Pre-Operative Study of PF-4691502 With Letrozole Compared To Letrozole Alone In Patients With Early Breast Cancer

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01430585
• Collaborator: (none)
• Enrollment: 14
• Locations: 5
• Arms: 3
• Duration (Months): 9
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Early Breast Cancer (Phase 2); Advanced Breast Cancer (Phase 1b)	Drug: PF-04691502; Drug: PF-04691502 in combination with Letrozole; Drug: Letrozole	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A	Drug: PF-04691502; 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.
Experimental: B	Drug: PF-04691502 in combination with Letrozole; 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.
Active Comparator: C	Drug: Letrozole; 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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs): Phase 1B [Phase 1B: Baseline up to 28 days after last administration of study treatment]

   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.

2. Change From Baseline in Ki-67 Percent Positive Tumor Cells in Biopsied Tumor Tissue at Week 6: Phase 2 [Phase 2: Baseline, Week 6]

   Nuclear proliferation marker Ki-67 was to be assessed by immunohistochemistry technique in all specimens.

Secondary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs): Phase 2 [Phase 2: Baseline up to 28 days after last administration of study treatment]

   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.

2. Number of Participants With Clinically Significant Laboratory Tests Abnormalities: Phase 1B and 2 [Phase 1B: Baseline up to end of treatment (Week 34); Phase 2: Baseline up to Week 16 or early termination (ET)]

   Laboratory analysis planned to include blood chemistry, hematology and urinalysis.

3. Number of Participants With Clinically Significant Abnormalities in Vital Signs: Phase 1B and 2 [Phase 1B: Baseline up to 28 days after last dose of study treatment (Week 34); Phase 2: Baseline up to Week 16 or ET]

   Vital signs assessments planned to include measurement of blood pressure and heart rate.

4. Number of Participants With Clinically Significant Abnormalities in Corrected QT (QTc) Interval: Phase 1B [Phase 1B: Baseline up to end of treatment (Week 34)]

5. Number of Participants With Objective Response (OR): Phase 1B and 2 [Phase 1B: Baseline, Week 12, end of treatment (Week 34); Phase 2: Baseline, Week 6, 16 or ET]

   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.

6. Pharmacokinetic (PK) Parameters of PF-04691502 and Letrozole: Phase 1B and 2 [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]

   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.

7. Change From Baseline in Pharmacodynamic, Cell Proliferation and Survival Biomarkers in Biopsied Tumor Tissue at Week 2 and 6: Phase 2 [Phase 2: Baseline, Week 2, 6]

   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.

8. Number of Participants With Genetic Alterations: Phase 2 [Phase 2: Baseline, Week 2, 6]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Charleroi		Belgium	6000
2	Pfizer Investigational Site	Milano		Italy	20132
3	Pfizer Investigational Site	Barcelona		Spain	08035
4	Pfizer Investigational Site	Goteborg		Sweden	413 45
5	Pfizer Investigational Site	Stockholm		Sweden	171 76

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01430585
• Other Study ID Numbers: B1271003
• First Posted: Sep 8, 2011
• Last Update Posted: Aug 12, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by Pfizer: Ki-67; postmenopausal early breast cancer; ER positive/HER2 negative early breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Letrozole

Study Results

Participant Flow

Pre-assignment Detail	Due to premature termination of the study, the planned treatments of Phase 2, PF-04691502, then PF-04691502 + Letrozole (Phase 2), PF-04691502 + Letrozole (Phase 2) and Letrozole (Phase 2), were not administered.

Arm/Group Title	PF-04691502 + Letrozole (Phase 1B)
Arm/Group Description	Letrozole 2.5 milligram (mg) tablet orally on Day 1 followed by PF-04691502 8 mg tablet orally once daily from Day 2 until Day 11 and then a combination of PF-04691502 8 mg tablet and letrozole 2.5 mg tablet orally once daily from Day 12 until progression of disease, occurrence of unacceptable toxicity or withdrawal of consent. Dose of PF-04691502 was reduced to 6 mg orally once daily based on preliminary safety analysis conducted in the first 7 participants evaluable for safety.
Period Title: Overall Study
STARTED	14
COMPLETED	0
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	PF-04691502 + Letrozole (Phase 1B)
Arm/Group Description	Letrozole 2.5 milligram (mg) tablet orally on Day 1 followed by PF-04691502 8 mg tablet orally once daily from Day 2 until Day 11 and then a combination of PF-04691502 8 mg tablet and letrozole 2.5 mg tablet orally once daily from Day 12 until progression of disease, occurrence of unacceptable toxicity or withdrawal of consent. Dose of PF-04691502 was reduced to 6 mg orally once daily based on preliminary safety analysis conducted in the first 7 participants evaluable for safety.
Overall Participants	14
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60.5
Sex: Female, Male (Count of Participants)
Female	14 100%
Male	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs): Phase 1B
Description	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.
Time Frame	Phase 1B: Baseline up to 28 days after last administration of study treatment

Outcome Measure Data

Analysis Population Description

Safety analysis set included all enrolled participants who started study treatment.

Arm/Group Title	PF-04691502 + Letrozole (Phase 1B)
Arm/Group Description	Letrozole 2.5 milligram (mg) tablet orally on Day 1 followed by PF-04691502 8 mg tablet orally once daily from Day 2 until Day 11 and then a combination of PF-04691502 8 mg tablet and letrozole 2.5 mg tablet orally once daily from Day 12 until progression of disease, occurrence of unacceptable toxicity or withdrawal of consent. Dose of PF-04691502 was reduced to 6 mg orally once daily based on preliminary safety analysis conducted in the first 7 participants evaluable for safety.
Measure Participants	14
SAEs	7 50%
AEs	14 100%

2. Primary Outcome

Title	Change From Baseline in Ki-67 Percent Positive Tumor Cells in Biopsied Tumor Tissue at Week 6: Phase 2
Description	Nuclear proliferation marker Ki-67 was to be assessed by immunohistochemistry technique in all specimens.
Time Frame	Phase 2: Baseline, Week 6

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to premature termination of the study. No participant was enrolled in phase 2 of the study.

Arm/Group Title	PF-04691502, Then PF-04691502 + Letrozole (Phase 2)	PF-04691502 + Letrozole (Phase 2)	Letrozole (Phase 2)
Arm/Group Description	PF-04691502 6 mg tablet orally once daily up to Week 2 followed by combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.
Measure Participants	0	0	0

3. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs): Phase 2
Description	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.
Time Frame	Phase 2: Baseline up to 28 days after last administration of study treatment

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to premature termination of the study. No participant was enrolled in phase 2 of the study.

Arm/Group Title	PF-04691502, Then PF-04691502 + Letrozole (Phase 2)	PF-04691502 + Letrozole (Phase 2)	Letrozole (Phase 2)
Arm/Group Description	PF-04691502 6 mg tablet orally once daily up to Week 2 followed by combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.
Measure Participants	0	0	0

4. Secondary Outcome

Title	Number of Participants With Clinically Significant Laboratory Tests Abnormalities: Phase 1B and 2
Description	Laboratory analysis planned to include blood chemistry, hematology and urinalysis.
Time Frame	Phase 1B: Baseline up to end of treatment (Week 34); Phase 2: Baseline up to Week 16 or early termination (ET)

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to premature termination of the study. No participant was enrolled in phase 2 of the study.

Arm/Group Title	PF-04691502 + Letrozole (Phase 1B)	PF-04691502, Then PF-04691502 + Letrozole (Phase 2)	PF-04691502 + Letrozole (Phase 2)	Letrozole (Phase 2)
Arm/Group Description	Letrozole 2.5 milligram (mg) tablet orally on Day 1 followed by PF-04691502 8 mg tablet orally once daily from Day 2 until Day 11 and then a combination of PF-04691502 8 mg tablet and letrozole 2.5 mg tablet orally once daily from Day 12 until progression of disease, occurrence of unacceptable toxicity or withdrawal of consent. Dose of PF-04691502 was reduced to 6 mg orally once daily based on preliminary safety analysis conducted in the first 7 participants evaluable for safety.	PF-04691502 6 mg tablet orally once daily up to Week 2 followed by combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.
Measure Participants	0	0	0	0

5. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormalities in Vital Signs: Phase 1B and 2
Description	Vital signs assessments planned to include measurement of blood pressure and heart rate.
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

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to premature termination of the study. No participant was enrolled in phase 2 of the study.

