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

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

Detailed Description
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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.

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

Conditions
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Endometrial Neoplasms

Intervention / Treatment
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* Drug: PF-05212384
* Drug: PF-05212384
* Drug: PF-05212384


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: B<br>PI3K Basal, IV Compound | Drug: PF-05212384<br>* 154mg IV weekly<br>* Other names: PKI-587;|
| Experimental: C<br>PI3K Activated, Oral Compound | Drug: PF-05212384<br>* 154mg IV weekly<br>* Other names: PKI-587;|
| Experimental: F<br>Japanese lead in cohort, IV compound | Drug: PF-05212384<br>* 154mg IV weekly<br>* Other names: PKI-587;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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uterine, uterine neoplasms, endometrial, cancer, PI3K, mTOR, PI3K/mTOR, recurrent, metastatic