- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01430585
Pre-Operative Study of PF-4691502 With Letrozole Compared To Letrozole Alone In Patients With Early Breast Cancer
July 18, 2014 updated by: Pfizer
An Open-Label, Randomised Phase 1b/2 Study Of PF-04691502 In Combination With Letrozole Compared With Letrozole Alone In Patients With Estrogen Receptor Positive, Her-2 Negative Early Breast Cancer
PF-04691502 is an inhibitor of PI3K and mTOR kinase.
Published data support the hypothesis that a PI3K/mTOR antagonist in combination with letrozole might mitigate the intrinsic or acquired resistance to hormonal therapy and restore hormone sensitivity in high risk (high Ki-67) patient population of hormone-sensitive breast cancers.
In addition, Ki-67, a marker of cellular proliferation, could be used to select those patients who benefit from treatment with a PI3K-pathway inhibitor.
Study Overview
Status
Terminated
Intervention / Treatment
Detailed Description
The study was prematurely discontinued on 09Oct2012 due to the tolerability findings in 2 clinical studies testing PF-04691502 that have prompted the Sponsor to re-evaluate the strategic goals of the program.
In the study B1271003 an unexpected frequency of severe skin toxicity was observed and in the study B1271004 5 cases of drug induced pneumonitis were reported.
Study Type
Interventional
Enrollment (Actual)
14
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Charleroi, Belgium, 6000
- Pfizer Investigational Site
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Milano, Italy, 20132
- Pfizer Investigational Site
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Barcelona, Spain, 08035
- Pfizer Investigational Site
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Goteborg, Sweden, 413 45
- Pfizer Investigational Site
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Stockholm, Sweden, 171 76
- Pfizer Investigational Site
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
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:
- Phase 1 - Postmenopausal women with diagnosis of breast cancer, metastatic disease or locally advanced disease / Estrogen Receptor positive and HER-2 negative / candidate to receive Letrozole
- Phase 2 - Postmenopausal women with newly diagnosed primary breast cancer / Estrogen Receptor positive and HER-2 negative / Ki-67 levels >10% positive cells
- Phase 1 & 2 - Glucose control, adequate bone marrow, liver, renal, and cardiac function
Exclusion Criteria:
- Inflammatory carcinoma / Prior therapy with an agent active on PI3K and/or mTOR / Significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drugs / Current or anticipated need for food or drugs that are known inhibitors or inducers of CYP3A4
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: A
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PF-04691502 administered as single agent for 2 weeks.
After this period, patients in this arm will take PF-04691502 in combination with Letrozole until Week 6.
Beyond Week 6, if considered appropriate, patients can be treated with the combination for up to 10 additional weeks until breast surgery.
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Experimental: B
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PF-04691502 in combination with Letrozole will be administered for 6 weeks.
Beyond Week 6, if considered appropriate, patients can be treated for up to 10 additional weeks until breast surgery.
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Active Comparator: C
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Letrozole will be administered for 6 weeks.
Beyond Week 6, if considered appropriate, patients can be treated for up to 10 additional weeks until breast surgery.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs): Phase 1B
Time Frame: Phase 1B: Baseline up to 28 days after last administration of study treatment
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An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship.
SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Treatment-emergent are events between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
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Phase 1B: Baseline up to 28 days after last administration of study treatment
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Change From Baseline in Ki-67 Percent Positive Tumor Cells in Biopsied Tumor Tissue at Week 6: Phase 2
Time Frame: Phase 2: Baseline, Week 6
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Nuclear proliferation marker Ki-67 was to be assessed by immunohistochemistry technique in all specimens.
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Phase 2: Baseline, Week 6
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs): Phase 2
Time Frame: Phase 2: Baseline up to 28 days after last administration of study treatment
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An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship.
SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Treatment-emergent are events between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
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Phase 2: Baseline up to 28 days after last administration of study treatment
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Number of Participants With Clinically Significant Laboratory Tests Abnormalities: Phase 1B and 2
Time Frame: Phase 1B: Baseline up to end of treatment (Week 34); Phase 2: Baseline up to Week 16 or early termination (ET)
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Laboratory analysis planned to include blood chemistry, hematology and urinalysis.
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Phase 1B: Baseline up to end of treatment (Week 34); Phase 2: Baseline up to Week 16 or early termination (ET)
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Number of Participants With Clinically Significant Abnormalities in Vital Signs: Phase 1B and 2
Time Frame: Phase 1B: Baseline up to 28 days after last dose of study treatment (Week 34); Phase 2: Baseline up to Week 16 or ET
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Vital signs assessments planned to include measurement of blood pressure and heart rate.
