A Phase 1 Study of Alisertib Participants With Advanced Solid Tumors Including Castration-Resistant Prostate Cancer Receiving a Standard Docetaxel Regimen

The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have advanced solid tumors including castration-resistant prostate cancer.

The study enrolled approximately 41 patients. Participants were enrolled to receive:

• Alisertib 10-40 mg + docetaxel 60-75 mg/m^2

All participants will receive alisertib (ECT) in dose escalating cohorts, orally, twice daily for 7 days followed by 14-day rest period in Cycle 1, 3 and onwards (21-day cycle) and orally twice daily from Day 3 to Day 7 followed by 14 day rest period in Cycle 2 [dose held for pharmacokinetic (PK) collection] along with docetaxel 75 mg/m^2, intravenous (IV) infusion on Day 1 of each cycle for maximum of 12 months, or until the occurrence of progressive disease (PD), unmanageable AEs or withdrawal of consent.

This multi-center trial is conducted in United States. The overall time to participate in this study was until there is evidence of disease progression or unacceptable treatment-related toxicity. Participants made multiple visits to the clinic, and were contacted every 12 weeks for up to 25.8 months after last dose of study drug for a follow-up assessment.

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 advanced tumors and candidates for docetaxel treatment
• Measurable or evaluable disease is required. Participants must have clinical evidence of progressive disease or persistent disease
• Participants with castration-resistant prostate cancer (CRPC) are required to have

• Pathologically confirmed adenocarcinoma of the prostate
• Evidence of metastatic disease on bone scan or other imaging. Participants with prostate-specific antigen (PSA) elevation as the only manifestation of disease are not eligible.
• Progressive disease after at least 1 hormonal treatment with documented testosterone levels less than 50 ng/dl
• Concurrent use of an agent for testosterone suppression (e.g., luteinizing hormone-releasing hormone [LHRH] agonist) is required if the participants has not been surgically castrated
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Recovered to less than or equal to Grade 1 toxicity (CTCAE), to participant's baseline status (except alopecia) or deemed irreversible from the effects of prior cancer therapy and must have evidence of progressive or persistent disease
• Adequate bone marrow, liver and renal function
• Any use of opiates must be stable for at least 2 weeks prior to study entry
• Female participants who are postmenopausal for at least 1 year OR are surgically sterile OR if of childbearing potential, agree to practice 2 effective methods of contraception at the same time
• Male participants who agree to practice effective barrier contraception during the entire study and through 6 months after the last dose of study drug OR agree to abstain from heterosexual intercourse
• Voluntary written consent
• Willing to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures
• Suitable venous access for blood sampling

Exclusion criteria

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

• Female participants who are lactating or pregnant
• Antineoplastic therapy or any experimental therapy within 21 days before the first dose of alisertib
• Prior or current investigational therapies within 4 weeks before the first dose of MLN8237
• Concurrent investigational treatment of treatment with any investigational products within 28 days before the first dose of alisertib
• Radiotherapy to greater than 40% of bone marrow or any radiotherapy (except localized, small field radiation) within 4 weeks prior to enrollment, unless reviewed and approved by the medical monitor
• 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 alisetib, or prior allogeneic stem cell transplant at any time.
• 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
• For CRPC participants:

• Radiotherapy or antiandrogen therapy for prostate cancer within 4 weeks prior to enrollment
• Prior treatment with antineoplastic chemotherapy or radioisotopes for advanced prostate cancer
• Use of products known to affect PSA levels within 4 weeks of enrollment
• Major surgery within 4 weeks of study enrollment
• Uncontrolled high blood pressure
• Participants with abnormal gastric or bowel function or who require continuous treatment with antacids or proton pump inhibitors
• Participants receiving chronic steroid therapy other than the following: low dose steroid for the control of nausea and vomiting, topical steroid, inhaled steroid or use of dexamethasone
• Known severe hypersensitivity to docetaxel or other drugs formulated in polysorbate 80
• Comorbid condition or unresolved toxicity that would preclude administration of docetaxel
• Prior history of Grade 2 or greater neurotoxicity or any toxicity that has not resolved to Grade 1 or below
• Symptomatic brain or other CNS metastasis
• 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
• Participants requiring full systemic anticoagulation
• Prior allogeneic bone marrow or other organ transplant
• Active infection requiring systemic therapy within 14 days preceding first dose, or other serious infection
• History of hemorrhagic or thrombotic cerebrovascular event in the past 12 months
• Serious medical or psychiatric illness that could interfere with protocol completion
• Inability to swallow oral medication
• Prior treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens
• Prior treatment with more than 1 prior taxane-containing regimen