Study of MLN8237 in Participants With Advanced Solid Tumors

The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have advanced solid tumors. This study will look at the relative bioavailability (BA) (Part A), food effect and multiple-dose PK and safety of the oral solution (OS) (Part B) and food effect and safety of the enteric-coated tablet (ECT) formulation (Part C).

The study enrolled 53 patients (pts). Prior to initiation of Part A, 4 participants were enrolled in a dose escalation cohort. Participants in the study received:

• Alisertib 15 mg to 50 mg orally In the first 2 cycles of all 3 parts of the study, a single dose of alisertib was administered on Day 1 (PIC or OS in Part A [n=19 pts]; OS, in the fed or fasted state, in Part B [n=6 pts]; ECT, in the fed or fasted state, in Part C [n=24 pts]), In Part A, participants then continued on the PIC formulation at 40 mg BID for 7 days (Days 3 - 9). In Part B, participants continued on the OS formulation at a calculated dose administered BID for 7 days (Days 3 - 9). In Part C, the ECT formulation was continued at 40 mg BID for 7 days (Days 3 - 9); however, dose escalation to 50 mg BID was permitted after Cycle 1 based on tolerability and safety findings in the prior cycles. All participants took doses at a gap of 12 hours each day for 7 days followed by a 14-day rest period in a 21-days cycle for the remaining cycles.

This multi-center trial was conducted in the United States. The overall time to participate in this study was 30 months. Participants made multiple visits to the clinic, and final assessments were performed approximately 30 days after last dose of study drug.

Inclusion criteria

Each participant 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
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse
• Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
• Voluntary written consent
• Suitable venous access for study-required blood sampling
• Measurable disease
• Recovered from effects of prior antineoplastic therapy
• Meet required entry laboratory and organ function levels

Exclusion criteria

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

• Female participants who are pregnant or lactating
• Serious medical or psychiatric illness that could interfere with protocol completion
• Major surgery within 14 days of first dose of alisertib
• Antineoplastic therapy, radiation therapy or any experimental therapy 21 days prior to first dose of alisertib
• Nitrosoureas or mitomycin-C within 6 weeks before the first dose of alisertib.
• Autologous stem cell transplant within 3 months before the first dose of alisertib, or prior allogeneic stem cell transplant at any time.
• Active infection requiring systemic therapy, or other serious infection
• Inability to swallow oral medication
• Gastrointestinal (GI) disease or GI procedure that could interfere with oral absorption or tolerance of alisertib
• Symptomatic brain metastasis
• Uncontrolled cardiovascular condition
• 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
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
• Lactose-intolerant (Parts A and B only)
• Prior history of metabolic acidosis (Parts A and B only)
• Use of enzyme-inducing antiepileptic drugs such as phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of alisertib
• A medical condition requiring use of pancreatic enzymes; or daily, chronic , or regular use of proton pump inhibitors (PPI); or histamine (H2) receptor antagonists. Participants who intermittently use these medications must meet the following:

• No use of PPI within 7 days of first dose of alisertib
• No use of H2 antagonist or pancreatic enzymes within 24 hours of first dose of alisertib
• Participants requiring full systemic anticoagulation