Arm/Group Title	PF-04691502 + Letrozole (Phase 1B)	PF-04691502, Then PF-04691502 + Letrozole (Phase 2)	PF-04691502 + Letrozole (Phase 2)	Letrozole (Phase 2)
Arm/Group Description	Letrozole 2.5 milligram (mg) tablet orally on Day 1 followed by PF-04691502 8 mg tablet orally once daily from Day 2 until Day 11 and then a combination of PF-04691502 8 mg tablet and letrozole 2.5 mg tablet orally once daily from Day 12 until progression of disease, occurrence of unacceptable toxicity or withdrawal of consent. Dose of PF-04691502 was reduced to 6 mg orally once daily based on preliminary safety analysis conducted in the first 7 participants evaluable for safety.	PF-04691502 6 mg tablet orally once daily up to Week 2 followed by combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.
Measure Participants	0	0	0	0

6. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to premature termination of the study.

Arm/Group Title	PF-04691502 + Letrozole (Phase 1B)
Arm/Group Description	Letrozole 2.5 milligram (mg) tablet orally on Day 1 followed by PF-04691502 8 mg tablet orally once daily from Day 2 until Day 11 and then a combination of PF-04691502 8 mg tablet and letrozole 2.5 mg tablet orally once daily from Day 12 until progression of disease, occurrence of unacceptable toxicity or withdrawal of consent. Dose of PF-04691502 was reduced to 6 mg orally once daily based on preliminary safety analysis conducted in the first 7 participants evaluable for safety.
Measure Participants	0

7. Secondary Outcome

Title	Number of Participants With Objective Response (OR): Phase 1B and 2
Description	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.
Time Frame	Phase 1B: Baseline, Week 12, end of treatment (Week 34); Phase 2: Baseline, Week 6, 16 or ET

Outcome Measure Data

Analysis Population Description

Data for phase 1B was reported in individual participant listings but not statistically summarized for analysis due to premature termination of the study. No participant was enrolled in phase 2 of the study.

Arm/Group Title	PF-04691502 + Letrozole (Phase 1B)	PF-04691502, Then PF-04691502 + Letrozole (Phase 2)	PF-04691502 + Letrozole (Phase 2)	Letrozole (Phase 2)
Arm/Group Description	Letrozole 2.5 milligram (mg) tablet orally on Day 1 followed by PF-04691502 8 mg tablet orally once daily from Day 2 until Day 11 and then a combination of PF-04691502 8 mg tablet and letrozole 2.5 mg tablet orally once daily from Day 12 until progression of disease, occurrence of unacceptable toxicity or withdrawal of consent. Dose of PF-04691502 was reduced to 6 mg orally once daily based on preliminary safety analysis conducted in the first 7 participants evaluable for safety.	PF-04691502 6 mg tablet orally once daily up to Week 2 followed by combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.
Measure Participants	0	0	0	0

8. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters of PF-04691502 and Letrozole: Phase 1B and 2
Description	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.
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

Outcome Measure Data

Analysis Population Description

Data for phase 1B was reported in individual participant listings but not statistically summarized for analysis due to premature termination of the study. No participant was enrolled in phase 2 of the study.

Arm/Group Title	PF-04691502 + Letrozole (Phase 1B)	PF-04691502, Then PF-04691502 + Letrozole (Phase 2)	PF-04691502 + Letrozole (Phase 2)	Letrozole (Phase 2)
Arm/Group Description	Letrozole 2.5 milligram (mg) tablet orally on Day 1 followed by PF-04691502 8 mg tablet orally once daily from Day 2 until Day 11 and then a combination of PF-04691502 8 mg tablet and letrozole 2.5 mg tablet orally once daily from Day 12 until progression of disease, occurrence of unacceptable toxicity or withdrawal of consent. Dose of PF-04691502 was reduced to 6 mg orally once daily based on preliminary safety analysis conducted in the first 7 participants evaluable for safety.	PF-04691502 6 mg tablet orally once daily up to Week 2 followed by combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.
Measure Participants	0	0	0	0

9. Secondary Outcome

Title	Change From Baseline in Pharmacodynamic, Cell Proliferation and Survival Biomarkers in Biopsied Tumor Tissue at Week 2 and 6: Phase 2
Description	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.
Time Frame	Phase 2: Baseline, Week 2, 6

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to premature termination of the study. No participant was enrolled in phase 2 of the study.

