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

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ClinicalTrials.gov Identifier: NCT02014636
Recruitment Status : Completed
First Posted : December 18, 2013
Last Update Posted : April 30, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE December 12, 2013
First Posted Date  ICMJE December 18, 2013
Last Update Posted Date April 30, 2019
Actual Study Start Date  ICMJE December 27, 2013
Actual Primary Completion Date February 27, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 12, 2013)
  • 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) [ Time Frame: 8 weeks ]
    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
  • 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 [ Time Frame: Average of 4 years ]
    Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test
  • Part 1: Change from baseline in vital signs [ Time Frame: 30 days after the last dose of study treatment ]
    Vital sign measurements will include heart rate, temperature and blood pressure
  • Part 1: Change from baseline in cardiac parameters [ Time Frame: 24 months ]
    Cardiac assessments will include Electrocardiogram (ECG) and Echocardiograms (ECHOs)
  • Part 1: Incidence and titer of anti MK 3475 antibodies [ Time Frame: 24 months ]
    Subjects will be monitored for anti-MK 3475 antibodies throughout the study
  • Part 2: Progression-free survival (PFS) [ Time Frame: Average of 4 years ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02014636 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2013)
  • Part 1: Dose escalation cohorts: pazopanib plasma concentrations and serum MK 3475 concentrations. [ 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 ]
    For analysis of plasma pazopanib and serum MK 3475 concentrations, blood samples will be collected from all subjects
  • Part 1: Pharmacokinetic (PK) parameters in Expansion cohort [ 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 ]
    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.
  • Part 1 and Part 2: Overall response rate (ORR) [ Time Frame: Average of 4 years ]
    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
  • Part 1 and Part 2: Clinical benefit rate [ Time Frame: Average of 4 years ]
    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.
  • Part 1 and Part 2: Time to response [ Time Frame: Average of 4 years ]
    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)
  • Part 1 and Part 2: Duration of response [ Time Frame: Average of 4 years ]
    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
  • 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) [ Time Frame: 18 months ]
    PFSR18 will be calculated based on Kaplan-Meier estimates of Progression-free survival (PFS) at 18 months by RECIST v1.1 and modified RECIST
  • Part 2: Overall survival (OS) at 18 months [ Time Frame: 18 months ]
    Overall survival at 18 months will be summarized based on the Kaplan-Meier method.
  • Part 2: Overall survival (OS) [ Time Frame: Average of 4 years ]
    Overall survival will be summarized using Kaplan-Meier survival curves
  • 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 [ Time Frame: Average of 4 years ]
    Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test
  • Part 2: Change from baseline in vital signs [ Time Frame: Average of 4 years ]
    Vital sign measurements will include heart rate, temperature and blood pressure
  • Part 2: Change from baseline in cardiac parameters [ Time Frame: Average of 4 years ]
    Cardiac assessments will include ECG and ECHOs
  • Part 2: Incidence and titer of anti MK 3475 antibodies in patients treated with pazopanib + MK 3475 and single-agent MK 3475 [ Time Frame: Until 6 months after the last dose of MK-3475 ]
    Subjects will be monitored for anti-MK 3475 antibodies throughout the study
  • Part 2: PK parameters in randomized phase [ Time Frame: For Pazopanib: Until Dose 49 of MK-3475. ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Study of Pazopanib and MK 3475 in Advanced Renal Cell Carcinoma (RCC; KEYNOTE-018)
Official Title  ICMJE A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and MK 3475 in Patients With Advanced Renal Cell Carcinoma
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Carcinoma, Renal Cell
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Pazopanib
    • Drug: MK-3475
  • 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

    Interventions:
    • Drug: Pazopanib
    • Drug: MK-3475
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 26, 2019)
42
Original Estimated Enrollment  ICMJE
 (submitted: December 12, 2013)
228
Actual Study Completion Date  ICMJE February 27, 2019
Actual Primary Completion Date February 27, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries Netherlands
 
Administrative Information
NCT Number  ICMJE NCT02014636
Other Study ID Numbers  ICMJE 200249
KEYNOTE-018 ( Other Identifier: Merck )
PZP034A2101 ( Other Identifier: Novartis )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
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

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP