Safety and Efficacy Study of Pazopanib and MK 3475 in Advanced Renal Cell Carcinoma (RCC; KEYNOTE-018)

A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and MK 3475 in Patients With Advanced Renal Cell Carcinoma

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 Overview

• Status: Completed
• Conditions: Carcinoma, Renal Cell
• Intervention / Treatment: Drug: Pazopanib; Drug: MK-3475

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W1G 6AD
    • Novartis Investigative Site
  • Lancashire
    • Manchester, Lancashire, United Kingdom, M20 4BX
      • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Novartis Investigative Site
    • Boston, Massachusetts, United States, 02215
      • Novartis Investigative Site
  • New York
    • New York, New York, United States, 10065
      • Novartis Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed written informed consent before performance of study-specific procedures or assessments and must be willing to comply with treatment and follow up
• Diagnosis of locally advanced or metastatic RCC that is predominantly clear cell histology
• Must have measurable disease
• Subject has received no prior systemic therapy
• A woman is eligible to participate in the study if she is of Non-childbearing potential, has a negative serum pregnancy test within 7 days of the first dose of study treatment, not lactating, and agrees to use adequate contraception during the study until at least 120 days after the last dose of investigational product
• Eastern Cooperative Oncology Group performance status 0 or 1
• Adequate organ function as defined in the protocol
• Left ventricular ejection fraction >= lower limit of normal as assessed by echocardiogram or multigated acquisition scan
• In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

Exclusion Criteria:

• Subject has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
• Subject is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study treatment
• Subject is expected to require any other form of systemic or localized antineoplastic therapy while on study
• Subject is on any systemic steroid therapy, within one week before the planned date for first dose of study treatment. Subject is on any other form of immunosuppressive medication
• Subject has a history of a malignancy (other than the disease under treatment in the study) within 5 years before first study treatment administration
• Central nervous system metastasis
• Unable to swallow and retain orally administered medication
• Subject has interstitial lung disease or a history of pneumonitis
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other Gastrointestinal conditions with increased risk of perforation; history of abdominal fistula, GI perforation, or intra-abdominal abscess within 4 weeks before beginning study treatment
• Known history of HIV infection or a known history of or is positive for Hepatitis B or Hepatitis C
• Presence of active infection requiring systemic therapy
• Corrected QT interval duration prolongation
• History of any one or more of the following cardiac conditions within the past 6 months: Cardiac angioplasty or stenting; Myocardial infarction; Unstable angina; History of Class III or IV congestive heart failure according to New York Heart Association classification
• History of cerebrovascular accident within the past 6 months
• Poorly controlled hypertension
• History of untreated deep venous thrombosis
• Presence of any non-healing wound, fracture, or ulcer, or presence of symptomatic peripheral vascular disease
• Evidence of bleeding diathesis or coagulopathy
• Recent hemoptysis
• Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage
• Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures
• Previous severe hypersensitivity reaction to another Monoclonal antibody. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the excipients in pazopanib tablets
• Has taken any prohibited medications that are listed in the protocol within 14 days of the first dose of study treatment. Subject has received or will receive a live vaccine within 30 days before the first administration of study treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1; Part 1 is a dose escalation phase in which subjects will receive pazopanib orally and the MK 3475 intravenously. Subjects will be evaluated for a minimum of 8 weeks before the next dose level cohort is enrolled.	Drug: Pazopanib; Pazopanib is an orally administered 200 mg tablet available in the dose range of 400 to 800 mg; Drug: MK-3475; MK 3475 is an intravenously administered 100 mg/ 4mL solution available in the potential dose range of 1 to 10 mg/kg.
Experimental: Part 2; Part 2 is a randomized phase in which subjects will be enrolled in each treatment arm: Pazopanib monotherapy Pazopanib+MK-3475 MK-3475 monotherapy	Drug: Pazopanib; Pazopanib is an orally administered 200 mg tablet available in the dose range of 400 to 800 mg; Drug: MK-3475; MK 3475 is an intravenously administered 100 mg/ 4mL solution available in the potential dose range of 1 to 10 mg/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs )		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	8 weeks
Part 1: Number of subjects with permanent discontinuation of treatment, dose reductions, interruptions, or delays		24 months
Part 1: Change from baseline in laboratory parameters	Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test	Average of 4 years
Part 1: Change from baseline in vital signs	Vital sign measurements will include heart rate, temperature and blood pressure	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)	24 months
Part 1: Incidence and titer of anti MK 3475 antibodies	Subjects will be monitored for anti-MK 3475 antibodies throughout the study	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.	Average of 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	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	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.	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)	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	Average of 4 years
Part 2: PFS by modified RECIST		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	18 months
Part 2: Overall survival (OS) at 18 months	Overall survival at 18 months will be summarized based on the Kaplan-Meier method.	18 months
Part 2: Overall survival (OS)	Overall survival will be summarized using Kaplan-Meier survival curves	Average of 4 years
Part 2: Incidence and severity of AEs and SAEs		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		Average of 4 years
Part 2: Change from baseline in laboratory parameters	Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test	Average of 4 years
Part 2: Change from baseline in vital signs	Vital sign measurements will include heart rate, temperature and blood pressure	Average of 4 years
Part 2: Change from baseline in cardiac parameters	Cardiac assessments will include ECG and ECHOs	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	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.	For Pazopanib: Until Dose 49 of MK-3475.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2013
• Primary Completion (Actual): February 27, 2019
• Study Completion (Actual): February 27, 2019

Study Registration Dates

• First Submitted: December 12, 2013
• First Submitted That Met QC Criteria: December 12, 2013
• First Posted (Estimate): December 18, 2013

Study Record Updates

• Last Update Posted (Actual): March 3, 2020
• Last Update Submitted That Met QC Criteria: February 28, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Renal cell carcinoma; Pazopanib (GW786034); MK 3475
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: 200249; KEYNOTE-018 (Other Identifier: Merck); PZP034A2101 (Other Identifier: Novartis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No