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

A RANDOMIZED PHASE 2 NON-COMPARATIVE STUDY OF THE EFFICACY OF PF-04691502 AND PF-05212384 IN PATIENTS WITH RECURRENT ENDOMETRIAL CANCER

This study will investigate the individual safety and efficacy of two dual PI3K/mTOR inhibitors in patients with recurrent endometrial cancer.

Study Overview

• Status: Terminated
• Conditions: Endometrial Neoplasms
• Intervention / Treatment: Drug: PF-05212384

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.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Peter MacCallum Cancer Centre, Division of Cancer Madicine
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Medical Center
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • British Columbia Cancer Agency - Vancouver Centre
  • Ontario
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario At Kingston General Hospital
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Montreal, Quebec, Canada, H3A 1A1
      • Royal Victoria Hospital
    • Montreal, Quebec, Canada, H3T 1M5
      • St. Mary's Hospital
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 464-8681
      • Aichi Cancer Center Hospital
  • Hyogo
    • Akashi, Hyogo, Japan, 673-8558
      • Hyogo Cancer Center
  • Saitama
    • Hidaka, Saitama, Japan, 350-1298
      • Saitama Medical University International Medical Center
  • Tokyo
    • Chuo-Ku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital
• Poland
  • Lodz, Poland, 93-509
    • Regionalny Osrodek Onkologiczny Wojewodzki Szpital Specjalistyczny im. M. Kopernika
  • Lodz, Poland, 93-513
    • Zaklad Radiologii
  • Lublin, Poland, 20-090
    • Centrum Onkologii Ziemi Lubelskiej im. św. Jana z Dukli
• Russian Federation
  • Krasnodar, Russian Federation, 350040
    • Clinical Oncology Dispensary 1 of Department of Healthcare of the Krasnodar Region
  • Pyatigorsk, Russian Federation, 357502
    • Pyatigorsk Oncology Center
  • Saint Petersburg, Russian Federation, 198255
    • Saint Petersburg State Healthcare Institution City Clinical Oncology Dispensary
  • Stavropol Territory
    • Lermontov, Stavropol Territory, Russian Federation, 357340
      • Federal State Healthcare Institution
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28040
    • Hospital Clínico San Carlos
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28033
    • Centro Oncologico MD Anderson Internacional España
  • Valencia, Spain, 46009
    • Fundacion Instituto Valenciano de Oncologia - I.V.O.
  • Valencia, Spain, 46009
    • Fundacion Instituto Valenciano de Oncologia - I.V.O
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Beatson Oncology Centre
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust
  • London, United Kingdom, NW1 2PG
    • University College London Hospital NHS Foundation Trust
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • The Royal Marsden NHS Foundation Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham, IDS Pharmacy
  • California
    • La Jolla, California, United States, 92093
      • Moores UC San Diego Cancer Center
    • La Jolla, California, United States, 92037
      • University of California Medical Center
    • San Diego, California, United States, 92103
      • University of California Medical Center
  • Florida
    • Miami, Florida, United States, 33133
      • Mercy Hospital
    • Miami, Florida, United States, 33133
      • Mercy Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • New Lenox, Illinois, United States, 60451
      • University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University Of Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Hospital
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center and Medical Pavilion
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Women's Cancer Care
    • Covington, Louisiana, United States, 70433
      • Mary Bird Perkins Cancer Center at St. Tammany Parish Hospital
    • Metairie, Louisiana, United States, 70006
      • Women's Cancer Care
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico 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: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: B; PI3K Basal, IV Compound	Drug: PF-05212384; 154mg IV weekly; Other Names: PKI-587
EXPERIMENTAL: C; PI3K Activated, Oral Compound	Drug: PF-05212384; 154mg IV weekly; Other Names: PKI-587
EXPERIMENTAL: F; Japanese lead in cohort, IV compound	Drug: PF-05212384; 154mg IV weekly; Other Names: PKI-587

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Benefit Response for PF-04691502	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.	16 weeks from Cycle 1 Day 1
Percentage of Participants With Clinical Benefit Response for PF-05212384	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.	16 weeks from Cycle 1 Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response for PF-04691502	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.	Randomization to objective progression, death or last tumor assessment without progression (up to 12 months)
Percentage of Participants With Objective Response for PF-05212384	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.	Randomization to objective progression, death or last tumor assessment without progression (up to 12 months)
Progression Free Survival for PF-04691502	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.	From Cycle 1 Day 1 to objective progressive disease or death due to any cause whichever occurs first (up to 12 months)
Progression Free Survival for PF-05212384	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.	From Cycle 1 Day 1 to objective progressive disease or death due to any cause whichever occurs first (up to 12 months)
Percentage of Participants With Progression Free Survival (PFS) at 6 Months for PF-05212384	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.	6 months
Overall Survival (OS) for PF-05212384	OS is defined as the time from the date of Cycle 1 Day 1 to the date of death.	12 months
Level of Each Pharmacodynamic Parameter at Specified Timepoints- Glucose (mg/dL)	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.	Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days
Level of Each Pharmacodynamic Parameter at Specified Timepoints- Insulin (UIU/mL)	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.	Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days
Level of Each Pharmacodynamic Parameter at Specified Timepoints- Glycosylated Hemoglobin (HbA1c)	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.	Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days
Level of Each Pharmacodynamic Parameter at Specified Timepoints- Cholesterol (mg/dL)	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.	Baseline (Day -3) and Cycle1 to Cycle 3 where each cycle consist of 28 days
Level of Each Pharmacodynamic Parameter at Specified Timepoints- Triglycerides (mg/dL)	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.	Baseline (Day -3) and Cycle1 to Cycle 3 where each cycle consist of 28 days
Stathmin H Score [Mean (SD)] for Each Treatment Arm With Gene and/or Protein Expression Biomarkers in Biopsied Tumor Tissue	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.	Prior to Cycle 1 Day 1
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.	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.	Baseline and Cycle1 to Cycle 5 where each cycle consist of 28 days
Area Under the Serum Concentration Time Profile From Time Zero Extrapolated to Infinity (AUCinf) of PF-05212384 at Each Specified Time Points.		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.		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.		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.		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.		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.		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.		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	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.	From baseline (-3 days) until 35 days post last dose
Summary of Treatment-emergent Adverse Events (TEAEs) - All Causalities	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.	From baseline (-3 days) until 35 days post last dose
Number of Treatment-related TEAEs	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.	From baseline (-3 days) until 35 days post last dose
Summary of Treatment-related TEAEs	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.	From baseline (-3 days) until 35 days post last dose

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Del Campo JM, Birrer M, Davis C, Fujiwara K, Gollerkeri A, Gore M, Houk B, Lau S, Poveda A, Gonzalez-Martin A, Muller C, Muro K, Pierce K, Suzuki M, Vermette J, Oza A. A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Gynecol Oncol. 2016 Jul;142(1):62-69. doi: 10.1016/j.ygyno.2016.04.019. Epub 2016 Apr 24.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 19, 2012
• Primary Completion (ACTUAL): April 30, 2014
• Study Completion (ACTUAL): December 25, 2015

Study Registration Dates

• First Submitted: August 17, 2011
• First Submitted That Met QC Criteria: August 17, 2011
• First Posted (ESTIMATE): August 19, 2011

Study Record Updates

• Last Update Posted (ACTUAL): January 8, 2019
• Last Update Submitted That Met QC Criteria: December 19, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: cancer; metastatic; mTOR; recurrent; endometrial; PI3K; uterine; PI3K/mTOR; uterine neoplasms
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Endometrial Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Gedatolisib
• Other Study ID Numbers: B1271004; 2011-003062-32 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.