Clinical Trial 18755

Cancer Type: Gynecological Tumor
Interventions:MLN0128; MLN1117; TAK-228 (MLN0128); Taxol (paclitaxel); paclitaxel

Study Type: Treatment
Phase of Study: Phase II
Investigators:

  • Robert Wenham

Overview

Study Title

A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), MLN0128 + MLN1117 (a PI3Ka Inhibitor), Weekly Paclitaxel, or the Combination of Weekly Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial Cancer

Summary

The primary purpose of this study is to determine if MLN0128 in combination with weekly paclitaxel improves progression-free survival (PFS) compared to weekly paclitaxel alone.

Objective

Primary: To determine if MLN0128 in combination with weekly paclitaxel improves progression-free survival (PFS) compared to weekly paclitaxel alone. 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.

Inclusion Criteria

  • Histologic or cytologic diagnosis of endometrial carcinoma (including endometrioid, serous, mixed adenocarcinoma, clear-cell carcinoma, or carcinosarcoma).
  • Evidence that the endometrial cancer is advanced, recurrent, or persistent and has relapsed or is refractory to curative therapy or established treatments.
  • 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 primary radiation as a radio-sensitized therapy will be considered a systemic chemotherapy regimen.
  • Measureable disease by Response Evaluation Criteria in Solid Tumors (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 computed tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by clinical exam. Lymph nodes must be ≥ 15 mm in short axis when measured by CT or MRI.
  • Tumor accessible and patient consents to undergo fresh tumor biopsies.
  • Female patients 18 years or older.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
  • Women of childbearing potential must agree to practice highly effective contraception or abstinence, as outlined in the protocol documentation.
  • Adequate hepatic, hematological, renal and bone marrow function within 4 weeks before the first dose of study drug.
  • Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.
  • Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

  • Exclusion Criteria

  • 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.
  • Previous treatment with any weekly taxane regimen.
  • History of severe hypersensitivity reactions to paclitaxel or any of its excipients.
  • Previous treatment with phosphoinositide 3-kinase (PI3K), serine/threonine-specific protein kinase (AKT), dual PI3K/ mammalian (or mechanistic) target of rapamycin (mTOR) inhibitors, target of rapamycin complex 1/2 (TORC1/2) inhibitors or TORC1 inhibitors.
  • Treatment with strong inhibitors and/or inducers of cytochrome P450 3A4 (CYP3A4), CYP2C9, or CYP2C19 within 1 week preceding the first dose of study drug.
  • Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either intravenous (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).
  • 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.
  • A prothrombin time (PT) or activated partial thromboplastin time (aPTT) above the ULN or a history of a coagulopathy or bleeding disorder.
  • Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
  • Sensory or motor neuropathy ≥ Grade 2.
  • Central nervous system (CNS) metastasis, endometrial leiomyosarcoma, or endometrial stromal sarcoma.
  • 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.
  • 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.
  • Known human immunodeficiency virus infection.
  • 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 artery revascularization 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; Pulmonary embolism.
  • Significant active cardiovascular or pulmonary disease before administration of the first dose of study drug.
  • Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
  • Patients with endometrioid histology and histologically confirmed expression of estrogen receptors (ER) and/or progesterone receptors (PgR) who have not received prior endocrine therapy and for whom endocrine therapy is currently indicated.