Arm/Group Title	PF-04691502, Then PF-04691502 + Letrozole (Phase 2)	PF-04691502 + Letrozole (Phase 2)	Letrozole (Phase 2)
Arm/Group Description	PF-04691502 6 mg tablet orally once daily up to Week 2 followed by combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.
Measure Participants	0	0	0

10. Secondary Outcome

Title	Number of Participants With Genetic Alterations: Phase 2
Description	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.
Time Frame	Phase 2: Baseline, Week 2, 6

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to premature termination of the study. No participant was enrolled in phase 2 of the study.

Arm/Group Title	PF-04691502, Then PF-04691502 + Letrozole (Phase 2)	PF-04691502 + Letrozole (Phase 2)	Letrozole (Phase 2)
Arm/Group Description	PF-04691502 6 mg tablet orally once daily up to Week 2 followed by combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Combination of PF-04691502 6 mg tablet and letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.	Letrozole 2.5 mg tablet orally once daily up to Week 6 or 16 as per investigator's discretion.
Measure Participants	0	0	0

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	PF-04691502 + Letrozole (Phase 1B)
Arm/Group Description	Letrozole 2.5 milligram (mg) tablet orally on Day 1 followed by PF-04691502 8 mg tablet orally once daily from Day 2 until Day 11 and then a combination of PF-04691502 8 mg tablet and letrozole 2.5 mg tablet orally once daily from Day 12 until progression of disease, occurrence of unacceptable toxicity or withdrawal of consent. Dose of PF-04691502 was reduced to 6 mg orally once daily based on preliminary safety analysis conducted in the first 7 participants evaluable for safety.
All Cause Mortality
	PF-04691502 + Letrozole (Phase 1B)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	PF-04691502 + Letrozole (Phase 1B)
	Affected / at Risk (%)	# Events
Total	7/14 (50%)
Gastrointestinal disorders
Diarrhoea	2/14 (14.3%)
Stomatitis	1/14 (7.1%)
Vomiting	1/14 (7.1%)
General disorders
Death	1/14 (7.1%)
Disease progression	1/14 (7.1%)
General physical health deterioration	1/14 (7.1%)
Pyrexia	1/14 (7.1%)
Infections and infestations
Lung infection	1/14 (7.1%)
Pneumocystis jiroveci pneumonia	1/14 (7.1%)
Metabolism and nutrition disorders
Dehydration	1/14 (7.1%)
Diabetic ketoacidosis	1/14 (7.1%)
Hypoglycaemia	1/14 (7.1%)
Renal and urinary disorders
Urinary retention	1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/14 (7.1%)
Skin and subcutaneous tissue disorders
Rash	2/14 (14.3%)
Rash maculo	2/14 (14.3%)
Toxic skin eruption	1/14 (7.1%)
Other (Not Including Serious) Adverse Events
	PF-04691502 + Letrozole (Phase 1B)
	Affected / at Risk (%)	# Events
Total	14/14 (100%)
Blood and lymphatic system disorders
Neutropenia	2/14 (14.3%)
Anaemia	1/14 (7.1%)
Polycythaemia	1/14 (7.1%)
Cardiac disorders
Angina pectoris	1/14 (7.1%)
Eye disorders
Conjunctivitis	1/14 (7.1%)
Gastrointestinal disorders
