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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01937715
Recruitment Status : Terminated (B2151007 was prematurely discontinued due to Pfizer's change in prioritization for the portfolio and is not due to any safety concerns or regulatory interaction)
First Posted : September 9, 2013
Results First Posted : August 18, 2016
Last Update Posted : August 18, 2016
Sponsor:
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Metastatic Colorectal Carcinoma Drug: PF-05212384 Drug: FOLFIRI regimen Biological: Bevacizumab Drug: FOLFIRI Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : February 2014
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

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




Primary Outcome Measures :
  1. 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).

  2. 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 Outcome Measures :
  1. Number of Participants With Best Overall Response (Phase 1B) [ Time Frame: 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).

  2. Number of Participants With All Causality Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations by Relationship and Seriousness [ Time Frame: 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.

  3. Number of Participants With All Causality AEs by System Organ Class (SOC) [ Time Frame: 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.

  4. Number of Participants With Treatment-Emergent AEs by Worst On-Study Grade [ Time Frame: 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.

  5. Number of Participants With Hematological Test Abnormalities [ Time Frame: Day 1 and Day 15 of each cycle ]
    Number of participants with NCI CTCAE version 4.0 grade 1 to 4 hematological test abnormalities.

  6. Number of Participants With Coagulation Test Abnormalities [ Time Frame: 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.

  7. Number of Participants With Chemistry Test Abnormalities [ Time Frame: Day 1 and Day 15 of each cycle ]
    Number of participants with NCI CTCAE version 4.0 grade 1 to 4 Chemistry test abnormalities.

  8. Number of Participants With Urinalysis Test Abnormalities [ Time Frame: 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.

  9. Maximum Observed Plasma Concentration (Cmax): PF-05212384, Irinotecan, and Fluorouracil [ Time Frame: 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

  10. Time to Reach Maximum Observed Plasma Concentration (Tmax): PF-05212384, Irinotecan, and Fluorouracil [ Time Frame: 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

  11. Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): PF-05212384 and Irinotecan [ Time Frame: 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

  12. Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf): PF-05212384 and Irinotecan [ Time Frame: 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

  13. Terminal Elimination Half-Life (t1/2): PF-05212384 and Irinotecan [ Time Frame: PF-05212384: Cycle 1 Day 3. Irinotecan: Cycle 1 Day 1. ]
    Terminal Elimination Half-Life of PF-05212384 and Irinotecan

  14. Number of Participants Meeting Maximum Post-Baseline QTc Interval Values [ Time Frame: 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.

  15. Number of Participants With Expression of Gene Sequences or Gene Amplications in Biopsied Tumor Tissue [ Time Frame: 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.

  16. Number of Participants With Gene and/or Protein Expression Biomarkers Relating to the PI3K and/or mTOR Pathway Activation in Biopsied Tumor Tissue [ Time Frame: 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.

  17. Number of Participants With Best Overall Response (Phase 2) [ Time Frame: 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).

  18. Duration of Response (Phase 2) [ Time Frame: 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.

  19. Overall Survival (Phase 2) [ Time Frame: Day 1 up to Day 28 ]
    Overall survival is the time from randomization date to date of death due to any cause.

  20. Number of Participants With Evidence of Pathway Signaling Related Genes and/or Proteins in Biopsied Tumor Tissue (Phase 2) [ Time Frame: 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.

  21. Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C) (Phase 2) [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01937715


Locations
Show Show 39 study locations
Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
Additional Information:
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01937715    
Other Study ID Numbers: B2151007
2013-002096-18 ( EudraCT Number )
First Posted: September 9, 2013    Key Record Dates
Results First Posted: August 18, 2016
Last Update Posted: August 18, 2016
Last Verified: July 2016
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Gedatolisib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action