Alisertib (MLN8237) in Participants With Ovarian, Fallopian Tube or Peritoneal Cancer Preceded by Phase 1 Study of MLN8237 Plus Paclitaxel Treatment of Ovary or Breast Cancer

Phase 2

Completed

Conditions: Ovarian Carcinoma
Breast Carcinoma
Fallopian Tube Cancer
Peritoneal Cancer

Interventions: Drug: Alisertib
Drug: Paclitaxel

Registration Number: NCT01091428

Lead Sponsor: Millennium Pharmaceuticals, Inc.

Brief Summary: This is an open-label, multicenter study with a nonrandomized Phase 1 portion and an open-label, randomized, Phase 2 portion evaluating MLN8237 in combination with weekly paclitaxel in adult female participants with advanced breast cancer (Phase 1 portion only) and recurrent ovarian cancer (both Phase 1 and Phase 2 portions).

Detailed Description: The drug tested in this study was called alisertib. Alisertib was tested to treat people who have ovarian and breast cancer. This study looked at safety, any anti-tumor effect, and it also determined a recommended dose of alisertib plus paclitaxel to take into further studies. Pharmacokinetic blood samples were studied to characterize any effects on the concentration of each of the drugs when administered together.

The study enrolled 191 patients. Participants with Breast Cancer and Ovarian Cancer received one of the following escalating doses of alisertib in combination with paclitaxel in the Phase 1 lead-in portion of the study:

* Alisertib 10 mg BID + Paclitaxel 80 mg/m\^2

* Alisertib 20 mg BID + Paclitaxel 80 mg/m\^2

* Alisertib 20 mg BID + Paclitaxel 60 mg/m\^2

* Alisertib 30 mg BID + Paclitaxel 60 mg/m\^2

* Alisertib 40 mg BID + Paclitaxel 60 mg/m\^2

* Alisertib 50 mg BID + Paclitaxel 60 mg/m\^2

Once the maximum tolerated dose (MTD)/ recommended phase 2 dose (RP2D) was determined, participants were randomized to receive the following treatments in the Phase 2 portion of the study:

* Alisertib 40 mg BID + Paclitaxel 60 mg/m\^2

* Paclitaxel 80 mg/m\^2

This multi-center trial was conducted in the United States, Poland and France. The overall time to participate in this study was approximately 5 years. Participants made multiple visits to the clinic, and who did not experience disease progression (PD) were followed off-treatment once every 8 weeks until the occurrence of 110 progression-free survival (PFS) events.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 191

Inclusion Criteria

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

Female participants 18 years or older
Previously treated, metastatic or locally recurrent malignancy with 1 of the following diagnoses, which has been confirmed histologically or cytologically: adenocarcinoma of the breast (Phase 1 only), recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (Phase 1 and 2)
In the Phase 1 portion of the study, participants with breast cancer must have received treatment with at least 1 but no more than 4 prior chemotherapy regimens not including regimens received in the neoadjuvant and/or adjuvant setting
Participants with breast cancer must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
No antineoplastic therapy or radiotherapy within 3 weeks before enrollment (2 weeks for regimens with recovery expected within 7 to 14 days) and recovered from toxicities of prior therapy (except alopecia); the participant must have recovered from all treatment-related toxicities and must have evidence of progressive disease (PD) or persistent disease
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Adequate bone marrow, liver and renal function
Postmenopausal at least 1 year, OR Surgically sterile, OR If childbearing potential, agree to 2 effective methods of nonhormonal contraception, or agree to completely abstain from heterosexual intercourse
Able to provide written informed consent
Willing to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures
Suitable venous access

Specific Inclusion Criteria for participants with Recurrent Ovarian, Fallopian Tube or Peritoneal Cancer:

