PF-04856884 (CVX-060) In Combination With Axitinib In Patients With Previously Treated Metastatic Renal Cell Carcinoma

Study Overview
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Brief Summary
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To evaluate the combination of PF-04856884 (CVX-060) in combination with Axitinib (AG-013736) in patients that have received one prior systemic regimen for metastatic renal cell carcinoma (mRCC) vs. axitinib alone.

Detailed Description
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The study was prematurely discontinued on 06Nov2012 due to tolerability findings in patients treated in Part I of the study that have prompted the Sponsor to re-evaluate the strategic development of the program. An unexpected frequency of arterial thrombotic events (ATEs) and venous thrombotic events (VTEs) were reported in patients treated in Part I.

Official Title
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A PHASE II TRIAL OF PF-04856884 (CVX-060), A SELECTIVE ANGIOPOIETIN-2 (ANG-2) INHIBITOR IN COMBINATION WITH AG-013736 (AXITINIB) IN PATIENTS WITH PREVIOUSLY TREATED METASTATIC RENAL CELL CARCINOMA

Conditions
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Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Biological: PF-04856884
* Drug: Axitinib (AG-013736)
* Drug: Axitinib (AG-013736)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female patients with histologically or cytologically confirmed renal cell cancer (RCC) with a component of clear cell subtype and evidence of metastasis Evidence of unidimensionally measurable disease Prior therapy: Part I: Having received 1 to 3 prior systemic regimens for treatment of mRCC Part II: Evidence of disease progression following 1 prior regimen administered as 1st line therapy for mRCC. The prior regimen must have contained one of the following: VEGFR2 tyrosine kinase inhibitor (TKI) or other anti VEGF [Vascular Endothelial Growth Factor] compounds, such as bevacizumab adequate bone marrow, liver and renal function Exclusion Criteria: Part I: Intolerant to prior AG 013736 therapy or prior treatment with compounds which contain the core platform antibody as PF 04856884 Part II: Prior AG 013736 therapy, more than one systemic first-line regimen for the treatment of mRCC and prior treatment with compounds which contain the core platform antibody as PF 04856884 major surgery <4 weeks or radiation therapy <2 weeks prior to start of therapy clinically significant gastrointestinal abnormalities current use or anticipated need for drugs that are known potent CYP3A4 inhibitors and drugs that are known CYP3A4 or CYP1A2 inducers history of bleeding diathesis or coagulopathy Grade 3 or greater hemorrhage from any cause <4 weeks prior to screening; hemoptysis >½ teaspoon of blood per day within 2 weeks prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM A<br>PF-04856884 in combination with AG-013736 | Biological: PF-04856884<br>* 15 mg/kg/week intravenously [IV] until toxicity or disease progression<br>Drug: Axitinib (AG-013736)<br>* 5 mg PO BID<br>|
| Active Comparator: ARM B<br>AG-013736 alone | Drug: Axitinib (AG-013736)<br>* 5 mg PO BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Non-serious Adverse Events (AEs) in Part I (Reported in ≥2 of the Participants Overall). | Incidence and severity of all treatment-emergent AEs (TEAEs) of both all-causality and treatment-related by preferred term (PT) categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades reported in ≥2 participants overall (CTCAE Grades 3, 4 and 5, combined) for any PT are presented. Participants who are included under all-causality TEAE PT are coded as NA if they appear for the same PT under treatment-related TEAE below. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). | 4 months | 
| Number of Participants With Serious Adverse Events (SAEs) in Part I | Incidence and severity of all-causality serious adverse events (SAEs) are presented by PT categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). Participants with treatment-related TEAE are coded as NA if they appear for the same preferred term under all-causality TEAE. | 4 months | 
| Progression Free Survival (PFS) in Adult Participants With Previously Treated Metastatic Renal Cell Cancer (mRCC) in Part II | PFS is defined as the time (in days) from date of randomization to first documentation of investigator assessed tumor progression or death, whichever comes first. Progression free survival was to be calculated as (first event date - the date of randomization +1). | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Non-serious AEs and SAEs | Incidence and severity of all-causality AEs and SAEs to be presented by PT categorized according to Common Terminology Criteria for Adverse Events (CTCAE) grades. Participants in Part I received PF-04856884 15 mg/kg/week and AG-013736 5 mg twice daily. Following the decision on 06 November 2012 not to continue with Part II of the study, any participant remaining in Part I continued to receive PF-04856884 at a reduced dose of 10 mg/kg/week in combination with AG-013736 (5 mg twice a week) or AG-013736 alone (5 mg twice a week). | 3 years | 
| Overall Response Rate (ORR) in Metastatic Renal Cell Cancer (mRCC) Patients Treated With PF-04856884 in Combination With AG-013736 vs. AG-013736 Alone. | ORR is defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST), relative to all randomized participants as defined in the FA Set. Confirmed responses are those that persist on repeat imaging study ≥ 4 weeks after initial documentation of response. Participants who do not have on-study radiographic tumor evaluation or who die, progress, or drop out for any reason prior to reaching a CR or PR will be counted as non-responders (NR) in the assessment of ORR. | 4 months | 
| Duration of Response (DR) in Metastatic Renal Cell Cancer (mRCC) Patients Treated With PF-04856884 in Combination With AG-013736 vs. AG-013736 Alone | DR is defined as the time from the first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of tumor progression or to death due to cancer. Duration of tumor response was to be calculated as (the end date for DR - first CR or PR that is subsequently confirmed +1). | 3 years | 
| Tmax (Time When Maximum Serum PF-04856884 Concentration Was Reached) | Pharmacokinetic parameter, Tmax (Time when maximum serum PF-04856884 concentration was reached) was done using non-compartmental methods. | Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment | 
| Cmax (Observed Peak Serum PF-04856884 Concentration) | Pharmacokinetic parameter Cmax (observed peak PF-04856884 serum concentration) was estimated using noncompartmental methods. | Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment | 
| Cmin (Trough PF-04856884 Serum Concentration) | Pharmacokinetic parameter Cmin (trough PF-04856884 serum concentration) was estimated using noncompartmental methods. | Pre-dose, 1, 2, 4, 6, 8, 192, 360, 361, 362, 365, 367 hours post dose and end of treatment | 
| Number of Anti-drug Antibodies (ADA) Samples Confirmed Positive | Detection of neutralizing anti-PF-04856884 antibodies was based on the ability of anti-PF-04856884 neutralizing antibodies to bind to Tag-PF-04856884. | 0 and 360 hours post dose and end of study | 
| Progression Free Survival (PFS) in Adult Participants With Previously Treated Metastatic Renal Cell Cancer (mRCC) as Measured by an Independent Radiological Assessment | PFS is defined as the time (in days) from date of randomization to first documentation of investigator assessed tumor progression or death, whichever comes first. PFS was to be calculated as (first event date - the date of randomization +1). | 3 years | 
| Overall Survival (OS) at 2 Years | OS is defined as the time from the first dose date to date of death. For participants not expiring, their survival times will be censored at the last date they are known to be alive, or 2 year whichever is earlier. The 2-year OS rate will be estimated from a time-to event analysis of OS. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CVX-060, second line, PF-04856884, AG-013736, axitinib, mRCC, metastatic renal cell cancer, anti-angiogenic, Ang-2