MLN8237 in Adults With Nonhematological Malignancies, Followed by MLN8237 in Lung, Breast, Head and Neck or Gastroesophageal Malignancies

• Phase 1: To assess the safety and tolerability of MLN8237, formulated as an enteric-coated tablet (ECT), on a 7-day dosing schedule for determining the recommended dose and schedule to be used in Phase 2 [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• Phase 2: To estimate the antitumor activity of MLN8237 as measured by overall response rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]

• Phase 1: To assess the safety and tolerability of MLN8237, formulated as an enteric-coated tablet (ECT), on a 7- and 14-day dosing schedule for determining the recommended dose and schedule to be used in Phase 2 [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• Phase 2: To estimate the antitumor activity of MLN8237 as measured by overall response rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]

• Phase 1: To characterize the pharmacokinetics of MLN8237, formulated as ECT, administered on a 7-day dosing schedule and to describe any antitumor activity that may be observed with treatment in patients with advanced nonhematological malignancies [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase 2: To assess the relationship between clinical response and molecular markers of response [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase 2: To assess additional measures of antitumor activity, including time to progression, progression-free survival and duration of response [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase 2: To characterize the safety profile associated with MLN8237 [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

• Phase 1: To characterize the pharmacokinetics of MLN8237, formulated as ECT, administered on a 7-and 14-day dosing schedule and to describe any antitumor activity that may be observed with treatment in patients with advanced nonhematological malignancies [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase 2: To assess the relationship between clinical response and molecular markers of response [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase 2: To assess additional measures of antitumor activity, including time to progression, progression-free survival and duration of response [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase 2: To characterize the safety profile associated with MLN8237 [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

This is an open-label, multicenter study with a phase 1 dose escalation portion and a 2-stage, phase 2 portion, investigating MLN8237 in patients with advanced nonhematological malignancies.

Following the determination of the Recommended Phase 2 Dose (RP2D) and schedule (Phase 1), 20 response-evaluable patients in each of the 5 tumor indications will be enrolled (Phase 2-Stage 1). An interim analysis will determine which tumor indications will proceed to enroll an additional 25 patients (Phase 2-Stage 2) to further evaluate Overall Response Rate (ORR) and other secondary endpoints.

• Advanced Nonhematological Malignancies
• Non-Small Cell Lung Cancer
• Small Cell Lung Cancer
• Metastatic Breast Cancer
• Head and Neck Squamous Cell Carcinoma
• Gastroesophageal Adenocarcinoma

Inclusion Criteria:

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

• 18 years or older
• Histologically or cytologically confirmed metastatic and/or advanced solid tumor (Phase 1 only)
• Phase 2 requires Non-small cell lung cancer (NSCLC); Small-cell lung cancer; Breast adenocarcinoma (female patients only); Squamous cell cancer of the head and neck (HNSCC); or Gastroesophageal adenocarcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse
• Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
• Voluntary written consent
• Wiling to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures
• Measurable disease (Phase 2 only)

Exclusion Criteria:

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

• Female patients who are pregnant or lactating
• Serious medical or psychiatric illness that could interfere with protocol completion
• Receipt of more than 2 previous cytotoxic chemotherapeutic regimens (4 previous regimens for breast cancer). There is no limit on the number of prior noncytotoxic therapies
• Prior treatment with Aurora A-targeted agents, including MLN8237
• Prior treatment with high-dose chemotherapy
• Prior allogeneic bone marrow or other organ transplant
• Antineoplastic therapy, radiation therapy or any experimental therapy 21 days prior to first dose of MLN8237
• Symptomatic brain metastasis
• Radiotherapy to greater than 25% of bone marrow
• Diagnosis or treatment of another malignancy within 2 years preceding first dose of study drug except nonmelanoma skin cancer or in situ malignancy completely resected
• Myocardial infarction within 6 months of enrollment
• Uncontrolled cardiovascular condition
• Major surgery within 14 days of first dose of MLN8237
• Active infection requiring systemic therapy, or other serious infection
• Inability to swallow oral medication
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
• Patients requiring full systemic anticoagulation
• History of uncontrolled sleep apnea syndrome
• Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of MLN8237 and during the study