| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ESTROGEN RECEPTOR POSITIVE, HER-2 NEGATIVE EARLY BREAST CANCER WITH KI-67 HIGHER THAN 10% |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10070575 |
| E.1.2 | Term | Estrogen receptor positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1B: To assess the tolerability of PF-04691502 combined with letrozole in postmenopausal patients with ER positive, HER 2 negative advanced breast cancer.
Phase 2: To compare the change in Ki-67 value from baseline to Week 6 in matched tumor biopsies from patients with ER positive, HER-2 negative early breast cancer treated with PF-04691502 in combination with letrozole or letrozole alone. |
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| E.2.2 | Secondary objectives of the trial |
Phase 1B: • evaluate the safety profile of PF-04691502 in combination with letrozole.
• evaluate the pharmacokinetics (PK) of PF-0461502 and letrozole when administered alone and in combination.
• characterize the effects, if any, of PF-0461502 combined with letrozole on QTc interval.
• explore preliminary anti-tumor activity of PF-04691502 combined with letrozole
Phase 2: • To evaluate the overall safety profile of the 2 regimens.
• explore tumor response in patients treated with the 2 regimens.
• evaluate the PK of PF-0461502 when given alone and in combination with letrozole.
• explore the pharmacodynamic effect of the 2 regimens in tumor tissue at the 2 week time point and at the 6 week time point as compared to baseline.
• evaluate genetic alterations, RNA and/or protein changes at baseline and after treatment with the 2 regimens, to explore novel patient selection biomarkers in ER positive, HER-2 negative early breast cancers.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. For patients enrolled in the Phase 1B - Lead-in portion:
• Postmenopausal female patients with histologically or cytologically proven diagnosis of breast cancer with evidence of metastatic disease or locally advanced disease, not amenable to resection or radiation therapy with curative intent.
• ER positive and HER-2 negative breast cancer (ie, immunohistochemistry (IHC) 0 or 1+; if IHC 2+, FISH or CISH negative).
• Measurable or non measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST).
• Patients must be candidates to receive letrozole as standard of care.
2. For patients enrolled in the Phase 2:
• Postmenopausal women with newly diagnosed primary breast cancer.
• ER positive and HER-2 negative breast cancer (ie, IHC 0 or 1+; if IHC 2+, FISH or CISH negative).
• Tumor size ≥2 cm (as measured by ultrasound or MRI).
• Ki-67 levels >10% positive cells determined by IHC at a central laboratory designated by the Sponsor.
• Sufficient tumor tissue from baseline core biopsies to enable testing of biomarkers
For patients enrolled in Phase 1b and Phase 2:
3. ECOG Performance Status 0, or 1.
4. Adequate organ function as defined by the following criteria:
• Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L.
• Platelets ≥100,000/mm3 or ≥100 x 109/L.
• Hemoglobin ≥9 g/dL.
• Fasting blood glucose ≤ 126 mg /dL
• Serum Aspartate Transaminase (AST) and serum Alanine Aminotransferase Transaminase (ALT) ≤2.5 x upper limit of normal (ULN).
• Alkaline phosphatase ≤2.5 x ULN.
• Total serum bilirubin ≤1 x ULN.
• Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as calculated using the method standard for the institution.
5. Adequate cardiac function, including:
• 12 Lead electrocardiogram (ECG) with normal tracing or non clinically significant changes that do not require medical intervention.
• QTc interval ≤470 msec (mean of replicate values, correction per institutional standard) and no history of Torsades des Pointes or other symptomatic QTc abnormality.
6. Resolution of all acute toxic effects of prior therapy or surgical procedures to grade ≤1.
7. At least 2 weeks since any prior hormone replacement therapy or phyto oestrogens herbal alternatives, or OTC sex hormone remedies.
8. Evidence of a personally signed and dated informed consent form document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment.
9. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
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| E.4 | Principal exclusion criteria |
1. Patients who are investigational site staff members or patients who are Pfizer employees directly involved in the conduct of the trial.
