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
Overview
- Phase
- Phase 1
- Intervention
- PF-05212384
- Conditions
- Metastatic Colorectal Carcinoma
- Sponsor
- Pfizer
- Enrollment
- 18
- Locations
- 37
- Primary Endpoint
- Percentage of Participants With Dose-Limiting Toxicities (DLTs) in First Cycle of Therapy
- Status
- Terminated
- Last Updated
- 9 years ago
Overview
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.
Investigators
Eligibility Criteria
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).
Arms & Interventions
Arm A
PF-05212384 plus FOLFIRI
Intervention: PF-05212384
Arm A
PF-05212384 plus FOLFIRI
Intervention: FOLFIRI regimen
Arm B
Bevacizumab plus FOLFIRI
Intervention: Bevacizumab
Arm B
Bevacizumab plus FOLFIRI
Intervention: FOLFIRI
Outcomes
Primary Outcomes
Percentage of Participants With Dose-Limiting Toxicities (DLTs) in First Cycle of Therapy
Time Frame: 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)
Time Frame: 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 Outcomes
- Number of Participants With Hematological Test Abnormalities(Day 1 and Day 15 of each cycle)
- 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 Chemistry Test Abnormalities(Day 1 and Day 15 of each cycle)
- 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 Best Overall Response (Phase 1B)(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(Baseline up to final study evaluation (within 28 days of last dose))
- Number of Participants With All Causality AEs by System Organ Class (SOC)(Baseline up to final study evaluation (within 28 days of last dose))
- Number of Participants With Treatment-Emergent AEs by Worst On-Study Grade(Baseline up to final study evaluation (within 28 days of last dose))
- 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.)
- 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.)
- 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 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.)
- Terminal Elimination Half-Life (t1/2): 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(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(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(Baseline and Cycle 2 Day 17)
- Number of Participants With Best Overall Response (Phase 2)(Day 1 up to Day 28)
- Duration of Response (Phase 2)(Day 1 to Day 28)
- Overall Survival (Phase 2)(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)(Baseline and Cycle 2 Day 17)
- Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C) (Phase 2)(Day 1 of each cycle)