A Study Of PF-05212384 Plus FOLFIRI Versus Bevacizumab Plus FOLFIRI In Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is a multicenter, open label Phase 1b/2 study in patients with metastatic colorectal carcinoma. The Phase 1b will identify the dose of the combination of PF-05212384 plus FOLFIRI. The randomized, two-arm Phase 2 portion will compare the efficacy and safety of PF-05212384 plus FOLFIRI to that of bevacizumab plus FOLFIRI. The study population will consist of patients with mCRC previously treated with an oxaliplatin-based regimen in the first line setting or who have progressed within 6 months of the end of an adjuvant oxaliplatin-based regimen.

Official Title
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An Open-Label, Multi-Center, Randomized Phase 1b/2 Study Of PF-05212384 Plus 5-Fluorouracil-Leucovorin-Irinotecan (FOLFIRI) Versus Bevacizumab Plus FOLFIRI In Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Carcinoma

Intervention / Treatment
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* Drug: PF-05212384
* Drug: FOLFIRI regimen
* Biological: Bevacizumab
* Drug: FOLFIRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced colorectal carcinoma. Progression on prior oxaliplatin-containing regimen used in 1st line setting for mCRC or progression within 6 months of end of oxaliplatin-containing regimen in the adjuvant setting. Tumor tissue available at time of screening for molecular profiling. Adequate performance status. Adequate glucose control, bone marrow, kidney, liver, and heart function. Exclusion Criteria: Participation in other studies involving investigational drug(s) (Phases 1-4) before the current study begins and/or during study participation. Prior irinotecan treatment. Prior radiation to the pelvis or abdomen in the metastatic or locally advanced setting. History of Gilbert's syndrome. Active brain metastases. Deep vein thrombosis in the preceding 2 months. History of interstitial lung disease. RAS (KRAS/NRAS) wild type mCRC not previously treated with an anti-EGFR containing regimen (unless contraindicated or not considered standard practice per clinical site or country guidelines).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>PF-05212384 plus FOLFIRI | Drug: PF-05212384<br>* PF-05212384 at the Recommended phase 2 dose (RP2D/MTD) weekly<br>Drug: FOLFIRI regimen<br>* The RP2D/MTD dose of FOLFIRI regimen every 2 weeks<br>|
| Active Comparator: Arm B<br>Bevacizumab plus FOLFIRI | Biological: Bevacizumab<br>* 5 mg/m^2 every 2 weeks or 7.5 mg/m^2 every 3 weeks<br>Drug: FOLFIRI<br>* Full dose FOLFIRI regimen every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Dose-Limiting Toxicities (DLTs) in First Cycle of Therapy | DLTs were classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and defined as any of the following events judged to be attributed to the combination of PF-05212384 plus FOLFIRI: hematologic (febrile neutropenia or a sustained temperature >=38 degrees Celcius for >1 hour, grade >=3 neutropenic infection, grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia); non-hematologic (grade >=2 pneumonitis, grade >=3 toxicities, toxicities which resulted in failure to deliver at least 75% of the planned total dose of PF-05212384 and/or 50% of the planned total dose of FOLFIRI during the first cycle, toxicities which resulted in delay of start of Cycle 2 by >2 weeks of scheduled day (Day 43 of study), Grade 3 QTc prolongation). | Day 1 up to Day 28 | 
| Progression-Free Survival (PFS) | Progression-free survival was the time from randomization the date to date of first documentation of progression or death due to any cause, whichever occurred first. Documentation of progression was by objective disease assessment as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Baseline (Day 1) up to disease progression or death whichever occurred first (up to 18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Best Overall Response (Phase 1B) | Best overall response is defined as the best response recorded from randomization (or first dose for patients in the Phase 1B) until disease progression, death, start of new anti-cancer treatment or end of study. The categories for best overall response include: complete response (CR) (complete disappearance of all target lesions with the exception of nodal disease and all target nodes must decrease to normal size (short axis <10 millimeters (mm)); partial response (PR) (at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); stable disease (SD) (not qualify for CR, PR or Progression); progressive disease (PD) (20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm); indeterminate (IND) (progression has not been documented). | Every 8 weeks from Cycle 1 Day 1 until 28 days of last dose | 
| Number of Participants With All Causality Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations by Relationship and Seriousness | An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. An AE was considered treatment emergent if the event occurred for the first time after the start of study treatment and within 28 days after final dose of study treatment and was not seen prior to the start of treatment; or the event was seen prior to the start of treatment but increased in CTCAE version 4.0 grade after the start of study treatment and within 28 days after final dose of study treatment. | Baseline up to final study evaluation (within 28 days of last dose) | 
| Number of Participants With All Causality AEs by System Organ Class (SOC) | An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. | Baseline up to final study evaluation (within 28 days of last dose) | 
