A Study Of Two Dual PI3K/mTOR Inhibitors, PF-04691502 And PF-05212384 In Patients With Recurrent Endometrial Cancer
- Registration Number
- NCT01420081
- Lead Sponsor
- Pfizer
- Brief Summary
This study will investigate the individual safety and efficacy of two dual PI3K/mTOR inhibitors in patients with recurrent endometrial cancer.
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- Female
- Target Recruitment
- 67
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description B PF-05212384 PI3K Basal, IV Compound C PF-05212384 PI3K Activated, Oral Compound F PF-05212384 Japanese lead in cohort, IV compound
- Primary Outcome Measures
Name Time Method Clinical Benefit Response for PF-04691502 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 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
Name Time Method Objective Response for PF-04691502 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 Progression Free Survival (PFS) at 6 Months for PF-05212384 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 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) 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) 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.
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 Percentage of Participants With Objective Response for PF-05212384 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 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 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.
Level of Each Pharmacodynamic Parameter at Specified Timepoints- Insulin (UIU/mL) 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) 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- Triglycerides (mg/dL) 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 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.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 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. 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.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 Number of Treatment-emergent Adverse Events (TEAEs) - All Causalities 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 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 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 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.
Trial Locations
- Locations (47)
University of Kansas Cancer Center and Medical Pavilion
🇺🇸Westwood, Kansas, United States
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
Mercy Hospital
🇺🇸Miami, Florida, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
University of Kansas Hospital
🇺🇸Kansas City, Kansas, United States
Fundacion Instituto Valenciano de Oncologia - I.V.O.
🇪🇸Valencia, Spain
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital
🇺🇸New Lenox, Illinois, United States
Mary Bird Perkins Cancer Center at St. Tammany Parish Hospital
🇺🇸Covington, Louisiana, United States
Women's Cancer Care
🇺🇸Metairie, Louisiana, United States
Fundacion Instituto Valenciano de Oncologia - I.V.O
🇪🇸Valencia, Spain
Centro Oncologico MD Anderson Internacional España
🇪🇸Madrid, Spain
Mercy Research Institute
🇺🇸Miami, Florida, United States
Hospital Universitari Vall d'hebron
🇪🇸Barcelona, Spain
The Royal Marsden NHS Foundation Trust
🇬🇧London, United Kingdom
University College London Hospital NHS Foundation Trust
🇬🇧London, United Kingdom
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Zaklad Radiologii
🇵🇱Lodz, Poland
Beatson Oncology Centre
🇬🇧Glasgow, United Kingdom
Hospital Clinico San Carlos
🇪🇸Madrid, Spain
Saint Petersburg State Healthcare Institution City Clinical Oncology Dispensary
🇷🇺Saint Petersburg, Russian Federation
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
Royal Victoria Hospital
🇨🇦Montreal, Quebec, Canada
St. Mary's Hospital
🇨🇦Montreal, Quebec, Canada
Moores UC San Diego Cancer Center
🇺🇸La Jolla, California, United States
University of Alabama at Birmingham, IDS Pharmacy
🇺🇸Birmingham, Alabama, United States
University of California Medical Center
🇺🇸San Diego, California, United States
University of Kansas
🇺🇸Fairway, Kansas, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Peter MacCallum Cancer Centre, Division of Cancer Madicine
🇦🇺East Melbourne, Victoria, Australia
Foothills Medical Center
🇨🇦Calgary, Alberta, Canada
Cancer Centre of Southeastern Ontario at Kingston General Hospital
🇨🇦Kingston, Ontario, Canada
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Hyogo Cancer Center
🇯🇵Akashi, Hyogo, Japan
Aichi cancer center hospital
🇯🇵Nagoya, Aichi, Japan
National Cancer Center Hospital
🇯🇵Chuo-Ku, Tokyo, Japan
Saitama Medical University International Medical Center
🇯🇵Hidaka, Saitama, Japan
Regionalny Osrodek Onkologiczny Wojewodzki Szpital Specjalistyczny im. M. Kopernika
🇵🇱Lodz, Poland
Federal State Healthcare Institution
🇷🇺Lermontov, Stavropol Territory, Russian Federation
Pyatigorsk Oncology Center
🇷🇺Pyatigorsk, Russian Federation
Clinical Oncology Dispensary 1 of Department of Healthcare of the Krasnodar Region
🇷🇺Krasnodar, Russian Federation
Centrum Onkologii Ziemi Lubelskiej im. Św. Jana z Dukli
🇵🇱Lublin, Poland
British Columbia Cancer Agency - Vancouver Centre
🇨🇦Vancouver, British Columbia, Canada