This is an open-label, 2 part study of pazopanib and/or MK 3475 in treatment naïve subjects with advanced RCC. Part 1 consists of a Phase I dose escalation of pazopanib + MK 3475 followed by an expansion cohort to determine the maximum tolerated regimen and the recommended Phase II dose. Part 2 is a randomized 3-arm Phase II study to evaluate the clinical efficacy and safety of pazopanib + MK 3475 as compared to single-agent pazopanib and single-agent MK 3475. The objectives of this Phase I/II study are to test the safety and tolerability of pazopanib in combination with MK 3475, and study the clinical efficacy of pazopanib in combination with MK 3475 in subjects with advanced RCC as compared with single-agent pazopanib and single-agent MK 3475. Following the Urgent Safety Measure (USM) released on February 09, 2017, the phase II (Part 2) portion of this study will not commence.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
42
Pazopanib is an orally administered 200 mg tablet available in the dose range of 400 to 800 mg
MK 3475 is an intravenously administered 100 mg/ 4mL solution available in the potential dose range of 1 to 10 mg/kg.
Novartis Investigative Site
Boston, Massachusetts, United States
Novartis Investigative Site
Boston, Massachusetts, United States
Novartis Investigative Site
New York, New York, United States
Novartis Investigative Site
Nashville, Tennessee, United States
Novartis Investigative Site
Manchester, Lancashire, United Kingdom
Novartis Investigative Site
London, United Kingdom
Part 1: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs )
Time frame: From the start of study treatment (first dose) and, until the post-treatment follow-up visit (at least 30 days after the last dose of investigational product) for AEs, and until 90 days after last dose for SAEs
Part 1: To determine the dose limiting toxicity (DLT) and maximum tolerated regimen (MTR)
MTR is defined as the highest dose of pazopanib in combination with the highest dose of MK 3475 at which no more than 1 of 6 subjects experiences a DLT after a minimum of 8 weeks of treatment. DLT is defined as a drug-related AE starting in the first 8 weeks of treatment
Time frame: 8 weeks
Part 1: Number of subjects with permanent discontinuation of treatment, dose reductions, interruptions, or delays
Time frame: 24 months
Part 1: Change from baseline in laboratory parameters
Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test
Time frame: Average of 4 years
Part 1: Change from baseline in vital signs
Vital sign measurements will include heart rate, temperature and blood pressure
Time frame: 30 days after the last dose of study treatment
Part 1: Change from baseline in cardiac parameters
Cardiac assessments will include Electrocardiogram (ECG) and Echocardiograms (ECHOs)
Time frame: 24 months
Part 1: Incidence and titer of anti MK 3475 antibodies
Subjects will be monitored for anti-MK 3475 antibodies throughout the study
Time frame: 24 months
Part 2: Progression-free survival (PFS)
PFS is defined as the interval between the date of randomization and the earlier date of disease progression (using RECIST v1.1) or death due to any cause.
Time frame: Average of 4 years
Part 1: Dose escalation cohorts: pazopanib plasma concentrations and serum MK 3475 concentrations.
For analysis of plasma pazopanib and serum MK 3475 concentrations, blood samples will be collected from all subjects
Time frame: For Pazopanib: before and after the 1st and 2nd dose of MK-3475. For MK-3475: Until 6 months after the last dose of MK-3475
Part 1: Pharmacokinetic (PK) parameters in Expansion cohort
Area under the plasma concentration-time curve from time 0 to 24 hrs (AUC\[0-24\], maximum observed concentration (Cmax), tmax, and concentration at 24 hours (C24) of pazopanib; Pre-dose (trough) concentration at the end of the dosing interval (Ctau), and apparent clearance following oral dosing CL/F of pazopanib will be determined if data permit.
Time frame: For Pazopanib: before and after the 1st and 2nd dose of MK-3475. For MK-3475: Until 6 months after the last dose of MK-3475
Part 1 and Part 2: Overall response rate (ORR)
Overall response rate is defined as the percentage of subjects, who achieved either a confirmed complete response (CR) or partial response (PR) by RECIST v1.1 and modified RECIST
Time frame: Average of 4 years
Part 1 and Part 2: Clinical benefit rate
Clinical benefit rate is defined as a confirmed response of CR or PR or at least 6-months stable disease by RECIST v1.1 and modified RECIST.
Time frame: Average of 4 years
Part 1 and Part 2: Time to response
Time to response is defined for all subjects with a confirmed CR or PR as per RECIST v1.1as the time from randomization until the first documented evidence of CR or PR (whichever status is recorded first)
Time frame: Average of 4 years
Part 1 and Part 2: Duration of response
Duration of response is defined for all subjects with confirmed CR or PR as the time from the first documented evidence of CR or PR until time of first documented disease progression or death due to any causes, whichever is first by RECIST v1.1 and modified RECIST
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Time frame: Average of 4 years
Part 2: PFS by modified RECIST
Time frame: Average of 4 years
Part 1 and Part 2: Progression-free survival rate at 18 months (PFSR18)
PFSR18 will be calculated based on Kaplan-Meier estimates of Progression-free survival (PFS) at 18 months by RECIST v1.1 and modified RECIST
Time frame: 18 months
Part 2: Overall survival (OS) at 18 months
Overall survival at 18 months will be summarized based on the Kaplan-Meier method.
Time frame: 18 months
Part 2: Overall survival (OS)
Overall survival will be summarized using Kaplan-Meier survival curves
Time frame: Average of 4 years
Part 2: Incidence and severity of AEs and SAEs
Time frame: From the start of study treatment (first dose) and, until the post-treatment follow-up visit (at least 30 days after the last dose of investigational product) for AEs, and until 90 days after last dose for SAEs
Part 2: Number of subjects with permanent discontinuation of treatment, dose reductions, interruptions, or delays
Time frame: Average of 4 years
Part 2: Change from baseline in laboratory parameters
Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test
Time frame: Average of 4 years
Part 2: Change from baseline in vital signs
Vital sign measurements will include heart rate, temperature and blood pressure
Time frame: Average of 4 years
Part 2: Change from baseline in cardiac parameters
Cardiac assessments will include ECG and ECHOs
Time frame: Average of 4 years
Part 2: Incidence and titer of anti MK 3475 antibodies in patients treated with pazopanib + MK 3475 and single-agent MK 3475
Subjects will be monitored for anti-MK 3475 antibodies throughout the study
Time frame: Until 6 months after the last dose of MK-3475
Part 2: PK parameters in randomized phase
For analysis of plasma pazopanib and serum MK 3475 concentrations, blood samples will be collected from all subjects. AUC\[0-24\], Cmax, tmax, and C24 of pazopanib alone and in combination with MK 3475; Cmax, Ctau, and apparent clearance following oral dosing CL/F of pazopanib will be determined if data permit.
Time frame: For Pazopanib: Until Dose 49 of MK-3475.