Diarrhoea	8/14 (57.1%)
Nausea	7/14 (50%)
Stomatitis	7/14 (50%)
Dyspepsia	4/14 (28.6%)
Vomiting	4/14 (28.6%)
Abdominal pain upper	1/14 (7.1%)
Constipation	1/14 (7.1%)
Haemorrhoids	1/14 (7.1%)
Oral discomfort	1/14 (7.1%)
Oral pain	1/14 (7.1%)
General disorders
Fatigue	6/14 (42.9%)
Asthenia	3/14 (21.4%)
Chills	3/14 (21.4%)
Mucosal inflammation	3/14 (21.4%)
Catheter site related reaction	1/14 (7.1%)
Early satiety	1/14 (7.1%)
General physical health deterioration	1/14 (7.1%)
Oedema peripheral	1/14 (7.1%)
Pyrexia	1/14 (7.1%)
Infections and infestations
Urinary tract infection	3/14 (21.4%)
Gastroenteritis	2/14 (14.3%)
Asymptomatic bacteriuria	1/14 (7.1%)
Escherichia urinary tract infection	1/14 (7.1%)
Infection	1/14 (7.1%)
Oesophageal candidiasis	1/14 (7.1%)
Oral fungal infection	1/14 (7.1%)
Injury, poisoning and procedural complications
Contusion	1/14 (7.1%)
Investigations
Blood creatinine increased	2/14 (14.3%)
Blood insulin increased	2/14 (14.3%)
Weight decreased	2/14 (14.3%)
Alanine aminotransferase increased	1/14 (7.1%)
Aspartate aminotransferase increased	1/14 (7.1%)
Blood lactate dehydrogenase increased	1/14 (7.1%)
Blood urine present	1/14 (7.1%)
Platelet count decreased	1/14 (7.1%)
Metabolism and nutrition disorders
Hyperglycaemia	8/14 (57.1%)
Decreased appetite	7/14 (50%)
Hypokalaemia	4/14 (28.6%)
Hyponatraemia	2/14 (14.3%)
Dehydration	1/14 (7.1%)
Diabetes mellitus	1/14 (7.1%)
Fluid retention	1/14 (7.1%)
Folate deficiency	1/14 (7.1%)
Hypermagnesaemia	1/14 (7.1%)
Hyperuricaemia	1/14 (7.1%)
Hypoalbuminaemia	1/14 (7.1%)
Vitamin D deficiency	1/14 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/14 (21.4%)
Back pain	2/14 (14.3%)
Musculoskeletal pain	2/14 (14.3%)
Bone pain	1/14 (7.1%)
Myalgia	1/14 (7.1%)
Nervous system disorders
Headache	4/14 (28.6%)
Dizziness	2/14 (14.3%)
Tremor	1/14 (7.1%)
Psychiatric disorders
Agitation	1/14 (7.1%)
Confusional state	1/14 (7.1%)
Renal and urinary disorders
Dysuria	1/14 (7.1%)
Oliguria	1/14 (7.1%)
Proteinuria	1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
Cough	4/14 (28.6%)
Dyspnoea	3/14 (21.4%)
Oropharyngeal pain	1/14 (7.1%)
Pulmonary embolism	1/14 (7.1%)
Skin and subcutaneous tissue disorders
Pruritus	6/14 (42.9%)
Rash	5/14 (35.7%)
Dry skin	3/14 (21.4%)
Erythema	2/14 (14.3%)
Alopecia	1/14 (7.1%)
Blister	1/14 (7.1%)
Decubitus ulcer	1/14 (7.1%)
Dermatitis acneiform	1/14 (7.1%)
Hair texture abnormal	1/14 (7.1%)
Onychoclasis	1/14 (7.1%)
Rash papular	1/14 (7.1%)
Skin exfoliation	1/14 (7.1%)
Toxic skin eruption	1/14 (7.1%)
Vascular disorders
Hot flush	2/14 (14.3%)
Lymphoedema	1/14 (7.1%)
Thrombophlebitis	1/14 (7.1%)
Varicose vein	1/14 (7.1%)

Limitations/Caveats

Study was prematurely terminated due to PF-04691502 tolerability findings that prompted Sponsor to re-evaluate strategic goals of program. Unexpected frequency of severe skin toxicity was observed and no participant was enrolled in phase 2 of study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.