| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The purpose of this study is to assess the efficacy and safety of XL147 in subjects with advanced or recurrent EC. |
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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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10014747 |
| E.1.2 | Term | Endometrial carcinoma recurrent |
| 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 |
The primary objectives of this study are:
• To evaluate the co-primary efficacy endpoints:
1) ORR (confirmed complete response [CR] or confirmed PR) and
2) rate of 6 month (183 days) progression-free survival (PFS6), in subjects receiving XL147 for advanced or recurrent EC
• To evaluate the safety and tolerability of XL147 in this population
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To assess duration of response and PFS
• To further characterize the pharmacokinetic (PK) and pharmacodynamic profiles of XL147 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (ie, persistent, locally advanced) or recurrent and is incurable by standard therapies, and has received one platinum based chemotherapy regimen 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 or 1.
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 of the Protocol).
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 Histopathologic evidence of persistent disease, ≥ 90 days after the completion of radiation therapy
5. Tissue samples of the subject's tumor of at least 125 micron thickness [175
micron preferable] of a cross-sectional area of at least 20 mm x 20 mm with
a tumor cell nuclei content of at least 25%, sections without cover slips from
archival or fresh tissue, or a tissue block 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.
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
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 must agree to use a medically accepted barrier method of contraception (ie, male condom or female condom) during the course of the study and for 3 months following discontinuation of study treatments. For subjects of childbearing potential, a barrier method and a second method of contraception must be used. Hormonal contraceptives are discouraged because of a possible decrease in effectiveness due to a possible drug-drug interaction.
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 months, with the exception of those who had prior hysterectomy, oophorectomy, or surgical sterilization). However, subjects who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression, or any reason other than menopause. |
|
| E.4 | Principal 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 anticancer 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 pretherapy 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. |
|
| E.5 End points |
| E.5.1 | 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 in the absence of disease progression or unacceptable toxicity |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumor assessments to be performed at day 1 of Weeks 9, 17, 27 and every 10 weeks thereafter
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|
| E.5.2 | Secondary end point(s) |
To assess duration of response and PFS -To further characterize the pharmacokinetic (PK) and pharmacodynamic profiles of XL147
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood samples will be obtained at the time points described in Appendix B for XL147 plasma concentration assessments. In addition, PK samples will also be collected, if possible, at the 30 day visit during the Post-Treatment Period and whenever a subject has study drug–related SAE(s) (eg, skin rash) and/or is withdrawn from the study.
|
|
| 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The last visit of the last patient |
|
| 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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