| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RECURRENT ENDOMETRIAL CANCER |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced tumour of the uterus |
|
| 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 | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014736 |
| E.1.2 | Term | Endometrial cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• Arm A: To assess the clinical benefit rate (CBR) of the oral PI3K/mTOR inhibitor PF-04691502 in patients with recurrent endometrial cancer which is classified as PI3K basal.
• Arm B: To assess the clinical benefit rate of the intravenous PI3K/mTOR inhibitor PF-05212384 in patients with recurrent endometrial cancer that is classified as PI3K basal.
• Arm C: To assess the clinical benefit rate of the oral PI3K/mTOR inhibitor PF-04691502 in patients with recurrent endometrial cancer which is classified as PI3K activated.
• Arm D: To assess the clinical benefit rate of the intravenous PI3K/mTOR inhibitor PF-05212384 in patients with recurrent endometrial cancer that is classified as PI3K activated.
|
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the anti-tumor activity of PF-04691502 and PF-05212384 individually in patients with PI3K basal and PI3K activated tumors.
• To further characterize the safety of PF-04691502 and PF-05212384 individually.
• To characterize the pharmacokinetics for PF-04691502 and PF-05212384 individually.
• To characterize genetic and protein biomarkers of PI3K pathway alterations (PIK3CA mutation, PTEN protein levels, etc) in FFPE tumor specimens.
• To explore the modulation of PI3K and mTOR pathways in pre and post dosing biopsies. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Women aged ≥18 years.
2. Histologically or cytologically confirmed diagnosis of endometrial carcinoma.
3. Recurrent endometrial cancer that is not amenable to curative surgery and/or radiation.
4. All patients must have tumor tissue available for central analysis of PI3K pathway activation status, performed by the sponsor-identified central laboratory prior to enrollment. Formalin fixed paraffin embedded (FFPE) block preferred, but freshly cut slides are acceptable.
5. Disease progression on or following a platinum containing chemotherapy regimen (alone or in combination with radiation or hormonal therapy) for the treatment of endometrial cancer in the adjuvant or metastatic setting. Patients must not have progression during or immediately following (within 3 months) this regimen.
6. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, V 1.1. Lesion must not have been previously irradiated.
7. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 (not declining within 2 weeks prior to signing of informed consent).
8. Adequate Bone Marrow Function, including:
a. Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 1000000000/L.
b. Platelets ≥100,000/mm3 or ≥100 x 1000000000/L.
c. Hemoglobin ≥9 g/dL.
9. Adequate Renal Function, including:
a. Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 60 ml/min as calculated using the method standard for the institution.
10. Adequate Liver Function, including:
a. Total serum bilirubin ≤1.5 x ULN or ≤1.0 mg/dL.
b. Aspartate and Alanine Aminotransferase (AST & ALT) ≤2.5 x ULN; ≤5.0 x ULN if there is liver involvement.
c. Alkaline phosphatase ≤2.5 x ULN; (≤5 x ULN in case of bone metastasis).
11. Adequate blood glucose control, as evidenced by HbA1c <8%.
12. Adequate Cardiac Function, including 12-Lead electrocardiogram (ECG) with normal tracing or non clinically significant changes that do not require medical intervention.
13. Resolved acute effects of any prior therapy to baseline severity or Grade ≤1 CTC AE except for AEs not constituting a safety risk by investigator judgement.
14. Serum/urine pregnancy test (for females of childbearing potential) negative within 72 hours of starting treatment.
15. Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment.
16. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
17. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures, including completion of patient reported outcomes. |
|
| E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the study:
1. Patients who are investigational site staff members or patients who are Pfizer employees directly involved in the conduct of the trial.
2. More than 2 prior cytotoxic chemotherapy regimens for endometrial carcinoma. Prior hormonal therapy is acceptable.
3. Patients with known active brain metastases. 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.
4. Chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, ie, non target lesions), hormonal, biological or investigational agents within 2 weeks of first dose of study drug (6 weeks for mitomycin C or nitrosoureas).
5. Any surgery (not including minor procedures such as lymph node biopsy, needle biopsy, and/or placement of port-a-cath) within 4 weeks of first dose of study drug; or not fully recovered from any side effects of previous procedures.
6. Prior therapy with an agent that is known or proposed to be active by action on PI3K, and/or mTOR, and/or AKT.
7. Current use or anticipated need for food or drugs that are known potent CYP3A4 inhibitors. Because inhibition of CYP3A4 isoenzymes may increase study drug exposure leading to a potential increases in toxicities, the use of known strong inhibitors (Strong CYP3A4 Inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, erythromycin, clarithromycin, telithromycin, varapamil, indinavir, saquinavir, ritonavir, nelfinavir, nefazodone, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine, troleandomycin, mibefradil, conivaptan) are not permitted from 10 days prior to the first dose of study drug until study treatment discontinuation.
8. Current or anticipated need for food or drugs that are known potent CYP3A4 inducers. Study drug metabolism may be induced when taking strong CYP3A4 inducers (eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, St. John’s Wort) resulting in reduced plasma concentrations. Therefore co administration of study drug in combination with these and other strong CYP3A4 inducers is not permitted from 10 days prior to the first dose of stud drug until study treatment discontinuation.
9. Concurrent administration of herbal preparations.
10. Breast feeding: No studies have been conducted in humans to assess the impact of PF 04691502 or PF-05212384 on milk production, its presence in breast milk and its effects on the breast fed child. Because drugs are commonly excreted in human milk and because of the potential for serious adverse reactions in nursing infants, lactating female patients are excluded from this study.
11. Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication in tablet or capsule form and malabsorption syndrome.
12. Any mental disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol.
13. Other severe acute or chronic medical condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into this trial.
14. Participation in other studies within 2 weeks before the current study begins and/or during study participation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Clinical Benefit Response (CBR) (CR+PR+SD 16 weeks) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Radiological tumor assessments will be conducted at baseline, during treatment as specified in the Schedule of Events, whenever disease
progression is suspected (eg, symptomatic deterioration), and at the time of withdrawal from
the study (if not done in the previous 6 weeks).
Assessment of response will be made using RECIST version 1.1. |
|
| E.5.2 | Secondary end point(s) |
• Objective tumor response, as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1.
• Overall Survival (OS).
• Progression Free Survival (PFS).
• PFS at 6 months.
• Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.0), timing, seriousness and relationship to study therapy.
• Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.0) and timing.
• Vital signs.
• Expression and/or phosphorylation in biopsied tumor tissue of PI3K pathway proteins (such as p-AKT, p-S6, p-S6K,p- mTOR, p-PRAS40, stathmin).
• 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, PIK3CA gene amplification, stathmin.
• Pharmacokinetics of PF-04691502 and PF-05212384. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Trial procedures are described in the ASSESSMENTS Section
and in the Schedule of Activities. Safety laboratory studies (hematology, blood chemistry,
urinalysis, pregnancy test (except for screen/baseline) if needed) and tumor assessments may
be done up to 96 hours prior to scheduled Day 1 visit on any cycle to facilitate availability of
results to investigator at the time of clinic visit.
Exploratory "Omics" analyses will be conducted as described in the Molecular Supplement. |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Canada |
| Germany |
| Japan |
| Philippines |
| Poland |
| Russian Federation |
| Slovakia |
| Spain |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
End of Trial in all participating countries is defined as last patient having the End of Treatment visit.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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