MLN8237 in Patients With Ovarian, Fallopian Tube or Peritoneal Cancer Preceded by Phase 1 Study of MLN8237 Plus Paclitaxel Treatment of Ovary or Breast Cancer

• To assess safety and tolerability of MLN8237 plus weekly paclitaxel by determining the maximum tolerated dose of MLN8237 [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
• In Phase 1 study, to determine the recommended dose and schedule of MLN8237 and dose of paclitaxel for Phase 2 combination treatment arm [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
• In Phase 2 study, to assess progression-free survival (PFS) [ Time Frame: 24 months ] [ Designated as safety issue: No ]

• To assess safety and tolerability of MLN8237 plus weekly paclitaxel by determining the maximum tolerated dose of MLN8237 [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• In Phase 1 study, to determine the recommended dose and schedule of MLN8237 and dose of paclitaxel for Phase 2 combination treatment arm [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• In Phase 2 study, to assess progression-free survival (PFS) [ Time Frame: 12 months ] [ Designated as safety issue: No ]

• In Phase 1 study, to characterize effect of concomitant administration of MLN8237 on the pharmacokinetics (PK) of paclitaxel [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• In Phase 1 study, to characterize the pharmacokinetics (PK) of MLN8237 administered concomitantly with paclitaxel [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• In Phase 1 study, to assess best overall combined response rate in patients with recurrent ovarian cancer or breast cancer [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• In Phase 2 study, to estimate overall response rate (ORR), duration of response (DOR), time to disease progression (TTP) & overall survival (OS) associated w/ MLN8237 + weekly paclitaxel & weekly paclitaxel alone in patients w/ recurrent ovarian cancer [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• To assess the banked tumor specimens for candidate markers of response to MLN8237 and taxanes [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• In Phase 2 study, to assess adverse events, serious adverse events, clinical laboratory values and vital sign measurements [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

• In Phase 1 study, to characterize effect of concomitant administration of MLN8237 on the pharmacokinetics (PK) of paclitaxel [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• In Phase 1 study, to characterize the PK of MLN8237 administered concomitantly with paclitaxel [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• In Phase 1 study, to assess best overall combined response rate in patients with recurrent ovarian cancer or breast cancer [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• In Phase 2 study, to estimate the overall response rate (ORR), duration of response (DOR), time to disease progression (TTP) & overall survival (OS) associated w/ MLN8237 + weekly paclitaxel & weekly paclitaxel alone in patients w/ recurrent OC [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• To assess the banked tumor specimens for candidate markers of response to MLN8237 and taxanes [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• In Phase 2 study, to assess adverse events, serious adverse events, clinical laboratory values and vital sign measurements [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

This is an open-label, multicenter study with a nonrandomized Phase 1 portion and an open-label, randomized, Phase 2 portion evaluating MLN8237 in combination with weekly paclitaxel in adult female patients with advanced breast cancer (Phase 1 portion only) and recurrent ovarian cancer (both Phase 1 and Phase 2 portions).

• Ovarian Carcinoma
• Fallopian Tube Cancer
• Peritoneal Cancer
• Breast Carcinoma

• Drug: MLN8237 + Paclitaxel

  Phase 1:

  MLN8237 administered orally twice daily on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel (Days 1, 8, 15) as an intravenous infusion repeated in 28-day cycles

• Drug: MLN8237+Paclitaxel vs. Paclitaxel alone

  Phase 2:

  Arm 1:

  MLN8237 administered orally twice daily on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel (Days 1, 8, 15) as an intravenous infusion repeated in 28-day cycles

  Arm 2:

  Paclitaxel will be administered as an intravenous infusion on Days 1, 8 and 15 of each 28-day cycle

• Experimental: Arm 1 (MLN8237 + Paclitaxel)
  Interventions:

  • Drug: MLN8237 + Paclitaxel
  • Drug: MLN8237+Paclitaxel vs. Paclitaxel alone
• Active Comparator: Arm 2 (Paclitaxel)
  Intervention: Drug: MLN8237+Paclitaxel vs. Paclitaxel alone

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

• Female patients 18 years or older
• Previously treated, metastatic or locally recurrent malignancy with 1 of the following diagnoses, which has been confirmed histologically or cytologically: adenocarcinoma of the breast (Phase 1 only), recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (Phase 1 and 2)
• In the Phase 1 portion of the study, patients with breast cancer must have received treatment with at least 1 but no more than 4 prior chemotherapy regimens not including regimens received in the neoadjuvant and/or adjuvant setting
• Patients with breast cancer must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• No antineoplastic therapy or radiotherapy within 3 weeks before enrollment (2 weeks for regimens with recovery expected within 7 to 14 days) and recovered from toxicities of prior therapy (except alopecia); the patient must have recovered from all treatment-related toxicities and must have evidence of PD or persistent disease
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate bone marrow, liver and renal function
• Postmenopausal at least 1 year, OR Surgically sterile, OR If childbearing potential, agree to 2 effective methods of nonhormonal contraception, or agree to completely abstain from heterosexual intercourse
• Able to provide written informed consent
• Willing to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures
• Suitable venous access

Specific Inclusion Criteria for Patients with Recurrent Ovarian, Fallopian Tube or Peritoneal Cancer:

• Prior treatments must have included a platinum and a taxane; the most recent treatment need not be a platinum-containing or taxane-containing regimen
• Disease must have recurred ≤ 12 months after discontinuation of platinum therapy
• Patients who previously received weekly taxane are potentially eligible, provided that they did not progress during therapy or within 3 months of completing therapy
• Patients with platinum-refractory disease, as defined by progression during primary or subsequent platinum-based therapy or persistent radiographic disease after primary or subsequent platinum-based therapy, will be included
• Patients must have measurable disease in target lesions or assessable disease (defined by CA-125 per protocol), and disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or modified Gynecologic Cancer Intergroup (GCIG) CA-125 criteria

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

• Prior treatment with an Aurora A-targeted agent (including MLN8237)
• Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of MLN8237 and during the study
• Treatment with more than 4 cytotoxic chemotherapy regimens in the metastatic setting; prior therapy cannot include more than 2 prior taxane-containing regimens
• Known hypersensitivity to Cremophor® EL, paclitaxel or its components
• Prior history of ≥ Grade 2 neurotoxicity or any toxicity requiring discontinuation from taxane chemotherapy that is not resolved to ≤ Grade 1
• Comorbid or unresolved toxicity that would preclude administration of weekly paclitaxel
• Primary central nervous system malignancy or carcinomatous meningitis
• Symptomatic brain metastasis
• Inability to swallow oral medications or maintain a fast
• History of hemorrhagic or thrombotic cerebrovascular event in past 12 months
• Surgery within 3 weeks before study enrollment and not fully recovered
• Diagnosis or treatment of another malignancy within 2 years preceding first dose of MLN8237 and have any evidence of residual disease except nonmelanoma skin cancer or in situ malignancy completely resected
• Pregnant or lactating
• Serious illness that could interfere with protocol completion
• Investigational treatment 21 days prior to first dose of MLN8237
• Prior allogeneic bone marrow or organ transplantation
• Infection requiring systemic antibiotic therapy within 14 days prior to first dose of MLN8237
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
• Radiotherapy to > 25% bone marrow or whole pelvic radiotherapy
• Requirement for constant administration of proton pump inhibitor, H2 antagonist, or pancreatic enzymes. Intermittent uses of antacids of H2 antagonists are allowed