Clinical trial NCT02133742: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Cell Carcinoma
Keywords: Axitinib and MK-3475
patients with advanced Renal Cell Cancer.
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2014-05-08
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities (DLT): Dose Finding Phase
timeFrame: Cycle 1 Day 1 to Cycle 2 Day 21 (up to 42 days)
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to 28 days after last dose of study drug (approximately up to 1552 days)
measure: Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to 28 days after last dose of study drug (approximately up to 1552 days)
measure: Number of Participants With Adverse Events (AEs) According to Severity of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03
timeFrame: Baseline up to 28 days after last dose of study drug (approximately up to 1552 days)
measure: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Hematology
timeFrame: Baseline up to a maximum of 1083 days
measure: Number of Participants With Laboratory Test Abnormalities: Urinalysis
timeFrame: Baseline up to a maximum of 1083 days
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Baseline up to a maximum of 1083 days
measure: Number of Participants With Eastern Cooperative Oncology Group [ECOG] Performance Status Score
timeFrame: Baseline up to Cycle 43 (up to 1083 days)
measure: Objective Response Rate
timeFrame: Baseline until disease progression or death due to any cause, up to a maximum of 1083 days
measure: Duration of Response (DR)
timeFrame: Baseline until disease progression or death due to any cause, up to a maximum of 1083 days
measure: Time to Response (TTR)
timeFrame: Baseline until disease progression or death due to any cause, up to a maximum of 1083 days
measure: Progression-Free Survival (PFS)
timeFrame: Baseline until disease progression or death due to any cause, up to a maximum of 1083 days
measure: Overall Survival (OS)
timeFrame: Baseline until disease progression or death due to any cause, up to a maximum of 1552 days
measure: Maximum Observed Plasma Concentration (Cmax) of Axitinib
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib
timeFrame: 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
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC 0-12) of Axitinib
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) of Axitinib
timeFrame: 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
measure: Apparent Volume of Distribution (Vz/F) of Axitinib
timeFrame: 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
measure: Number of Participants With Positive Anti-Drug Antibodies (ADA) of Pembrolizumab (MK-3475)
timeFrame: Day 1 of Cycle 1 up to Day 21 of Cycle 56 (up to 1176 days)
measure: Number of Participants With Programmed Death-Ligand 1 (PD-L1) Tumor Proportion Score
timeFrame: Baseline up to Cycle 43 (up to 1083 days)
measure: Number of Participants With Vascular Endothelial Growth Factor A (VEGF-A) Tumor Proportion Score
timeFrame: Baseline up to Cycle 64 (up to 1344 days)
measure: Concentration of Vascular Endothelial Growth Factor A (VEGF-A) in Serum
timeFrame: Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days)
measure: Concentration of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in Serum
timeFrame: Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days)
measure: Concentration of Interleukin 8 (IL-8) in Serum
timeFrame: Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days)
Other outcomes:
Locations:
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute, Inc.
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Attn. Alicia Sammarco, RPh, NYU Investigational Pharmacy
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: NYU Langone
state: New York
city: Columbus
country: United States
facility: Investigational Drug Services
state: Ohio
city: Columbus
country: United States
facility: James Cancer Hospital
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Brain and Spine Hospital
state: Ohio
city: Columbus
country: United States
facility: Martha Morehouse Medical Plaza
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Henry-Joyce Cancer Clinic
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Oncology Pharmacy
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.