Prior treatments must have included a platinum and a taxane; the most recent treatment need not be a platinum-containing or taxane-containing regimen
Disease must have recurred ≤ 12 months after discontinuation of platinum therapy
Participants who previously received weekly taxane are potentially eligible, provided that they did not progress during therapy or within 3 months of completing therapy
Participants with platinum-refractory disease, as defined by progression during primary or subsequent platinum-based therapy or persistent radiographic disease after primary or subsequent platinum-based therapy, will be included
Participants must have measurable disease in target lesions or assessable disease (defined by cancer antigen-125 - CA-125 per protocol), and disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or modified Gynecologic Cancer Intergroup (GCIG) CA-125 criteria

Exclusion Criteria

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

Prior treatment with an Aurora A-targeted agent (including MLN8237)
Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of MLN8237 and during the study
Treatment with more than 4 cytotoxic chemotherapy regimens in the metastatic setting; prior therapy cannot include more than 2 prior taxane-containing regimen. Current use of tamoxifen, thalidomide, or any agent used as maintenance or consolidation therapy for OC.
Known hypersensitivity to Cremophor® EL, paclitaxel or its components
Prior history of ≥ Grade 2 neurotoxicity or any toxicity requiring discontinuation from taxane chemotherapy that is not resolved to ≤ Grade 1
Comorbid or unresolved toxicity that would preclude administration of weekly paclitaxel
Primary central nervous system malignancy or carcinomatous meningitis
Symptomatic brain metastasis
Inability to swallow oral medications or maintain a fast
History of hemorrhagic or thrombotic cerebrovascular event in past 12 months
Surgery within 3 weeks before study enrollment and not fully recovered
Diagnosis or treatment of another malignancy within 2 years preceding first dose of MLN8237 and have any evidence of residual disease except nonmelanoma skin cancer or in situ malignancy completely resected
Pregnant or lactating
Serious illness that could interfere with protocol completion
Investigational treatment 21 days prior to first dose of MLN8237
Prior allogeneic bone marrow or organ transplantation
Infection requiring systemic antibiotic therapy within 14 days prior to first dose of MLN8237
Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
Radiotherapy to > 25% bone marrow or whole pelvic radiotherapy
Requirement for constant administration of proton pump inhibitor, H2 antagonist, or pancreatic enzymes. Intermittent uses of antacids of H2 antagonists are allowed

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Alisertib (Phase 1 - Ovarian cancer)	Alisertib	Participants with ovarian cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).
Alisertib (Phase 1 - Breast cancer)	Alisertib	Participants with breast cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).
Alisertib (Phase 1 - Ovarian cancer)	Paclitaxel	Participants with ovarian cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).
Alisertib (Phase 1 - Breast cancer)	Paclitaxel	Participants with breast cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).
Alisertib 40 mg BID+Paclitaxel 60 mg/m^2 (Phase 2)	Alisertib	Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).
Alisertib 40 mg BID+Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel	Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).
Paclitaxel 80 mg/m^2 (Phase 2)	Paclitaxel	Paclitaxel 80 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Primary Outcome Measures

Name	Time	Method
Phase 1: Number of Participants With Clinically Significant Laboratory Values	First dose to 30 days past last dose (Up to 36 Months)	Abnormal clinical laboratory values (serum chemistry, hematology and urinalysis) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention.
Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination With Paclitaxel	Cycle 1 (Up to 28 days)	The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT). DLT was evaluated according to National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.02 and was defined as any of the following events: 1. Grade 4 neutropenia and thrombocytopenia lasting ≥7 consecutive days; 2. Grade 4 neutropenia with fever and/or infection; 3. Platelet count \<10,000/mm\^3; 4. Grade 3 thrombocytopenia with bleeding; 5. Any other ≥Grade 3 nonhematologic toxicity, with following exceptions: ≥Grade 3 nausea/emesis, ≥Grade 3 diarrhoea, Grade 3 fatigue, Grade 3 nonhematological toxicity that could be controlled to ≤Grade 2 with appropriate treatment; 6. Other alisertib-related nonhematologic toxicities ≥Grade 2 that, in opinion of investigator, required a dose reduction or discontinuation of therapy with alisertib.
Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity	Baseline up to Month 36
Phase 2: Progression-Free Survival (PFS)	At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)	PFS is defined as the time from the date randomization for Phase 2 participants to the date of first documented progressive disease (PD) or death as assessed by the investigator using both RECIST 1.1 criteria and CA-125 criteria. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease or CA-125 criteria with elevated (\>70 units/mL) levels on 2 occasions. CA 125 progression for participants with normal CA 125 levels is defined as a CA 125 level \> 2 times the upper limit of normal and for participants with elevated values during the trial, is defined as a CA 125 level greater than 2 times the nadir value of CA 125.
Phase 1: MTD and RP2D for Paclitaxel in Combination With Alisertib	Cycle 1 (Up to 28 days)	The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of cycle 1).
Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	First dose to 30 days past last dose (Up to 36 Months)	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious 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.
Phase 1: Number of Participants With Clinically Significant Vital Sign Findings	First dose to 30 days past last dose (Up to 36 Months)	Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.

