [ Time Frame: Baseline, up to 28 days after last dose of study drug (up to 1111 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.

  4. Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Hematology [ Time Frame: Baseline up to end of treatment (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.

  5. Number of Participants With Laboratory Test Abnormalities: Urinalysis [ Time Frame: Baseline up to end of treatment (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.

  6. Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Baseline up to end of treatment (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.

  7. Number of Participants With Eastern Cooperative Oncology Group [ECOG] Performance Status Score [ Time Frame: 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.

  8. Objective Response Rate [ Time Frame: 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.

  9. Duration of Response (DR) [ Time Frame: 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.

  10. Time to Response (TTR) [ Time Frame: 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.

  11. Progression-Free Survival (PFS) [ Time Frame: 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.

  12. Overall Survival (OS) [ Time Frame: Baseline until disease progression or death due to any cause, up to a maximum of 1083 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.

  13. Maximum Observed Plasma Concentration (Cmax) of Axitinib and Pembrolizumab (MK-3475) [ Time Frame: Pre dose, 1, 2, 3, 4, 6, 8 hours post dose ]
  14. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib and Pembrolizumab (MK-3475) [ Time Frame: Pre dose, 1, 2, 3, 4, 6, 8 hours post dose ]
  15. Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC 0-12) of Axitinib and Pembrolizumab (MK-3475) [ Time Frame: Pre dose, 1, 2, 3, 4, 6, 8 hours post dose ]
  16. Apparent Oral Clearance (CL/F) of Axitinib and Pembrolizumab (MK-3475) [ Time Frame: Pre dose, 1, 2, 3, 4, 6, 8 hours post dose ]
  17. Apparent Volume of Distribution (Vz/F) of Axitinib and Pembrolizumab (MK-3475) [ Time Frame: Pre dose, 1, 2, 3, 4, 6, 8 hours post dose ]
  18. Number of Participants With Positive Anti-Drug Antibodies (ADA) of Pembrolizumab (MK-3475) [ Time Frame: Day 1 of Cycle 1, 3, 5, 11 and every 12 weeks afterwards up to maximum of 43 weeks (up to 1083 days) ]
  19. Number of Participants With Programmed Death-Ligand 1 (PD-L1) Tumor Proportion Score [ Time Frame: 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%.

  20. Number of Participants With Vascular Endothelial Growth Factor A (VEGF-A) Tumor Proportion Score [ Time Frame: Baseline up to Cycle 43 (up to 1083 days) ]
  21. Change From Baseline in Vascular Endothelial Growth Factor A (VEGF-A), Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and Interleukin 8 (IL-8) in Serum at Cycle 43 Day 21 [ Time Frame: Baseline, Cycle 2 Day 1: Predose and end of treatment or withdrawal (up to Cycle 43) ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02133742


Locations
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United States, District of Columbia
Georgetown University Medical Center
Washington, District of Columbia, United States, 20007
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute, Inc.
Tampa, Florida, United States, 33612
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Brigham & Women's Hospital
Boston, Massachusetts, United States, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Attn. Alicia Sammarco, RPh, NYU Investigational Pharmacy
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
United States, Ohio
Investigational Drug Services
Columbus, Ohio, United States, 43210
James Cancer Hospital
Columbus, Ohio, United States, 43210
The Ohio State University Brain and Spine Hospital
Columbus, Ohio, United States, 43210
Martha Morehouse Medical Plaza
Columbus, Ohio, United States, 43221
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
United States, Tennessee
Henry-Joyce Cancer Clinic
Nashville, Tennessee, United States, 37232
United States, Texas
Texas Oncology - Baylor Charles A. Sammons Cancer Center
Dallas, Texas, United States, 75246
Sponsors and Collaborators
Pfizer
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Study Protocol  [PDF] March 18, 2015
Statistical Analysis Plan  [PDF] July 14, 2015


Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02133742     History of Changes
Other Study ID Numbers: A4061079
First Posted: May 8, 2014    Key Record Dates
Results First Posted: June 21, 2019
Last Update Posted: June 21, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
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.

Keywords provided by Pfizer:
Axitinib and MK-3475
patients with advanced Renal Cell Cancer.

Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Pembrolizumab
Axitinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action