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

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.

Time frame: 16 weeks from Cycle 1 Day 1

Population: Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.

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.

Time frame: 16 weeks from Cycle 1 Day 1

Population: Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.

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

Population: Participants were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.

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

Population: Participants were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.

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

Population: Participants were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.

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.

Time frame: Baseline (Day -3) and Cycle1 to Cycle 3 where each cycle consist of 28 days

Population: Participants were analyzed on PD analysis set which consisted of all enrolled patients who started treatment and had a baseline as well as at least one post-baseline measurement for at least one PD biomarker. The PD biomarkers include serum glucose, insulin, HbA1c, cholesterol, and triglycerides.

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.

Time frame: Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days

Population: Participants were analyzed on PD analysis set which consisted of all enrolled patients who started treatment and had a baseline as well as at least one post-baseline measurement for at least one PD biomarker. The PD biomarkers include serum glucose, insulin, HbA1c, cholesterol, and triglycerides.

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.

Time frame: Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days

Population: participants were analyzed on PD analysis set which consisted of all enrolled patients who started treatment and had a baseline as well as at least one post-baseline measurement for at least one PD biomarker. The PD biomarkers include serum glucose, insulin, HbA1c, cholesterol, and triglycerides.

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.

Time frame: Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days

Population: Participants were analyzed on PD analysis set which consisted of all enrolled patients who started treatment and had a baseline as well as at least one post-baseline measurement for at least one PD biomarker. The PD biomarkers include serum glucose, insulin, HbA1c, cholesterol, and triglycerides.

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.

Time frame: Baseline (Day -3) and Cycle1 to Cycle 3 where each cycle consist of 28 days

Population: Participants were analyzed on PD analysis set which consisted of all enrolled patients who started treatment and had a baseline as well as at least one post-baseline measurement for at least one PD biomarker. The PD biomarkers include serum glucose, insulin, HbA1c, cholesterol, and triglycerides.

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

Population: Participants were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.

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.

Time frame: From baseline (-3 days) until 35 days post last dose

Population: Participants were analyzed on safety analysis set which was defined as all enrolled patients who started treatment.

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.

Time frame: From baseline (-3 days) until 35 days post last dose

Population: Participants were analyzed on safety analysis set which was defined as all enrolled patients who started treatment.

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.

Time frame: Randomization to objective progression, death or last tumor assessment without progression (up to 12 months)

Population: Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.

OS is defined as the time from the date of Cycle 1 Day 1 to the date of death.

Time frame: 12 months

Population: Survival analysis was not performed as the study was terminated early. No data are available because data were not collected. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.

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 frame: Baseline and Cycle1 to Cycle 5 where each cycle consist of 28 days

Population: Participants were analyzed as the molecular profiling tumor analysis set was defined as all enrolled patients who started treatment and had baseline tumor tissues (archived paraffin block or unstained slides or fresh tumor tissue sample) successfully analyzed for at least one of the biomarkers.

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.

Time frame: Randomization to objective progression, death or last tumor assessment without progression (up to 12 months)

Population: Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.

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.

Time frame: 6 months

Population: Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.

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.

Time frame: From Cycle 1 Day 1 to objective progressive disease or death due to any cause whichever occurs first (up to 12 months)

Population: Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.

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.

Time frame: From Cycle 1 Day 1 to objective progressive disease or death due to any cause whichever occurs first (up to 12 months)

Population: Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.

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.

Time frame: Prior to Cycle 1 Day 1

Population: Participants were analyzed as the molecular profiling tumor analysis set was defined as all enrolled patients who started treatment and had baseline tumor tissues (archived paraffin block or unstained slides or fresh tumor tissue sample) successfully analyzed for at least one of the biomarkers.

Time frame: Pre-dose: 0 hours, and Post dose: 0.5 (after end of infusion), 1, 2, 4, 6, 24, 72, and 120 hours

Population: Participants were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.

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.

Time frame: From baseline (-3 days) until 35 days post last dose

Population: Participants were analyzed on safety analysis set which was defined as all enrolled patients who started treatment.

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.

Time frame: From baseline (-3 days) until 35 days post last dose

Population: Participants were analyzed on safety analysis set which was defined as all enrolled patients who started treatment.

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

Population: Participants were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.

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

Population: Participants were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.