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Phase 1B: Baseline up to 28 days after last dose of study treatment (Week 34); Phase 2: Baseline up to Week 16 or ET
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Number of Participants With Clinically Significant Abnormalities in Corrected QT (QTc) Interval: Phase 1B
Time Frame: Phase 1B: Baseline up to end of treatment (Week 34)
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Phase 1B: Baseline up to end of treatment (Week 34)
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Number of Participants With Objective Response (OR): Phase 1B and 2
Time Frame: Phase 1B: Baseline, Week 12, end of treatment (Week 34); Phase 2: Baseline, Week 6, 16 or ET
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Number of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST).
CR was defined as complete disappearance of all target lesions and non-target lesions, with the exception of nodal disease.
All nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 millimeter [mm]).
No appearance of new lesions and normalization of tumor marker levels.
PR was defined as greater than or equal to (>=) 30 percent (%) decrease from baseline of the sum of diameters of all target lesions, using the short diameter in the sum for target nodes and the longest diameter in the sum for all other target lesions.
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Phase 1B: Baseline, Week 12, end of treatment (Week 34); Phase 2: Baseline, Week 6, 16 or ET
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Pharmacokinetic (PK) Parameters of PF-04691502 and Letrozole: Phase 1B and 2
Time Frame: Phase 1B: 0 (pre-dose), 1, 2, 4, 6, 24 hours on Day 1 (letrozole alone), Day 2 (PF-0491502 alone), Day 12, Week 5 (PF-0491502 and letrozole in combination); Phase 2: 0 (pre-dose), 1, 2, 4, 6, 24 hours on Day 1, pre-dose on Week 2, 6
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Phase 1B: Following PK parameters were planned to be calculated from the plasma concentration time data using standard non-compartmental methods.
For PF-04691502: area under the curve from time zero to last quantifiable concentration (AUClast), area under the curve from time zero to end of dosing interval (AUCtau), maximum observed plasma concentration (Cmax), minimum observed plasma trough concentration (Cmin), average plasma concentration (Cavg), time to reach maximum observed plasma concentration (Tmax), observed accumulation ratio (Rac [obs]); for letrozole: AUClast, Cmax.
Phase 2: Following PK parameters were planned to be calculated for PF-04691502 from the plasma concentration time data using standard non-compartmental methods- AUClast, Cmax and Tmax.
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Phase 1B: 0 (pre-dose), 1, 2, 4, 6, 24 hours on Day 1 (letrozole alone), Day 2 (PF-0491502 alone), Day 12, Week 5 (PF-0491502 and letrozole in combination); Phase 2: 0 (pre-dose), 1, 2, 4, 6, 24 hours on Day 1, pre-dose on Week 2, 6
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Change From Baseline in Pharmacodynamic, Cell Proliferation and Survival Biomarkers in Biopsied Tumor Tissue at Week 2 and 6: Phase 2
Time Frame: Phase 2: Baseline, Week 2, 6
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Change from baseline in following pharmacodynamic parameters were planned to be calculated: expression and/or phosphorylation of Phosphoinositide-3-kinase (PI3K) pathway proteins in biopsied tumor tissue and markers of cell cycle and survival.
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Phase 2: Baseline, Week 2, 6
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Number of Participants With Genetic Alterations: Phase 2
Time Frame: Phase 2: Baseline, Week 2, 6
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Following genetic alterations were planned to be analyzed: mutations in Phosphoinositide 3-kinase, catalytic, alpha (PIK3CA), amplification of PIK3CA, Phosphate and tensin homolog (PTEN) deficiency, and changes in other genes or proteins in, or impacting V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), Insulin-like Growth Factor 1 Receptor (IGF-1R), phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway.
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Phase 2: Baseline, Week 2, 6
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
March 1, 2012
Primary Completion (Actual)
December 1, 2012
Study Completion (Actual)
December 1, 2012
Study Registration Dates
First Submitted
August 18, 2011
First Submitted That Met QC Criteria
September 6, 2011
First Posted (Estimate)
September 8, 2011
Study Record Updates
Last Update Posted (Estimate)
August 12, 2014
Last Update Submitted That Met QC Criteria
July 18, 2014
Last Verified
July 1, 2014
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Skin Diseases
- Neoplasms
- Neoplasms by Site
- Breast Diseases
- Breast Neoplasms
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Hormone Antagonists
- Aromatase Inhibitors
- Steroid Synthesis Inhibitors
- Estrogen Antagonists
- Letrozole
Other Study ID Numbers
- B1271003
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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