Clinical trial NCT02014636: Safety and Efficacy Study of Pazopanib and MK 3475 in Advanced Renal Cell Carcinoma (RCC; KEYNOTE-018)
Official title: A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and MK 3475 in Patients With Advanced Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Carcinoma, Renal Cell
Keywords: Pazopanib (GW786034)
MK 3475
Renal cell carcinoma
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2013-12-18
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Part 1: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs )
timeFrame: 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
measure: Part 1: To determine the dose limiting toxicity (DLT) and maximum tolerated regimen (MTR)
timeFrame: 8 weeks
measure: Part 1: Number of subjects with permanent discontinuation of treatment, dose reductions, interruptions, or delays
timeFrame: 24 months
measure: Part 1: Change from baseline in laboratory parameters
timeFrame: Average of 4 years
measure: Part 1: Change from baseline in vital signs
timeFrame: 30 days after the last dose of study treatment
measure: Part 1: Change from baseline in cardiac parameters
timeFrame: 24 months
measure: Part 1: Incidence and titer of anti MK 3475 antibodies
timeFrame: 24 months
measure: Part 2: Progression-free survival (PFS)
timeFrame: Average of 4 years
Secondary outcomes:
measure: Part 1: Dose escalation cohorts: pazopanib plasma concentrations and serum MK 3475 concentrations.
timeFrame: 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
measure: Part 1: Pharmacokinetic (PK) parameters in Expansion cohort
timeFrame: 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
measure: Part 1 and Part 2: Overall response rate (ORR)
timeFrame: Average of 4 years
measure: Part 1 and Part 2: Clinical benefit rate
timeFrame: Average of 4 years
measure: Part 1 and Part 2: Time to response
timeFrame: Average of 4 years
measure: Part 1 and Part 2: Duration of response
timeFrame: Average of 4 years
measure: Part 2: PFS by modified RECIST
timeFrame: Average of 4 years
measure: Part 1 and Part 2: Progression-free survival rate at 18 months (PFSR18)
timeFrame: 18 months
measure: Part 2: Overall survival (OS) at 18 months
timeFrame: 18 months
measure: Part 2: Overall survival (OS)
timeFrame: Average of 4 years
measure: Part 2: Incidence and severity of AEs and SAEs
timeFrame: 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
measure: Part 2: Number of subjects with permanent discontinuation of treatment, dose reductions, interruptions, or delays
timeFrame: Average of 4 years
measure: Part 2: Change from baseline in laboratory parameters
timeFrame: Average of 4 years
measure: Part 2: Change from baseline in vital signs
timeFrame: Average of 4 years
measure: Part 2: Change from baseline in cardiac parameters
timeFrame: Average of 4 years
measure: Part 2: Incidence and titer of anti MK 3475 antibodies in patients treated with pazopanib + MK 3475 and single-agent MK 3475
timeFrame: Until 6 months after the last dose of MK-3475
measure: Part 2: PK parameters in randomized phase
timeFrame: For Pazopanib: Until Dose 49 of MK-3475.
Other outcomes:
Locations:
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
state: Lancashire
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: