Breast Carcinoma, Fallopian Tube Cancer, Ovarian Carcinoma, Peritoneal Cancer
Conditions
Keywords
RECIST: Response Evaluation Criteria in Solid Tumors, OC: Ovarian Cancer, GCIG: Gynecologic Cancer Intergroup, Breast carcinoma (Phase 1), Drug therapy
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.
Interventions
DRUGAlisertib
Alisertib tablets
DRUGPaclitaxel
Paclitaxel intravenous infusion
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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: 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: 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 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: 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. |
| Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity | Baseline up to Month 36 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 | — |
| 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 | — |
| 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 | — |
| 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 | — |
| 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: 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. |
| 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: 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. |
| 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 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 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. |
| 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 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). |
| 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 | — |
| 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 | — |
| 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 | — |
| 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 | — |
| 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 | — |
Other
| Measure | Time frame |
|---|---|
| Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes | Up to 24 Months |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 33 investigative sites in France, Poland and the United States from 16 April 2010 to 19 July 2017. Data cutoff for the primary analysis was 12 August 2014.
Pre-assignment details
Participants with a diagnosis of ovarian cancer or breast cancer were enrolled equally in a dose escalation study to determine the recommended Phase 2 dose. In Phase 2 participants were randomized equally to receive alisertib 40 mg BID + paclitaxel 60 mg/m\^2 or single agent paclitaxel 80 mg/m\^2.
Participants by arm
| Arm | Count |
|---|---|
| Alisertib (Phase 1 - Ovarian Cancer) 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). | 38 |
| Alisertib (Phase 1 - Breast Cancer) 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). | 11 |
| Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) 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). | 73 |
| Paclitaxel 80 mg/m^2 (Phase 2) Paclitaxel 80 mg/m\^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles). | 69 |
| Total | 191 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase 1 | Adverse Event | 2 | 0 | 0 | 0 |
| Phase 1 | Progressive Disease | 24 | 8 | 0 | 0 |
| Phase 1 | Reason not specified | 0 | 1 | 0 | 0 |
| Phase 1 | Single-Patient IND | 2 | 0 | 0 | 0 |
| Phase 1 | Symptomatic Deterioration | 3 | 2 | 0 | 0 |
| Phase 1 | Withdrawal by Subject | 7 | 0 | 0 | 0 |
| Phase 2 | Adverse Event | 0 | 0 | 12 | 5 |
| Phase 2 | Physician Decision | 0 | 0 | 2 | 0 |
| Phase 2 | Progressive Disease | 0 | 0 | 44 | 46 |
| Phase 2 | Reason not specified | 0 | 0 | 4 | 3 |
| Phase 2 | Symptomatic Deterioration | 0 | 0 | 1 | 6 |
| Phase 2 | Unsatisfactory Therapeutic Response | 0 | 0 | 1 | 1 |
| Phase 2 | Withdrawal by Subject | 0 | 0 | 9 | 8 |
Baseline characteristics
| Characteristic | Alisertib (Phase 1 - Ovarian Cancer) | Total | Alisertib (Phase 1 - Breast Cancer) | Paclitaxel 80 mg/m^2 (Phase 2) | Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2) |
|---|---|---|---|---|---|
| Age, Continuous | 55.8 years STANDARD_DEVIATION 10.29 | 59.8 years STANDARD_DEVIATION 10.32 | 58.6 years STANDARD_DEVIATION 10.06 | 60.8 years STANDARD_DEVIATION 8.41 | 61.0 years STANDARD_DEVIATION 11.6 |
| Body Surface Area | 1.850 m^2 STANDARD_DEVIATION 0.21 | 1.802 m^2 STANDARD_DEVIATION 0.21 | 1.865 m^2 STANDARD_DEVIATION 0.1 | 1.794 m^2 STANDARD_DEVIATION 0.24 | 1.776 m^2 STANDARD_DEVIATION 0.2 |
| Height | 164.2 cm STANDARD_DEVIATION 6.41 | 162.7 cm STANDARD_DEVIATION 6.99 | 164.5 cm STANDARD_DEVIATION 6.38 | 161.9 cm STANDARD_DEVIATION 7.3 | 162.4 cm STANDARD_DEVIATION 7.02 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 participants | 2 participants | 0 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 4 participants | 0 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants | 11 participants | 0 participants | 6 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 participants | 9 participants | 0 participants | 4 participants | 1 participants |
| Race/Ethnicity, Customized Missing | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 34 participants | 170 participants | 10 participants | 62 participants | 64 participants |
| Race/Ethnicity, Customized Not Reported | 0 participants | 11 participants | 1 participants | 3 participants | 7 participants |
| Race/Ethnicity, Customized Other | 0 participants | 2 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 34 participants | 166 participants | 11 participants | 55 participants | 66 participants |
| Region of Enrollment France | 0 participants | 31 participants | 0 participants | 16 participants | 15 participants |
