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A Study Of Two Dual PI3K/mTOR Inhibitors, PF-04691502 And PF-05212384 In Patients With Recurrent Endometrial Cancer

This study has been terminated.
(See termination reason in detailed description.)
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01420081
First received: August 17, 2011
Last updated: May 23, 2017
Last verified: May 2017
  Purpose
This study will investigate the individual safety and efficacy of two dual PI3K/mTOR inhibitors in patients with recurrent endometrial cancer.

Condition Intervention Phase
Endometrial Neoplasms Drug: PF-05212384 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Randomized Phase 2 Non-comparative Study Of The Efficacy Of Pf-04691502 And Pf-05212384 In Patients With Recurrent Endometrial Cancer

Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Clinical Benefit Response for PF-04691502 [ Time Frame: 16 weeks from Cycle 1 Day 1 ]
    Clinical benefit response was defined as best overall response of complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks from Cycle 1 Day 1 (C1D1) to the first time of disease progression. The outcome data table below presents the number of participants with clinical benefit response as "yes" or "no". On 09 Oct 2012, Pfizer decided to stop enrollment into PF-04691502. While tumor assessment for PF-04691502 was included as a listing in the final report, formal efficacy analysis for PF-04691502 was not performed.

  • Percentage of Participants With Clinical Benefit Response for PF-05212384 [ Time Frame: 16 weeks from Cycle 1 Day 1 ]
    Clinical benefit response was defined as best overall response of complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks from Cycle 1 Day 1 (C1D1) to the first time of disease progression. The primary analysis is based on the clinical benefit rate which is calculated as proportion of participants with a clinical benefit response relative to total number of response evaluable participants. Per RECIST v1.1 for target lesions: CR defined as disappearance of all target lesions; PR defined as >=30% decrease in the sum of the longest diameter of target lesions; SD does not qualify for CR, PR or Progression. All target lesions must be assessed. SD can follow PR only in the rare case that the sum increases by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds. A Clopper-Pearson exact 95% CI for the clinical benefit rate is presented in the below table.


Secondary Outcome Measures:
  • Objective Response for PF-04691502 [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression (up to 12 months) ]
    Objective response is defined as CR or PR. CR: Complete response: 2 or more objective statuses of CR a minimum of 4 weeks apart documented before PD. Partial response: 2 or more objective statuses of PR or better a minimum of 4 weeks apart documented before PD, but not qualifying as CR. Per RECIST v1.1 for target lesions: CR defined as disappearance of all target lesions; PR defined as >=30% decrease in the sum of the longest diameter of target lesions. The outcome data table below presents the number of participants with objective response as "yes" or "no". On 09 Oct 2012, Pfizer decided to stop enrollment into PF-04691502. While tumor assessment for PF-04691502 was included as a listing in the final report, formal efficacy analysis for PF-04691502 was not performed.

  • Percentage of Participants With Objective Response for PF-05212384 [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression (up to 12 months) ]
    Objective response is defined as CR or PR. CR: Complete response: 2 or more objective statuses of CR a minimum of 4 weeks apart documented before PD. Partial response: 2 or more objective statuses of PR or better a minimum of 4 weeks apart documented before PD, but not qualifying as CR. Per RECIST v1.1 for target lesions: CR defined as disappearance of all target lesions; PR defined as >=30% decrease in the sum of the longest diameter of target lesions.

  • Progression Free Survival for PF-04691502 [ Time Frame: From Cycle 1 Day 1 to objective progressive disease or death due to any cause whichever occurs first (up to 12 months) ]
    PFS is defined as the time from the date of cycle 1 day 1 to the date that objective progressive disease is documented or death due to any cause, whichever occurs first. PFS was characterized in terms of the median. Approximate 95% confidence interval corresponding to this estimate was computed. Progression is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions with a minimum absolute increase of 5 mm, or an unequivocal progression of non-target lesion, or the appearance of new lesions. On 09 Oct 2012, Pfizer decided to stop enrollment into PF-04691502. While tumor assessment for PF-04691502 was included as a listing in the final report, formal efficacy analysis for PF-04691502 was not performed.

  • Progression Free Survival for PF-05212384 [ Time Frame: From Cycle 1 Day 1 to objective progressive disease or death due to any cause whichever occurs first (up to 12 months) ]
    PFS is defined as the time from the date of cycle 1 day 1 to the date that objective progressive disease is documented or death due to any cause, whichever occurs first. PFS was characterized in terms of the median. Approximate 95% confidence interval corresponding to this estimate was computed. Progression is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions with a minimum absolute increase of 5 mm, or an unequivocal progression of non-target lesion, or the appearance of new lesions.

