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

NCT02014636 | Completed Phase 1 DMC FDA Drug

• 3 other identifiers: 200249KEYNOTE-018PZP034A2101
• Study Type: interventional
• Target: 42
• Locations: 2 countries
• Sites: 6

Brief Summary

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.

Conditions

Carcinoma, Renal Cell

Keywords

Pazopanib (GW786034); MK 3475; Renal cell carcinoma

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (17)

• Part 1: Dose escalation cohorts: pazopanib plasma concentrations and serum MK 3475 concentrations.

  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

  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)

  Average of 4 years

• Part 1 and Part 2: Clinical benefit rate

  Average of 4 years

• Part 1 and Part 2: Time to response

  Average of 4 years

Study Arms (2)

Part 1

EXPERIMENTAL

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; Drug: MK-3475

Part 2

EXPERIMENTAL

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; Drug: MK-3475

Interventions

Pazopanib DRUG

Pazopanib is an orally administered 200 mg tablet available in the dose range of 400 to 800 mg

Part 1; Part 2

MK-3475 DRUG

MK 3475 is an intravenously administered 100 mg/ 4mL solution available in the potential dose range of 1 to 10 mg/kg.

Part 1; Part 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (6)

Novartis Investigative Site

Boston, Massachusetts, 02115, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02215, United States

Location

Novartis Investigative Site

New York, New York, 10065, United States

Location

Novartis Investigative Site

Nashville, Tennessee, 37203, United States

Location

Novartis Investigative Site

Manchester, Lancashire, M20 4BX, United Kingdom

Location

Novartis Investigative Site

London, W1G 6AD, United Kingdom

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

pazopanib; pembrolizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2013
• First Posted: December 18, 2013
• Study Start: December 27, 2013
• Primary Completion: February 27, 2019
• Study Completion: February 27, 2019
• Last Updated: March 3, 2020

Record last verified: 2020-02

Locations

GB (2); US (4)