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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced Solid Tumors, Adenocarcinoma of the Prostate

Intervention / Treatment
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* Drug: Alisertib
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alisertib + Docetaxel<br>Alisertib in escalating dose (10-40 mg), enteric-coated tablets (ECT), 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 along with docetaxel 60-75 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 adverse events (AEs) or withdrawal of consent. The starting alisertib dose is 10 mg, orally, twice daily (total 20 mg/day). | Drug: Alisertib<br>* Alisertib ECT<br>* Other names: MLN8237;Drug: Docetaxel<br>* Docetaxel IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. | From enrollment through 30 days after the last dose of study drug (approximately up to 77 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration for Docetaxel |  | Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2 | 
| AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel |  | Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2 | 
| AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel |  | Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2 | 
| Terminal Phase Elimination Half-life (T1/2) for Docetaxel |  | Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2 | 
| Cmax: Maximum Observed Plasma Concentration for Alisertib |  | Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1 | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib |  | Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1 | 
| AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib |  | Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1 | 
| Overall Response Rate (ORR) Assessed for Overall Participant Population | ORR is defined as percentage of participants who achieved complete response (CR) or partial response (PR) as assessed by response evaluation criteria in solid tumors (RECIST) v 1.1. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as ≥30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline. RECIST-Evaluable Population is subset of safety population who had measurable disease by RECIST v 1.1 at baseline and had at least 1 post baseline response. prostate specific antigen (PSA)-Evaluable Population is subset of the safety population who had a baseline PSA reference value (>5 ng/mL) and at least 12 weeks post-baseline PSA assessment for participants with no decline from baseline, or PSA progression within 12 weeks of treatment for participants with PSA decline from baseline. | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | 
| Overall Response Rate for Prostate Cancer Participants | ORR is defined as percentage of participants who achieved CR or PR as assessed by either RECIST v 1.1 or PSA response by prostate cancer working group 2 (PCWG2) criteria. According to RECIST v 1.1, CR: disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: ≥30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PSA response by PCWG2 is defined as PSA at least 50% decrease in PSA value from baseline for 2 consecutive evaluations. PCWG2 defines PSA progression as the date that a 25% or greater increase and an absolute increase of 2 ng/mL or more from the nadir is documented, which is confirmed by a second value obtained 3 or more weeks later. | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | 
| Best Overall Response Rate Assessed by RECIST Criteria | Best response rate is defined as the percentage of participants with CR, PR, CR+PR, stable disease (SD) and progressive disease (PD) as assessed by RECIST criteria 1.1 for target lesions and assessed by CT, PET or MRI. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | 
| Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria | Best Response Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria PSA response is defined as at least 50% decrease in PSA value from baseline for 2 consecutive evaluations. | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | 
| Duration of Response | Duration of response is defined as the time from the date of first documentation of a response to the date of first documented progressive disease (PD), or censored at last SD or better. | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | 
| Duration of Stable Disease (SD) | Duration of SD is defined as the time from first dose to first PD, or censored at last SD or better. | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) |