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

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

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.

Study Overview

• Status: Terminated
• Conditions: Metastatic Colorectal Carcinoma
• Intervention / Treatment: Drug: PF-05212384; Drug: FOLFIRI regimen; Biological: Bevacizumab; Drug: FOLFIRI

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8 L6
      • The Ottawa Hospital Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28009
    • Hospital General Universitario Gregorio Marañon
• United States
  • California
    • Fullerton, California, United States, 92835
      • St. Jude Hospital Yorba Linda dba St. Joseph Heritage Healthcare
    • Irvine, California, United States, 92604
      • UCLA Hematology Oncology
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Los Angeles, California, United States, 90095
      • TRIO-US Central Administration
    • Los Angeles, California, United States, 90095
      • Westwood Bowyer Clinic, Peter Morton Medical Building
    • Los Angeles, California, United States, 90095-7349
      • Drug Management Only: UCLA West Medical Pharmacy
    • Los Angeles, California, United States, 90095-7349
      • Drug Management Only: UCLA West Medical Pharmacy, Attn Steven L. Wong, Pharm .D.
    • Los Angeles, California, United States, 90095-7349
      • UCLA West Medical Pharmacy, Att: Steven L. Wong, Pharm D.
    • Los Angeles, California, United States, 90095
      • Ronald Regan UCLA Medical Center, Drug Information Center
    • Los Angeles, California, United States, 90095
      • TRIO-US Central Administration, Regulatory Management Only
    • Los Angeles, California, United States, 90095
      • TRIO_US
    • Los Angeles, California, United States, 90095
      • UCLA Hematology Oncology Administrative Address
    • Northridge, California, United States, 91328
      • West Valley Hematology/Oncology Med Group
    • Pasadena, California, United States, 91105
      • UCLA/Pasadena Healthcare
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology Corporation
    • Santa Monica, California, United States, 90404
      • UCLA Hematology Oncology
    • Santa Monica, California, United States, 90404
      • UCLA Santa Monica Medical Center & Orthopaedic Hospital
    • Valencia, California, United States, 91355
      • UCLA/Santa Clarita Valley Cancer Center
    • Westlake Village, California, United States, 91361
      • UCLA Cancer Center
  • Nevada
    • Henderson, Nevada, United States, 89074
      • Comprehensive Cancer Centers of Nevada
    • Henderson, Nevada, United States, 89052
      • Comprehensive Cancer Centers of Nevada
    • Henderson, Nevada, United States, 89014
      • Comprehensive Cancer Centers of Nevada Research Department
    • Las Vegas, Nevada, United States, 89148
      • Comprehensive Cancer Centers of Nevada
    • Las Vegas, Nevada, United States, 89128
      • Comprehensive Cancer Centers of NV
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers for Nevada
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Spartanburg Regional Medical Center
    • Spartanburg, South Carolina, United States, 29303
      • Medical Group of the Carolinas - Hematology Spartanburg
  • Washington
    • Kennewick, Washington, United States, 99336
      • Kadlec Clinic Hematology and Oncology
    • Richland, Washington, United States, 99352
      • Kadlec Medical Center
    • Richland, Washington, United States, 99352
      • Outpatient Imaging Center
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
    • Seattle, Washington, United States, 98101
      • Investigational Drug Services
    • Spokane, Washington, United States, 99208
      • Medical Oncology Associates, PS
    • Spokane Valley, Washington, United States, 99216
      • Spokane Valley Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: August 27, 2013
• First Submitted That Met QC Criteria: September 4, 2013
• First Posted (Estimate): September 9, 2013

Study Record Updates

• Last Update Posted (Estimate): August 18, 2016
• Last Update Submitted That Met QC Criteria: July 8, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Bevacizumab; Gedatolisib
• Other Study ID Numbers: B2151007; 2013-002096-18 (EudraCT Number)