2. Clinical presentation of inflammatory carcinoma.
3. (For patients enrolled in the Phase 2) Patients unwilling to undergo core biopsies after 2 and 6 weeks of treatment.
4. (For patients enrolled in the Phase 1B - Lead-in portion) Presence of active brain metastases, presence of spinal cord compression, or carcinomatous meningitis, or leptomeningeal disease. Patients with previously diagnosed brain metastases are eligible if they have completed their CNS treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.
5. Prior therapy with an agent that is known or proposed to be active by action on PI3K and/or mTOR.
6. Known hypersensitivity to letrozole or to any of the excipients.
7. Any surgery (not including minor procedures such as lymph node biopsy, primary tumor core biopsy, fine needle aspiration) within 4 weeks of start of study treatment; or not fully recovered from any side effects of previous procedures.
8. Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell carcinoma, or squamous cell skin carcinoma, or in situ cervical carcinoma.
9. Current use or anticipated need for food or drugs that are known potent CYP3A4 inhibitors.
10. Current or anticipated need for food or drugs that are known potent CYP3A4 inducers.
11. Concurrent administration of herbal preparations.
12. Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drugs, such as the inability to take oral medication in tablet form and malabsorption syndrome.
13. Any mental disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol.
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and in the judgement of the investigator would make the patient inappropriate for entry into this study.
15. Participation in other studies within 4 weeks before the current study begins and/or during study participation. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint Phase 1B (Lead-in portion): Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.0) timing, seriousness and relationship to study therapy
Primary Endpoint - Phase 2: Ki 67 (% positive tumor cells) as tested by IHC (central lab).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Phase 1B - The primary end point is Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAEv.4.0) timing, seriousness and relationship to study therapy. The timepoint of evaluation of adverse event is through continous monitoring until up to 28 days after last dose of study treatment or until a new antitumor agent is administered. Phase 2 - The primary end point Ki-67 (% positive tumor cells) as tested by IHC (central lab). The timepoint is baseline, week 2 and Week 6. |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints Phase 1B (Lead-in portion):
a) Laboratory test abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.0) and timing.
b) Vital Signs.
c) QTc Interval.
d) PK parameters of PF-04691502 and letrozole when administered alone and in combination.
e) Objective tumor response.
Secondary Endpoints - Phase 2:
a) Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.0) timing, seriousness and relationship to study therapy.
b) Laboratory test abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.0) and timing.
c) Vital Signs.
d) Objective tumor response.
e) PK parameters of PF-04691502 when administered alone and in combination with letrozole.
f) Expression levels of PI3K pathway proteins (eg, pAKT, pS6, stathmin) and markers of cellular proliferation and survival (eg, Ki 67, apoptosis assays) in biopsied tumor tissue.
g) Genetic alteration, RNA and protein expression data in biopsied tumor tissue relating to PI3K pathway signaling (eg, PIK3CA, AKT mutations, PIK3CA amplification, PTEN protein levels) and other pathways relevant to the biology of ER positive, HER 2 negative early breast cancer. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1B:
a) baseline, day 1, week 3, week 5, week 7, every 4 weeks between weeks 9 and 52. SOC beyond 52 weeks
b) baseline, day 1, week 3, week 5, week 7, every 4 weeks between weeks 9 and 52. SOC beyond 52 weeks
c) baseline, day 1, day 2, day 12, end of treatment
d) day 1, day 2, day 12
e) baseline, week 12, week 36 and as per SOC at the EOT
Phase 2:
a) continous
b) baseline, day 1 and instead of/or week 6/EOT
c) baseline, day 1, week 6/EOT, follow up
d) baseline, week 6/EOT
e) day 1, week 2 and week 6/EOT (Only patients treated with PF-04691502 and PF-04691502 combined with letrozole)
f) baseline, week 2 and week 6/EOT
g) baseline, week 2 and week 6/EOT |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| evaluate combination treatment of PF-04691502 and Letrozole |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| European Union |
| Switzerland |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| End of Trial in all participating countries is defined as last patient having the End of Treatment visit. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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