Secondary Outcome Measures

Name	Time	Method
AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1	Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1	Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1	Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1	Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1	Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Phase 2: Number of Participants With Clinically Significant Laboratory Values	First dose to 30 days past last dose (Up to 27 Months)	Abnormal clinical laboratory values (serum chemistry, hematology and urinalysis) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention.
Phase 1: Combined Best Overall Response Rate (ORR) in Participants With Recurrent Ovarian Cancer or Breast Cancer	At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)	Combined objective response rate is defined as the percentage of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 or response by Cancer antigen (CA) 125 criteria. According to RECIST: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions. CA 125 response criteria is defined as either: A 50% decrease from 2 initially elevated samples; the sample demonstrating the 50% decrease must have been confirmed by a fourth sample 28 days later (a total of 4 samples required) or A serial decrease of \> 75% over 3 samples; the third sample was to be obtained 28 days after the second (a total of 3 samples required).
t½: Terminal Half-Life for Paclitaxel in Phase 1	Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1	Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Phase 2: Overall Survival (OS)	Up to data-cut off: 12 August 2014 (approximately 24 months)	OS was defined as the time form the date of the randomization to the date of death.
Cmax: Maximum Observed Concentration for Alisertib in Phase 1	Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
Phase 2: Time to Disease Progression (TTP)	Up to data-cut off: 12 August 2014 (approximately 24 months)	TTP was defined as the time from the date of randomization to the date of first documentation of PD. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease or per CA-125 criteria with elevated (\>70 units/mL) levels on 2 occasions. CA 125 progression for participants with normal CA 125 levels is defined as a CA 125 level \> 2 times the upper limit of normal and for participants with elevated values during the trial, is defined as a CA 125 level greater than 2 times the nadir value of CA 125.
Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	First dose to 30 days past last dose (Up to 27 Months)	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious 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.
Phase 2: Number of Participants With Clinically Significant Vital Sign Findings	First dose to 30 days past last dose (Up to 27 Months)	Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1	Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
AUC∞: Area Under the Concentration-Time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1	Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Phase 2: Combined Best Overall Response Rate (ORR)	At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)	Combined objective response rate is defined as the percentage of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 or response by Cancer antigen (CA) 125 criteria. According to RECIST: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions. CA 125 response criteria is defined as either: A 50% decrease from 2 initially elevated samples; the sample demonstrating the 50% decrease must have been confirmed by a fourth sample 28 days later (a total of 4 samples required) or A serial decrease of \> 75% over 3 samples; the third sample was to be obtained 28 days after the second (a total of 3 samples required).
Phase 2: Duration of Response (DOR)	Up to data-cut off: 12 August 2014 (approximately 24 months)	DOR was defined as the time from the date of first documentation of a response to the date of first documentation of PD or the last response assessment that is stable disease (SD) or better for a participant who started alternate therapy without progression. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease or per CA-125 criteria with elevated (\>70 units/mL) levels on 2 occasions. CA 125 progression for participants with normal CA 125 levels is defined as a CA 125 level \> 2 times the upper limit of normal and for participants with elevated values during the trial, is defined as a CA 125 level greater than 2 times the nadir value of CA 125. A responder that did not experience disease progression is censored at the last response assessment that is SD.
CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1	Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion