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

Endometrial Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01420081
• Other study ID #: B1271004
• Secondary ID: 2011-003062-32
• Status: Terminated
• Phase: Phase 2
• Start date: January 19, 2012
• Est. completion date: December 25, 2015

Study information

• Verified date: December 2018
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Terminated
• Enrollment: 67
• Est. completion date: December 25, 2015
• Est. primary completion date: April 30, 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Endometrial Neoplasms

Intervention

Drug:
• PF-05212384
154mg IV weekly
• PF-05212384
154mg IV weekly
• PF-05212384
154mg IV weekly

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre, Division of Cancer Madicine	East Melbourne	Victoria
Canada	Foothills Medical Center	Calgary	Alberta
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Royal Victoria Hospital	Montreal	Quebec
Canada	St. Mary's Hospital	Montreal	Quebec
Canada	Princess Margaret Hospital	Toronto	Ontario
Canada	British Columbia Cancer Agency - Vancouver Centre	Vancouver	British Columbia
Japan	Hyogo Cancer Center	Akashi	Hyogo
Japan	National Cancer Center Hospital	Chuo-Ku	Tokyo
Japan	Saitama Medical University International Medical Center	Hidaka	Saitama
Japan	Aichi cancer center hospital	Nagoya	Aichi
Poland	Regionalny Osrodek Onkologiczny Wojewodzki Szpital Specjalistyczny im. M. Kopernika	Lodz
Poland	Zaklad Radiologii	Lodz
Poland	Centrum Onkologii Ziemi Lubelskiej im. Sw. Jana z Dukli	Lublin
Russian Federation	Clinical Oncology Dispensary 1 of Department of Healthcare of the Krasnodar Region	Krasnodar
Russian Federation	Federal State Healthcare Institution	Lermontov	Stavropol Territory
Russian Federation	Pyatigorsk Oncology Center	Pyatigorsk
Russian Federation	Saint Petersburg State Healthcare Institution City Clinical Oncology Dispensary	Saint Petersburg
Spain	Hospital Universitari Vall d'hebron	Barcelona
Spain	Centro Oncologico MD Anderson Internacional España	Madrid
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Fundacion Instituto Valenciano de Oncologia - I.V.O	Valencia
Spain	Fundacion Instituto Valenciano de Oncologia - I.V.O.	Valencia
United Kingdom	Beatson Oncology Centre	Glasgow
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	University College London Hospital NHS Foundation Trust	London
United Kingdom	The Royal Marsden NHS Foundation Trust	Sutton	Surrey
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	University of Alabama at Birmingham, IDS Pharmacy	Birmingham	Alabama
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Mary Bird Perkins Cancer Center at St. Tammany Parish Hospital	Covington	Louisiana
United States	Women's Cancer Care	Covington	Louisiana
United States	University of Kansas	Fairway	Kansas
United States	University of Kansas Hospital	Kansas City	Kansas
United States	Moores UC San Diego Cancer Center	La Jolla	California
United States	University of California Medical Center	La Jolla	California
United States	Women's Cancer Care	Metairie	Louisiana
United States	Mercy Hospital	Miami	Florida
United States	Mercy Research Institute	Miami	Florida
United States	University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital	New Lenox	Illinois
United States	University of California Medical Center	San Diego	California
United States	University of Kansas Cancer Center and Medical Pavilion	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Japan,  Poland,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

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