endometrium cancer uterus cancer
Conditions
Interventions
Paclitaxel will be administered intravenously (IV) whereas MLN0128 and MLN1117
will be administered by mouth (PO) throughout the study. Patients in Arm A and
Arm B will receive paclitaxel alone or p
endometrial cancer
endometrial carcinoma
gynecological cancer
Sponsors
Millenium Pharmaceuticals
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Histologic or cytologic diagnosis of endometrial carcinoma (including endometrioid, serous, mixed adenocarcinoma, clear-cell carcinoma, or carcinosarcoma) 2. Evidence that the endometrial cancer is advanced, recurrent, or persistent and has relapsed or is refractory to curative therapy or established treatments. 3. At least 1 prior platinum-based chemotherapeutic regimen, but not more than 2 prior chemotherapeutic regimens, for management of endometrial carcinoma. Prior treatment may include chemotherapy, chemotherapy/radiation therapy, and/or consolidation/maintenance therapy. Chemotherapy administered in conjunction with primaryradiation as a radio-sensitized therapy will be considered a systemic chemotherapy regimen. 4. Measureable disease by RECIST 1.1, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be >= 10 mm in long axis when measured by CT, MRI, or caliper measurement by clinical exam. Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI. 5. Tumor accessible and patient consents to undergo fresh tumor biopsies. 6. Female patients 18 years or older. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 8. Female patients who: - Are postmenopausal for at least 1 year before the screening visit, OR - Are surgically sterile, OR - If they are of childbearing potential, agree to practice 1 highly effective method of contraception, and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling [eg, USPI, SmPC, etc.]) after the last dose of study drug, OR - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg,calendar, ovulation, symptothermal, postovulation methods] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) 9. Clinical laboratory values as specified below within 4 weeks before the first dose of study drug: - Bone marrow reserve consistent with absolute neutrophil count (ANC) >= 1500/uL; platelet count >= 100,000/uL; hemoglobin A1c (HbA1c) = 50 mL/min/1.73 m2 based either on Cockcroft-Gault estimate or based on a 12- or 24-hour urine collection. - Fasting serum glucose
Exclusion criteria
Exclusion criteria: 1. Positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug. Women who are lactating and breastfeeding are not eligible. 2. Previous treatment with any weekly taxane regimen. 3. History of severe hypersensitivity reactions to paclitaxel or any of its excipients. 4. Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors,TORC1/2 inhibitorsor TORC1 inhibitors. 5. Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either IV or oral steroids, excluding inhalers) within 1 week before administration of the first dose of study drug (patients already receiving erythropoietin on a chronic basis for >= 4 weeks are eligible). 6. Patients who are taking proton pump inhibitors (PPIs) within 7 days of the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug. 7. A prothrombin time (PT) or activated partial thromboplastin time (aPTT) above the ULN or a history of a coagulopathy or bleeding disorder. 8. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection. 9. Sensory or motor neuropathy >= Grade 2. 10. Central nervous system (CNS) metastasis, endometrial leiomyosarcoma, or endometrial stromal sarcoma. 11. Manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal disease, or for some other reason that may alter the absorption of MLN0128 or MLN1117. In addition, patients with enteric stomata are also excluded. 12. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection, or any other condition that could compromise participation of the patient in the study. 13. Known human immunodeficiency virus infection. 14. History of any of the following within the last 6 months before administration of the first dose of study drug: - Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures. - Ischemic cerebrovascular event, including transient ischemic attack and arteryrevascularization procedures. - Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia). - Placement of a pacemaker for control of rhythm. - New York Heart Association Class III or IV heart failure (see Section 14.3). - Pulmonary embolism. 15. Significant active cardiovascular or pulmonary disease before administration of the first dose of study drug, including: - Uncontrolled hypertension (ie, either systolic blood pressure >180 mm Hg; diastolic blood pressure > 95 mm Hg). - Uncontrolled asthma or oxygen saturation 480 ms, or history
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary • To determine if MLN0128 in combination with weekly paclitaxel improves progression free survival (PFS) compared to weekly paclitaxel alone. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary • To determine if single-agent MLN0128 improves PFS compared to weekly paclitaxel alone. • To determine if MLN0128 + MLN1117 improves PFS compared to weekly paclitaxel alone. • To assess the safety and tolerability of single-agent MLN0128, MLN0128 in combination with paclitaxel, and MLN0128 + MLN1117. • To evaluate improvement in efficacy measures (endpoints other than PFS) of MLN0128 in combination with weekly paclitaxel, single-agent MLN0128, and MLN0128 + MLN1117 to weekly paclitaxel alone. • To collect plasma concentration-time data with sparse pharmacokinetic (PK) sampling to contribute to future population PK analysis. Quality of Life (QOL) • To assess the QOL and symptoms in patients treated with MLN0128 in combination with weekly paclitaxel, single-agent MLN0128, and MLN0128 + MLN1117 to weekly paclitaxel alone. Exploratory • To identify clinical response markers in archival and fresh tumor tissue specimens and circulating tumor DNA (ctDNA). • To identify adaptive response mechanisms to single-agent MLN0128 or MLN0128 + MLN1117. • To understand the effects of genetic polymorphisms in drug metabolizing enzymes and/or transporters that may be implicated in the disposition of MLN0128 and/or MLN1117 as part of population PK analyses. | — |
Countries
Belgium, France, Spain, United Kingdom
Outcome results
None listed