| Number of Participants With Treatment-Emergent AEs by Worst On-Study Grade | An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. AE grades were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria. | Baseline up to final study evaluation (within 28 days of last dose) | 
| Number of Participants With Hematological Test Abnormalities | Number of participants with NCI CTCAE version 4.0 grade 1 to 4 hematological test abnormalities. | Day 1 and Day 15 of each cycle | 
| Number of Participants With Coagulation Test Abnormalities | Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Coagulation test abnormalities. | Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 and subsequent cycles | 
| Number of Participants With Chemistry Test Abnormalities | Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Chemistry test abnormalities. | Day 1 and Day 15 of each cycle | 
| Number of Participants With Urinalysis Test Abnormalities | Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Urinalysis test abnormalities. | Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 and subsequent cycles | 
| Maximum Observed Plasma Concentration (Cmax): PF-05212384, Irinotecan, and Fluorouracil | Maximum Plasma Concentration of PF-05212384, Irinotecan, and Fluorouracil | PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. Fluorouracil: Cycle 1 Day 1. | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax): PF-05212384, Irinotecan, and Fluorouracil | Time to Reach Maximum Observed Plasma Concentration of PF-05212384, Irinotecan, and Fluorouracil | PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. Fluorouracil: Cycle 1 Day 1. | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): PF-05212384 and Irinotecan | Area Under the Curve From Time Zero to Last Quantifiable Concentration of PF-05212384, and Irinotecan | PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. | 
| Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf): PF-05212384 and Irinotecan | Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time of PF-05212384 and Irinotecan | PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. | 
| Terminal Elimination Half-Life (t1/2): PF-05212384 and Irinotecan | Terminal Elimination Half-Life of PF-05212384 and Irinotecan | PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. | 
| Number of Participants Meeting Maximum Post-Baseline QTc Interval Values | Criteria for corrected QT interval using Fridericia's formula (QTcF) meeting potential clinical concern included: an absolute value >=450 - <480 msec, >=480-<500 msec, >500 msec; an absolute change 30 - <60, >=60 msec. | Baseline, Cycle 1 Day 1, and Cycle 2 Day 2 | 
| Number of Participants With Expression of Gene Sequences or Gene Amplications in Biopsied Tumor Tissue | Biomarker evaluation were to be performed on fresh biopsies, as well as on archival biopsies collected during the study. Samples were to be analyzed for biomarkers indicative of pathway modulation or for genetic markers correlated to drug sensitivity. | Baseline and Cycle 2 Day 17 | 
| Number of Participants With Gene and/or Protein Expression Biomarkers Relating to the PI3K and/or mTOR Pathway Activation in Biopsied Tumor Tissue | Biomarker evaluation were to be performed on fresh biopsies, as well as on archival biopsies collected during the study. Samples were to be analyzed for biomarkers indicative of pathway modulation or for genetic markers correlated to drug sensitivity. | Baseline and Cycle 2 Day 17 | 
| Number of Participants With Best Overall Response (Phase 2) | Best overall response is defined as the best response recorded from randomization (or first dose for patients in the Phase 1B) until disease progression, death, start of new anti-cancer treatment or end of study. The categories for best overall response include: complete response (CR) (complete disappearance of all target lesions with the exception of nodal disease and all target nodes must decrease to normal size (short axis <10 millimeters (mm)); partial response (PR) (at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); stable disease (SD) (not qualify for CR, PR or Progression); progressive disease (PD) (20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm); indeterminate (IND) (progression has not been documented). | Day 1 up to Day 28 | 
| Duration of Response (Phase 2) | Duration of response is the time from first documentation of CR or PR to date of first documentation of objective progression or death. | Day 1 to Day 28 | 
| Overall Survival (Phase 2) | Overall survival is the time from randomization date to date of death due to any cause. | Day 1 up to Day 28 | 
| Number of Participants With Evidence of Pathway Signaling Related Genes and/or Proteins in Biopsied Tumor Tissue (Phase 2) | Biomarker evaluation were to be performed on these fresh biopsies, as well as on archival biopsies collected during the study. Samples were to be analyzed for biomarkers indicative of pathway modulation or for genetic markers correlated to drug sensitivity. | Baseline and Cycle 2 Day 17 | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C) (Phase 2) | The FACT-C was to assess health-related quality of life and colorectal cancer (CRC)-related symptoms. It includes a total of 36 items, which are summarized into 6 subscales: physical well-being (7 items), functional well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), CRC subscale (9 items) which addresses a subset of CRC concerns such as diarrhea. | Day 1 of each cycle |