A Phase 2 Study of XL147 in Subjects with Advanced or Recurrent Endometrial Carcinoma

Phase 1

Conditions: The purpose of this study is to assess the efficacy and safety of XL147 in subjects with Advanced or Recurrent Endometrial Carcinoma.
MedDRA version: 12.0Level: LLTClassification code 10014747Term: Endometrial carcinoma recurrent

Registration Number: EUCTR2009-016707-30-FR

Lead Sponsor: Exelixis, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Female

Target Recruitment: 80

Inclusion Criteria

Inclusion Criteria
1. The subject has a histologically confirmed diagnosis of EC (endometrioid, serous, clear cell adenocarcinoma, adenosquamous carcinoma, or mixed histology, any grade) that is advanced or recurrent and is incurable by standard therapies, and has received at least one platinum based chemotherapy regimen and no more than two prior systemic treatment regimens (including cytotoxic chemotherapy regimen, hormonal therapy, and targeted therapy or any other investigational treatment in the adjuvant or the metastatic setting) for EC.
2. The subject is at least 18 years old.
3. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
4. The subject has at least one lesion that is measurable on computerized tomography (CT) or magnetic resonance imaging (MRI) scan determined by investigator per RECIST Version 1.1 (Appendix E).
a) A lesion within a previously radiated field is only considered measurable if there has been demonstrated progression in the lesion and documented by:
o At least two sequential CT or MRI scans performed after the completion of radiation, or
o Histopathological evidence of persistent disease, = 90 days after the completion of radiation therapy
5. At least fifteen (15) 4-10 micron tissue sections (= 15 unstained slides [20 preferable], without cover slips) from archival or fresh tissue, or a tissue block of the subject’s tumor should be identified, in the possession of the participating site/institution, and designated for shipment to the sponsor, or a laboratory designated by the sponsor.
a) If after the enrollment of the first 20 subjects, the incidence of molecular alterations directly affecting the PI3K pathway in these 20 subjects is not between 40% and 60%, subject pre-selection will be implemented, and subsequent enrollment will be gated by pathway alteration status to ensure that the frequency of PI3K pathway alterations falls within the range of 40-60% for the study population. In addition, if a decision is made, based on the results of the futility analysis (Section 7.6), to enroll only a subgroup of the study population, eligibility will be based on the presence or absence of these PI3K pathway alterations in the subject’s tumor.
6. The subject has organ and marrow function as follows:
a) Absolute neutrophil count = 1500/mm3
b) Platelets = 100,000/mm3
c) Hemoglobin = 9 g/dL
d) Bilirubin = 1.5 × the upper limit of normal (ULN)
e) Serum creatinine = 1.5 × ULN, calculated creatinine clearance = 60 mL/min, or glomerular filtration rate = 40 mL/min
f) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 × ULN if no liver involvement or = 5 × ULN with liver involvement
7. The subject is capable of understanding the informed consent and complying with the protocol and has signed the informed consent document before any study-specific screening procedures or evaluations are performed.
8. Sexually active subjects of childbearing potential and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 3 months after discontinuation of study drug.
9. Subjects of childbearing potential must have a negative pregnancy test at screening. Subjects of childbearing potential are defined as premenopausal subjects capable of becoming pregnant (ie, subjects who have had any evidence of menses in the past 12 m

Exclusion Criteria

Exclusion Criteria
1. The subject has previously been treated with a selective PI3K inhibitor, mTOR inhibitor, or AKT inhibitor.
2. The subject has uterine sarcomas (leiomyosarcoma), mixed Mullerian tumors, squamous carcinoma of the uterus, and/or adenosarcomas of the uterus.
3. The following restrictions on prior treatment apply:
a) Cytotoxic chemotherapy (including investigational cytotoxic agents) or biologic agents (antibodies, immune modulators, cytokines) within 4 weeks, or nitrosoureas or mitomycin C within 6 weeks, before the first dose of XL147
b) A small-molecule kinase inhibitor (including investigational small-molecule kinase inhibitors) within 2 weeks, or five half-lives of the drug or active metabolites, whichever is longer, before the first dose of XL147
c) Any other investigational therapy within 4 weeks before the first dose of XL147
d) Prior hormonal therapy within 2 weeks before the first dose of XL147
e) Prior whole pelvic radiation therapy or palliative radiation within 2 weeks before the first dose of XL147
f) Prior major surgery within 4 weeks before the first dose of XL147 or if the subject has not recovered or stabilized from the surgery
4. The subject has not recovered from toxicity due to prior therapy to Grade = 1 (excluding alopecia and peripheral neuropathy) or to pre-therapy baseline. Grade 2 peripheral neuropathy or Grade 2 alopecia related to prior therapies will not affect the eligibility of the subject.
5. The subject has a known primary brain tumor or brain metastasis.
6. The subject has any other diagnosis of malignancy or evidence of malignancy (except non-melanoma skin cancer or in situ carcinoma of the cervix) within 2 years before screening for this study.
7. The subject has a diagnosis of uncontrolled diabetes mellitus (glycosylated hemoglobin A1C = 8%) or has a fasting plasma glucose > 160 mg/dL.
8. The subject is currently receiving anticoagulation with therapeutic doses of warfarin (low-dose warfarin = 1 mg/day is permitted).
9. The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test results at screening that are above 1.3 × the laboratory ULN.
10. The subject has uncontrolled, significant intercurrent illness including, but not limited to:
a) Ongoing or active infection requiring systemic treatment
b) Symptomatic congestive heart failure
c) Uncontrolled hypertension (sustained blood pressure readings of > 140 mmHg systolic, or > 90 mmHg diastolic)
d) Unstable angina pectoris, a myocardial infarction, or a stroke within 3 months before entering the study
e) Clinically significant cardiac arrhythmias
11. The subject has a baseline corrected QT interval = 470 ms.
12. The subject is known to be positive for the human immunodeficiency virus (HIV). (Note: Baseline HIV screening is not required.)
13. The subject is pregnant or breastfeeding.
14. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objectives of this study are:<br>• To estimate the efficacy endpoints of: 1) ORR (confirmed complete response [CR] or confirmed PR), and 2) rate of 6-month PFS (PFS6) of XL147 in relation to the presence or absence of tumor PI3K pathway alterations (ie, molecular alterations that directly affect the PI3K pathway: PIK3CA mutation/amplification and/or PTEN deficiency) in subjects with advanced or recurrent EC<br>• To evaluate the safety and tolerability of XL147 in this population;Secondary Objective: The secondary objectives of this study are:<br>• To assess duration of response and PFS<br>• To further characterize the pharmacokinetic (PK) and pharmacodynamic profiles of XL147;Primary end point(s): Subjects may continue to receive XL147 for up to 1 year at the discretion of the investigator and beyond 1 year with the agreement of the investigator and sponsor. Efficacy endpoints: 1) ORR (confirmed complete response [CR] or confirmed PR), and 2) rate of 6-month PFS (PFS6) of XL147

Secondary Outcome Measures

Name	Time	Method

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