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

A Phase 1 Study of MLN8237, an Aurora A Kinase Inhibitor, in Patients With Advanced Solid Tumors Including Castration-Resistant Prostate Cancer Receiving a Standard Docetaxel Regimen

The purpose of this study is to evaluate the safety and tolerability of alisertib in combination with docetaxel as a treatment for participants with advanced solid tumors, including castration-resistant prostate cancer, who were deemed by the investigator to be medically appropriate candidates for docetaxel therapy.

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