  • Percentage of Participants With Progression Free Survival (PFS) at 6 Months for PF-05212384 [ Time Frame: 6 months ]
    Progression free survival is defined as the time from the date of cycle 1 day 1 to the date that objective progressive disease is documented or death due to any cause, whichever occurs first. PFS was characterized in terms of the probability of remaining progression-free at 6 months (based on Kaplan-Meier estimates). Progression is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions with a minimum absolute increase of 5 mm, or an unequivocal progression of non-target lesion, or the appearance of new lesions.

  • Overall Survival (OS) for PF-05212384 [ Time Frame: 12 months ]
    OS is defined as the time from the date of Cycle 1 Day 1 to the date of death.

  • Level of Each Pharmacodynamic Parameter at Specified Timepoints- Glucose (mg/dL) [ Time Frame: Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days ]
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected. This outcome measure will be updated once the data is available with the supplemental clinical study report.

  • Level of Each Pharmacodynamic Parameter at Specified Timepoints- Insulin (UIU/mL) [ Time Frame: Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days ]
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected. This outcome measure will be updated once the data is available with the supplemental clinical study report.

  • Level of Each Pharmacodynamic Parameter at Specified Timepoints- Glycosylated Hemoglobin (HbA1c) [ Time Frame: Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days ]
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected. This outcome measure will be updated once the data is available with the supplemental clinical study report.

  • Level of Each Pharmacodynamic Parameter at Specified Timepoints- Cholesterol (mg/dL) [ Time Frame: Baseline (Day -3) and Cycle1 to Cycle 3 where each cycle consist of 28 days ]
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected. This outcome measure will be updated once the data is available with the supplemental clinical study report.

  • Level of Each Pharmacodynamic Parameter at Specified Timepoints- Triglycerides (mg/dL) [ Time Frame: Baseline (Day -3) and Cycle1 to Cycle 3 where each cycle consist of 28 days ]
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected. This outcome measure will be updated once the data is available with the supplemental clinical study report.

  • Stathmin H Score [Mean (SD)] for Each Treatment Arm With Gene and/or Protein Expression Biomarkers in Biopsied Tumor Tissue [ Time Frame: Prior to Cycle 1 Day 1 ]

    Gene and/or protein expression biomarkers in biopsied tumor tissue relating to PI3K and/or mTOR pathway activation, such as PIK3CA and PIK3R1 mutations, PTEN protein levels, and PIK3CA gene amplification were to be assessed.

    Each slide was imaged by whole slide scanning and patient samples were scored as follows:

    • Pathologist manual score (0, 1+, 2+, 3+) for overall staining intensity of tumor tissue.
    • Percentage of positive tumor cells staining at 0, 1+, 2+, and 3+.
    • H-score value (integer between 0 and 300) for tumor cell staining was calculated. The higher the stathmin staining, the higher the stathmin H-score.

  • Percentage of Participants in Each Treatment Arm With Gene and/or Protein Expression Biomarkers- PIK3CA Amplification, KRAS Mutation P/N, KRAS Mutation OBSV, PTEN Stroma Manual Score, PTEN Tumor Manual Score, KRAS SCC and Stathmin H/L,Tissue. [ Time Frame: Baseline and Cycle1 to Cycle 5 where each cycle consist of 28 days ]

    Gene and/or protein expression biomarkers in biopsied tumor tissue relating to PI3K and/or mTOR pathway activation, such as PIK3CA and PIK3R1 mutations, Phosphatase And Tensin Homolog (PTEN) protein levels, and PIK3CA gene amplification were to be assessed.

    Stained tissues were evaluated by a board-certified pathologist who provided a manual pathology score (i.e., 0, 1+, 2+, or 3+) and, if appropriate, comments upon the staining of the specimen.

    The directionality increases from 0 to 3+ with 0 being no staining for PTEN by IHC and 3+ being high staining intensity for PTEN.


