A Study Of PF-05212384 Plus FOLFIRI Versus Bevacizumab Plus FOLFIRI In Metastatic Colorectal Cancer
- Conditions
- Metastatic Colorectal Carcinoma
- Interventions
- Registration Number
- NCT01937715
- Lead Sponsor
- Pfizer
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 18
- 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.
- 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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Arm A PF-05212384 PF-05212384 plus FOLFIRI Arm A FOLFIRI regimen PF-05212384 plus FOLFIRI Arm B Bevacizumab Bevacizumab plus FOLFIRI Arm B FOLFIRI Bevacizumab plus FOLFIRI
- Primary Outcome Measures
Name Time Method Percentage of Participants With Dose-Limiting Toxicities (DLTs) in First Cycle of Therapy Day 1 up to Day 28 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).
Progression-Free Survival (PFS) Baseline (Day 1) up to disease progression or death whichever occurred first (up to 18 months) 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With Hematological Test Abnormalities Day 1 and Day 15 of each cycle Number of participants with NCI CTCAE version 4.0 grade 1 to 4 hematological test abnormalities.
Number of Participants With Coagulation Test Abnormalities Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 and subsequent cycles Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Coagulation test abnormalities.
Number of Participants With Chemistry Test Abnormalities Day 1 and Day 15 of each cycle Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Chemistry test abnormalities.
Number of Participants With Urinalysis Test Abnormalities Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 and subsequent cycles Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Urinalysis test abnormalities.
Number of Participants With Best Overall Response (Phase 1B) Every 8 weeks from Cycle 1 Day 1 until 28 days of last dose 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).
Number of Participants With All Causality Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations by Relationship and Seriousness Baseline up to final study evaluation (within 28 days of last dose) 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.
Number of Participants With All Causality AEs by System Organ Class (SOC) Baseline up to final study evaluation (within 28 days of last dose) An AE was any untoward medical occurrence without regard to causality in a participant who received study drug.
Number of Participants With Treatment-Emergent AEs by Worst On-Study Grade Baseline up to final study evaluation (within 28 days of last dose) 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.
Maximum Observed Plasma Concentration (Cmax): PF-05212384, Irinotecan, and Fluorouracil PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. Fluorouracil: Cycle 1 Day 1. Maximum Plasma Concentration of PF-05212384, Irinotecan, and Fluorouracil
Time to Reach Maximum Observed Plasma Concentration (Tmax): 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 of PF-05212384, Irinotecan, and Fluorouracil
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): PF-05212384 and Irinotecan PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. Area Under the Curve From Time Zero to Last Quantifiable Concentration of PF-05212384, and Irinotecan
Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf): 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 of PF-05212384 and Irinotecan
Terminal Elimination Half-Life (t1/2): PF-05212384 and Irinotecan PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. Terminal Elimination Half-Life of PF-05212384 and Irinotecan
Number of Participants Meeting Maximum Post-Baseline QTc Interval Values Baseline, Cycle 1 Day 1, and Cycle 2 Day 2 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.
Number of Participants With Expression of Gene Sequences or Gene Amplications in Biopsied Tumor Tissue Baseline and Cycle 2 Day 17 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.
Number of Participants With Gene and/or Protein Expression Biomarkers Relating to the PI3K and/or mTOR Pathway Activation in Biopsied Tumor Tissue Baseline and Cycle 2 Day 17 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.
Number of Participants With Best Overall Response (Phase 2) Day 1 up to Day 28 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).
Duration of Response (Phase 2) Day 1 to Day 28 Duration of response is the time from first documentation of CR or PR to date of first documentation of objective progression or death.
Overall Survival (Phase 2) Day 1 up to Day 28 Overall survival is the time from randomization date to date of death due to any cause.
Number of Participants With Evidence of Pathway Signaling Related Genes and/or Proteins in Biopsied Tumor Tissue (Phase 2) Baseline and Cycle 2 Day 17 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.
Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C) (Phase 2) Day 1 of each cycle 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.
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Trial Locations
- Locations (37)
Drug Management Only: UCLA West Medical Pharmacy, Attn Steven L. Wong, Pharm .D.
🇺🇸Los Angeles, California, United States
Comprehensive Cancer Centers of Nevada
🇺🇸Henderson, Nevada, United States
Spartanburg Regional Medical Center
🇺🇸Spartanburg, South Carolina, United States
Metrohealth Medical Center
🇺🇸Cleveland, Ohio, United States
Comprehensive Cancer Centers of NV
🇺🇸Las Vegas, Nevada, United States
Ronald Reagan UCLA Medical Center
🇺🇸Los Angeles, California, United States
Medical Oncology Associates, PS
🇺🇸Spokane, Washington, United States
COmprehensive Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
Comprehensive Cancer Centers for Nevada
🇺🇸Las Vegas, Nevada, United States
Comprehensive Cancer Centers of Nevada Research Department
🇺🇸Henderson, Nevada, United States
Medical Group of the Carolinas - Hematology Spartanburg
🇺🇸Spartanburg, South Carolina, United States
St. Jude Hospital Yorba Linda DBA St. Joseph Heritage Healthcare
🇺🇸Fullerton, California, United States
UCLA Hematology Oncology
🇺🇸Santa Monica, California, United States
UCLA Hematology Oncology Administrative Address
🇺🇸Los Angeles, California, United States
UCLA West Medical Pharmacy, Att: Steven L. Wong, Pharm D.
🇺🇸Los Angeles, California, United States
TRIO-US Central Administration, Regulatory Management Only
🇺🇸Los Angeles, California, United States
TRIO_US
🇺🇸Los Angeles, California, United States
Westwood Bowyer Clinic, Peter Morton Medical Building
🇺🇸Los Angeles, California, United States
TRIO-US Central Administration
🇺🇸Los Angeles, California, United States
Central Coast Medical Oncology Corporation
🇺🇸Santa Maria, California, United States
West Valley Hematology/Oncology Med Group
🇺🇸Northridge, California, United States
UCLA/Pasadena Healthcare
🇺🇸Pasadena, California, United States
UCLA Santa Monica Medical Center & Orthopaedic Hospital
🇺🇸Santa Monica, California, United States
Kadlec Medical Center
🇺🇸Richland, Washington, United States
Kadlec Clinic Hematology and Oncology
🇺🇸Kennewick, Washington, United States
Outpatient Imaging Center
🇺🇸Richland, Washington, United States
Investigational Drug Services
🇺🇸Seattle, Washington, United States
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
Virginia Mason Medical Center
🇺🇸Seattle, Washington, United States
Spokane Valley Cancer Center
🇺🇸Spokane Valley, Washington, United States
The Ottawa Hospital Cancer Centre
🇨🇦Ottawa, Ontario, Canada
Hospital General Universitario Gregorio Marañón
🇪🇸Madrid, Spain
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Drug Management Only: UCLA West Medical Pharmacy
🇺🇸Los Angeles, California, United States
Ronald Regan UCLA Medical Center, Drug Information Center
🇺🇸Los Angeles, California, United States
UCLA/Santa Clarita Valley Cancer Center
🇺🇸Valencia, California, United States
UCLA Cancer Center
🇺🇸Westlake Village, California, United States