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

The drug tested in this study was called alisertib. Alisertib was tested to treat people who
have ovarian and breast cancer. This study looked at safety, any anti-tumor effect, and it
also determined a recommended dose of alisertib plus paclitaxel to take into further studies.
Pharmacokinetic blood samples were studied to characterize any effects on the concentration
of each of the drugs when administered together.

The study enrolled 191 patients. Participants with Breast Cancer and Ovarian Cancer received
one of the following escalating doses of alisertib in combination with paclitaxel in the
Phase 1 lead-in portion of the study:

- Alisertib 10 mg BID + Paclitaxel 80 mg/m^2

- Alisertib 20 mg BID + Paclitaxel 80 mg/m^2

- Alisertib 20 mg BID + Paclitaxel 60 mg/m^2

- Alisertib 30 mg BID + Paclitaxel 60 mg/m^2

- Alisertib 40 mg BID + Paclitaxel 60 mg/m^2

- Alisertib 50 mg BID + Paclitaxel 60 mg/m^2

Once the maximum tolerated dose (MTD)/ recommended phase 2 dose (RP2D) was determined,
participants were randomized to receive the following treatments in the Phase 2 portion of
the study:

- Alisertib 40 mg BID + Paclitaxel 60 mg/m^2

- Paclitaxel 80 mg/m^2

This multi-center trial was conducted in the United States, Poland and France. The overall
time to participate in this study was approximately 5 years. Participants made multiple
visits to the clinic, and who did not experience disease progression (PD) were followed
off-treatment once every 8 weeks until the occurrence of 110 progression-free survival (PFS)
events.

Inclusion Criteria:

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

- Female participants 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, participants 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

- Participants 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 participant must have recovered from all
treatment-related toxicities and must have evidence of progressive disease (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 participants 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

- Participants who previously received weekly taxane are potentially eligible, provided
that they did not progress during therapy or within 3 months of completing therapy

- Participants 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

- Participants must have measurable disease in target lesions or assessable disease
(defined by cancer antigen-125 - 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:

Participants 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 regimen. Current use
of tamoxifen, thalidomide, or any agent used as maintenance or consolidation therapy
for OC.

- 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