  • Area Under the Serum Concentration Time Profile From Time Zero Extrapolated to Infinity (AUCinf) of PF-05212384 at Each Specified Time Points. [ Time Frame: Pre-dose: 0 hours, and Post dose: 0.5 (after end of infusion), 1, 2, 4, 6, 24, 72, and 120 hours at Day 1 ]
  • Area Under the Serum Concentration Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PF-05212384 at Each Specified Time Points. [ Time Frame: Pre-dose: 0 hours, and Post dose: 0.5 (after end of infusion), 1, 2, 4, 6, 24, 72, and 120 hours at Day 1 ]
  • Maximum Plasma Concentration (Cmax) of PF-05212384 at Each Specified Time Points. [ Time Frame: Pre-dose: 0 hours, and Post dose: 0.5 (after end of infusion), 1, 2, 4, 6, 24, 72, and 120 hours at Day 1 ]
  • Terminal Elimination Half Life (t½) of PF-05212384 at Each Specified Time Points. [ Time Frame: Pre-dose: 0 hours, and Post dose: 0.5 (after end of infusion), 1, 2, 4, 6, 24, 72, and 120 hours at Day 1 ]
  • Time for Cmax (Tmax) of PF-05212384 at Each Specified Time Points. [ Time Frame: Pre-dose: 0 hours, and Post dose: 0.5 (after end of infusion), 1, 2, 4, 6, 24, 72, and 120 hours at Day 1 ]
  • Clearance (CL) of PF-05212384 at Each Specified Time Points. [ Time Frame: Pre-dose: 0 hours, and Post dose: 0.5 (after end of infusion), 1, 2, 4, 6, 24, 72, and 120 hours at Day 1 ]
  • Steady State Volume of Distribution (Vss) of PF-05212384 at Each Specified Time Points. [ Time Frame: Pre-dose: 0 hours, and Post dose: 0.5 (after end of infusion), 1, 2, 4, 6, 24, 72, and 120 hours ]
  • Number of Treatment-emergent Adverse Events (TEAEs) - All Causalities [ Time Frame: From baseline (-3 days) until 35 days post last dose ]
    Safety of participants in terms of TEAEs. Note: One subject treated with PF-05212384 had the stathmin status changed after randomization and was categorized under the corresponding arm.

  • Summary of Treatment-emergent Adverse Events (TEAEs) - All Causalities [ Time Frame: From baseline (-3 days) until 35 days post last dose ]
    Safety of participants in terms of TEAEs. Note: One subject treated with PF-05212384 had the stathmin status changed after randomization and was categorized under the corresponding arm.

  • Number of Treatment-related TEAEs [ Time Frame: From baseline (-3 days) until 35 days post last dose ]

    Safety of subject in terms of number of participants with treatment related AEs.

    Note: One subject treated with PF-05212384 had the stathmin status changed after randomization and was categorized under the corresponding arm.


  • Summary of Treatment-related TEAEs [ Time Frame: From baseline (-3 days) until 35 days post last dose ]

    Safety of subject in terms of number of participants with treatment related AEs.

    Note: One subject treated with PF-05212384 had the stathmin status changed after randomization and was categorized under the corresponding arm.



Enrollment: 67
Actual Study Start Date: January 19, 2012
Study Completion Date: December 25, 2015
Primary Completion Date: April 30, 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: B
PI3K Basal, IV Compound
Drug: PF-05212384
154mg IV weekly
Other Name: PKI-587
Experimental: C
PI3K Activated, Oral Compound
Drug: PF-05212384
154mg IV weekly
Other Name: PKI-587
Experimental: F
Japanese lead in cohort, IV compound
Drug: PF-05212384
154mg IV weekly
Other Name: PKI-587

Detailed Description:
The study was prematurely discontinued due to lack confidence in the Stathmin assay as a patient selection criteria and subsequent lack of confidence in the efficacy signal that was observed. The decision to terminate the study was made on January 23, 2014. It should be noted that safety concerns have not been seen in this study and have not factored into this decision.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Recurrent endometrial carcinoma
  • Disease progression following one or two lines of prior treatment with platinum containing chemotherapy
  • Tumor tissue available at time of screening for PI3K analysis
  • Adequate performance status
  • Adequate glucose control, bone marrow, kidney, liver, and heart function

Exclusion Criteria:

  • More than 2 prior cytotoxic chemo regimens for endometrial carcinoma
  • Prior therapy with an agent known to be a PI3K, and or mTOR and or AKT inhibitor
  • Active brain metastases
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01420081

  Show 55 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01420081     History of Changes
Other Study ID Numbers: B1271004
2011-003062-32 ( EudraCT Number )
Study First Received: August 17, 2011
Results First Received: April 30, 2015
Last Updated: May 23, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Pfizer:
uterine neoplasms
endometrial
uterine
cancer
PI3K
mTOR
PI3K/mTOR
recurrent
metastatic

Additional relevant MeSH terms:
Endometrial Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Diseases
Genital Diseases, Female

ClinicalTrials.gov processed this record on August 16, 2017