Back to resultsAlisertib (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
Primary Purpose
Ovarian Carcinoma, Fallopian Tube Cancer, Peritoneal Cancer
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Alisertib
Paclitaxel
Sponsored by
About this trial
This is an interventional treatment trial for Ovarian Carcinoma focused on measuring RECIST: Response Evaluation Criteria in Solid Tumors, OC: Ovarian Cancer, GCIG: Gynecologic Cancer Intergroup, Breast carcinoma (Phase 1), Drug therapy
Eligibility Criteria
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
Alisertib (Phase 1 - Ovarian cancer)
Alisertib (Phase 1 - Breast cancer)
Alisertib 40 mg BID+Paclitaxel 60 mg/m^2 (Phase 2)
Paclitaxel 80 mg/m^2 (Phase 2)
Arm Description
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).
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, 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, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).
Outcomes
Primary Outcome Measures
Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination With Paclitaxel
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: MTD and RP2D for Paclitaxel in Combination With Alisertib
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)
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 Laboratory Values
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: Number of Participants With Clinically Significant Vital Sign Findings
Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity
Phase 2: Progression-Free Survival (PFS)
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.
Secondary Outcome Measures
Phase 1: Combined Best Overall Response Rate (ORR) in Participants With Recurrent Ovarian Cancer or Breast Cancer
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).
Cmax: Maximum Observed Concentration for Alisertib in Phase 1
Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1
AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1
AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1
Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1
AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1
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
t½: Terminal Half-Life for Paclitaxel in Phase 1
CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1
Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1
Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1
Phase 2: Combined Best Overall Response Rate (ORR)
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)
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.
Phase 2: Time to Disease Progression (TTP)
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: Overall Survival (OS)
OS was defined as the time form the date of the randomization to the date of death.
Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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 Laboratory Values
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 2: Number of Participants With Clinically Significant Vital Sign Findings
Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
Full Information
NCT ID
NCT01091428
First Posted
March 17, 2010
Last Updated
May 1, 2018
Sponsor
Millennium Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT01091428
Brief Title
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
Official Title
Randomized Phase 2 Study of MLN8237, an Aurora A Kinase Inhibitor, Plus Weekly Paclitaxel or Weekly Paclitaxel Alone in Patients With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer, Preceded by a Phase 1 Portion in Patients With Ovarian or Breast Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
April 16, 2010 (Actual)
Primary Completion Date
August 12, 2014 (Actual)
Study Completion Date
July 19, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Millennium Pharmaceuticals, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ovarian Carcinoma, Fallopian Tube Cancer, Peritoneal Cancer, Breast Carcinoma
Keywords
RECIST: Response Evaluation Criteria in Solid Tumors, OC: Ovarian Cancer, GCIG: Gynecologic Cancer Intergroup, Breast carcinoma (Phase 1), Drug therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
191 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Alisertib (Phase 1 - Ovarian cancer)
Arm Type
Experimental
Arm Description
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).
Arm Title
Alisertib (Phase 1 - Breast cancer)
Arm Type
Experimental
Arm Description
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).
Arm Title
Alisertib 40 mg BID+Paclitaxel 60 mg/m^2 (Phase 2)
Arm Type
Experimental
Arm Description
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).
Arm Title
Paclitaxel 80 mg/m^2 (Phase 2)
Arm Type
Experimental
Arm Description
Paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).
Intervention Type
Drug
Intervention Name(s)
Alisertib
Other Intervention Name(s)
MLN8237
Intervention Description
Alisertib tablets
Intervention Type
Drug
Intervention Name(s)
Paclitaxel
Intervention Description
Paclitaxel intravenous infusion
Primary Outcome Measure Information:
Title
Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination With Paclitaxel
Description
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.
Time Frame
Cycle 1 (Up to 28 days)
Title
Phase 1: MTD and RP2D for Paclitaxel in Combination With Alisertib
Description
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).
Time Frame
Cycle 1 (Up to 28 days)
Title
Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
First dose to 30 days past last dose (Up to 36 Months)
Title
Phase 1: Number of Participants With Clinically Significant Laboratory Values
Description
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.
Time Frame
First dose to 30 days past last dose (Up to 36 Months)
Title
Phase 1: Number of Participants With Clinically Significant Vital Sign Findings
Description
Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
Time Frame
First dose to 30 days past last dose (Up to 36 Months)
Title
Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity
Time Frame
Baseline up to Month 36
Title
Phase 2: Progression-Free Survival (PFS)
Description
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.
Time Frame
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)
Secondary Outcome Measure Information:
Title
Phase 1: Combined Best Overall Response Rate (ORR) in Participants With Recurrent Ovarian Cancer or Breast Cancer
Description
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).
Time Frame
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)
Title
Cmax: Maximum Observed Concentration for Alisertib in Phase 1
Time Frame
Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
Title
Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1
Time Frame
Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
Title
AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1
Time Frame
Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
Title
AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1
Time Frame
Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose
Title
Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1
Time Frame
Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Title
AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1
Time Frame
Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Title
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
Time Frame
Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Title
t½: Terminal Half-Life for Paclitaxel in Phase 1
Time Frame
Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Title
CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1
Time Frame
Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Title
Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1
Time Frame
Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Title
Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1
Time Frame
Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion
Title
Phase 2: Combined Best Overall Response Rate (ORR)
Description
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).
Time Frame
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)
Title
Phase 2: Duration of Response (DOR)
Description
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.
Time Frame
Up to data-cut off: 12 August 2014 (approximately 24 months)
Title
Phase 2: Time to Disease Progression (TTP)
Description
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.
Time Frame
Up to data-cut off: 12 August 2014 (approximately 24 months)
Title
Phase 2: Overall Survival (OS)
Description
OS was defined as the time form the date of the randomization to the date of death.
Time Frame
Up to data-cut off: 12 August 2014 (approximately 24 months)
Title
Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
First dose to 30 days past last dose (Up to 27 Months)
Title
Phase 2: Number of Participants With Clinically Significant Laboratory Values
Description
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.
Time Frame
First dose to 30 days past last dose (Up to 27 Months)
Title
Phase 2: Number of Participants With Clinically Significant Vital Sign Findings
Description
Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
Time Frame
First dose to 30 days past last dose (Up to 27 Months)
Other Pre-specified Outcome Measures:
Title
Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes
Time Frame
Up to 24 Months
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Millennium Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
City
Bronx
State/Province
New York
Country
United States
City
Philadelphia
State/Province
Pennsylvania
Country
United States
City
Houston
State/Province
Texas
Country
United States
City
Seattle
State/Province
Washington
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
30347019
Citation
Falchook G, Coleman RL, Roszak A, Behbakht K, Matulonis U, Ray-Coquard I, Sawrycki P, Duska LR, Tew W, Ghamande S, Lesoin A, Schwartz PE, Buscema J, Fabbro M, Lortholary A, Goff B, Kurzrock R, Martin LP, Gray HJ, Fu S, Sheldon-Waniga E, Lin HM, Venkatakrishnan K, Zhou X, Leonard EJ, Schilder RJ. Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):e183773. doi: 10.1001/jamaoncol.2018.3773. Epub 2019 Jan 10.
Results Reference
derived
Learn more about this trial
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
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