| Region of Enrollment Poland | 0 participants | 18 participants | 0 participants | 8 participants | 10 participants |
| Region of Enrollment United States | 38 participants | 142 participants | 11 participants | 45 participants | 48 participants |
| Sex: Female, Male Female | 38 Participants | 191 Participants | 11 Participants | 69 Participants | 73 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Weight | 75.86 kg STANDARD_DEVIATION 16.41 | 72.59 kg STANDARD_DEVIATION 16.37 | 76.29 kg STANDARD_DEVIATION 7.29 | 72.50 kg STANDARD_DEVIATION 18.71 | 70.42 kg STANDARD_DEVIATION 14.78 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 38 / 38 | 11 / 11 | 73 / 73 | 64 / 69 |
| serious Total, serious adverse events | 13 / 38 | 2 / 11 | 30 / 73 | 19 / 69 |
Outcome results
Primary
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.
Time frame: Cycle 1 (Up to 28 days)
Population: DLT-Evaluable Population was defined as all participants in the phase 1 who either experienced DLT during Cycle 1 or completed treatment with at least 15 of the planned 18 doses of alisertib and 2 of the planned 3 doses of paclitaxel in Cycle 1 and had sufficient follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination With Paclitaxel | 40 mg |
Primary
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).
Time frame: Cycle 1 (Up to 28 days)
Population: DLT-Evaluable Population was defined as all participants in the phase 1 who either experienced DLT during Cycle 1 or completed treatment with at least 15 of the planned 18 doses of alisertib and 2 of the planned 3 doses of paclitaxel in Cycle 1 and had sufficient follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 1: MTD and RP2D for Paclitaxel in Combination With Alisertib | 60 mg/m^2 |
Primary
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.
Time frame: First dose to 30 days past last dose (Up to 36 Months)
Population: Safety population was defined as all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 38 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 13 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 11 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
Primary
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.
Time frame: First dose to 30 days past last dose (Up to 36 Months)
Population: Safety population was defined as all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Aspartate aminotransferase increased | 3 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Alanine aminotransferase increased | 2 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Ammonia increased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Transaminases increased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Blood alkaline phosphatase increased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | High density lipoprotein decreased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Urine output decreased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Granulocyte count decreased | 0 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | White blood cell count decreased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Neutrophil count decreased | 3 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Granulocyte count decreased | 1 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Aspartate aminotransferase increased | 1 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | High density lipoprotein decreased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Alanine aminotransferase increased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Neutrophil count decreased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Ammonia increased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Urine output decreased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Transaminases increased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | White blood cell count decreased | 1 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Blood alkaline phosphatase increased | 1 participants |
Primary
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.
Time frame: First dose to 30 days past last dose (Up to 36 Months)
Population: Safety population was defined as all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Vital Sign Findings | Pyrexia | 8 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Vital Sign Findings | Heart rate irregular | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Vital Sign Findings | Blood pressure increased | 0 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Clinically Significant Vital Sign Findings | Weight decreased | 3 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Vital Sign Findings | Weight decreased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Vital Sign Findings | Pyrexia | 5 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Vital Sign Findings | Blood pressure increased | 1 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Clinically Significant Vital Sign Findings | Heart rate irregular | 0 participants |
Primary
Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity
Time frame: Baseline up to Month 36
Population: Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.~Safety population was defined as all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity | Hypersensitivity | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity | Neurotoxicity | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity | Hypersensitivity | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Number of Participants With Hypersensitivity and Neurotoxicity | Neurotoxicity | 0 participants |
Primary
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.
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)
Population: The modified intent-to-treat (mITT) population was defined as all participants who were randomized and received at least 1 dose of any study drug. For a participant that has not progressed and has not died or has started the alternate therapy, PFS is censored at the last response assessment that is stable disease (SD) or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Progression-Free Survival (PFS) | 204 days |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Progression-Free Survival (PFS) | 142 days |
Secondary
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
Population: PK analysis set for paclitaxel was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration time data to permit noncompartmental PK analysis. Number analyzed is the number of participants with evaluable data at the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (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 | Cycle 1, Day 1 | 5317.8 ng/mL*hr | Standard Deviation 1052.4 |
| Alisertib + Paclitaxel (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 | Cycle 2, Day 1 | 4606.4 ng/mL*hr | Standard Deviation 1391.35 |
| Alisertib (Phase 1 - Breast Cancer) | 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 | Cycle 2, Day 1 | 5584.0 ng/mL*hr | Standard Deviation 1367.51 |
| Alisertib (Phase 1 - Breast Cancer) | 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 | Cycle 1, Day 1 | 5238.0 ng/mL*hr | Standard Deviation 812.26 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | 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 | Cycle 2, Day 1 | 3185.0 ng/mL*hr | Standard Deviation 176.78 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | 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 | Cycle 1, Day 1 | 3860.0 ng/mL*hr | Standard Deviation 824.2 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | 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 | Cycle 2, Day 1 | 3415.0 ng/mL*hr | Standard Deviation 1010.82 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | 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 | Cycle 1, Day 1 | 3375.0 ng/mL*hr | Standard Deviation 1130.56 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | 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 | Cycle 2, Day 1 | 2680.0 ng/mL*hr | Standard Deviation 607.22 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | 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 | Cycle 1, Day 1 | 3175.5 ng/mL*hr | Standard Deviation 933.1 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | 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 | Cycle 1, Day 1 | 2535.0 ng/mL*hr | Standard Deviation 657.61 |
Secondary
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
Population: PK analysis set for alisertib was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (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 | Cycle 1, Day 1 | 2519.3 ng/mL*hr | Standard Deviation 937.52 |
| Alisertib + Paclitaxel (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 | Cycle 1, Day 3 | 3966.7 ng/mL*hr | Standard Deviation 1112.11 |
| Alisertib (Phase 1 - Breast Cancer) | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 1 | 5175.0 ng/mL*hr | Standard Deviation 1766.11 |
| Alisertib (Phase 1 - Breast Cancer) | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 3 | 7745.0 ng/mL*hr | Standard Deviation 2233.91 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 1 | 5610.0 ng/mL*hr | Standard Deviation 2105.42 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 3 | 6155.0 ng/mL*hr | Standard Deviation 1737.69 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 1 | 8581.7 ng/mL*hr | Standard Deviation 3225.64 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 3 | 12478.3 ng/mL*hr | Standard Deviation 6013.93 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 1 | 9594.0 ng/mL*hr | Standard Deviation 4600.42 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 3 | 17557.3 ng/mL*hr | Standard Deviation 7856.3 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 1 | 14666.7 ng/mL*hr | Standard Deviation 3707.2 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1 | Cycle 1, Day 3 | 35500.0 ng/mL*hr | Standard Deviation 12842.12 |
Secondary
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
Population: PK analysis set for paclitaxel was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration time data to permit noncompartmental PK analysis. Number analyzed is the number of participants with evaluable data at the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (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 | Cycle 1, Day 1 | 4437.7 ng/mL*hr | Standard Deviation 1053.87 |
| Alisertib + Paclitaxel (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 | Cycle 2, Day 1 | 4061.7 ng/mL*hr | Standard Deviation 1298.86 |
| Alisertib (Phase 1 - Breast Cancer) | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 4825.0 ng/mL*hr | Standard Deviation 735.17 |
| Alisertib (Phase 1 - Breast Cancer) | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 5301.7 ng/mL*hr | Standard Deviation 1183.31 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 3355.0 ng/mL*hr | Standard Deviation 865.89 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 2660.0 ng/mL*hr | Standard Deviation 307.9 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 3056.0 ng/mL*hr | Standard Deviation 812.67 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 3366.0 ng/mL*hr | Standard Deviation 1139.25 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 2652.7 ng/mL*hr | Standard Deviation 651.32 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 2231.5 ng/mL*hr | Standard Deviation 604.76 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 2460.0 ng/mL*hr | Standard Deviation 14.14 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 2190.0 ng/mL*hr | Standard Deviation 387.43 |
Secondary
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
Population: PK analysis set for alisertib was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day 1 | 2519.3 ng/mL*hour(hr) | Standard Deviation 937.52 |
| Alisertib + Paclitaxel (Phase 1) | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day3 | 3966.7 ng/mL*hour(hr) | Standard Deviation 1112.11 |
| Alisertib (Phase 1 - Breast Cancer) | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day 1 | 5175.0 ng/mL*hour(hr) | Standard Deviation 1766.11 |
| Alisertib (Phase 1 - Breast Cancer) | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day3 | 7745.0 ng/mL*hour(hr) | Standard Deviation 2233.91 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day 1 | 5610.0 ng/mL*hour(hr) | Standard Deviation 2105.42 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day3 | 6155.0 ng/mL*hour(hr) | Standard Deviation 1737.69 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day 1 | 8581.7 ng/mL*hour(hr) | Standard Deviation 3225.64 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day3 | 12478.3 ng/mL*hour(hr) | Standard Deviation 6013.93 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day3 | 17557.3 ng/mL*hour(hr) | Standard Deviation 7856.3 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day 1 | 9594.0 ng/mL*hour(hr) | Standard Deviation 4600.42 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day3 | 35500.0 ng/mL*hour(hr) | Standard Deviation 12842.12 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | AUC(Tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1 | Cycle 1, Day 1 | 14666.7 ng/mL*hour(hr) | Standard Deviation 3707.2 |
Secondary
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
Population: PK analysis set for paclitaxel was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration time data to permit noncompartmental PK analysis. Number analyzed is the number of participants with evaluable data at the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 29.756 liter per hour | Standard Deviation 6.8175 |
| Alisertib + Paclitaxel (Phase 1) | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 35.827 liter per hour | Standard Deviation 10.4005 |
| Alisertib (Phase 1 - Breast Cancer) | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 28.240 liter per hour | Standard Deviation 7.3748 |
| Alisertib (Phase 1 - Breast Cancer) | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 28.220 liter per hour | Standard Deviation 5.1804 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 33.900 liter per hour | Standard Deviation 5.2326 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 26.800 liter per hour | Standard Deviation 7.5386 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 34.250 liter per hour | Standard Deviation 8.2614 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 40.950 liter per hour | Standard Deviation 17.5268 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 42.440 liter per hour | Standard Deviation 10.4296 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 38.055 liter per hour | Standard Deviation 13.7095 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 38.950 liter per hour | Standard Deviation 11.243 |
Secondary
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
Population: Pharmacokinetic (PK) analysis set for alisertib was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day1) | 428.7 ng/mL | Standard Deviation 189.59 |
| Alisertib + Paclitaxel (Phase 1) | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day3) | 594.3 ng/mL | Standard Deviation 228.46 |
| Alisertib (Phase 1 - Breast Cancer) | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day1) | 766.8 ng/mL | Standard Deviation 312.1 |
| Alisertib (Phase 1 - Breast Cancer) | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day3) | 1042.3 ng/mL | Standard Deviation 280.95 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day1) | 900.00 ng/mL | Standard Deviation 392.17 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day3) | 871.3 ng/mL | Standard Deviation 268.23 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day1) | 1365.3 ng/mL | Standard Deviation 466.51 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day3) | 1708.5 ng/mL | Standard Deviation 820.54 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day1) | 1398.7 ng/mL | Standard Deviation 607.7 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day3) | 2493.4 ng/mL | Standard Deviation 955.31 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day1) | 1960.0 ng/mL | Standard Deviation 515.65 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Alisertib in Phase 1 | Cycle1 (Day3) | 4456.7 ng/mL | Standard Deviation 947.33 |
Secondary
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
Population: PK analysis set for paclitaxel was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration time data to permit noncompartmental PK analysis. Number analyzed is the number of participants with evaluable data at the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 3097.3 ng/mL | Standard Deviation 1114.51 |
| Alisertib + Paclitaxel (Phase 1) | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 2654.6 ng/mL | Standard Deviation 696.45 |
| Alisertib (Phase 1 - Breast Cancer) | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 3120.0 ng/mL | Standard Deviation 447.75 |
| Alisertib (Phase 1 - Breast Cancer) | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 3231.7 ng/mL | Standard Deviation 615.64 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 2117.5 ng/mL | Standard Deviation 745.54 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 1733.3 ng/mL | Standard Deviation 541.97 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 2448.0 ng/mL | Standard Deviation 988.65 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 2478.3 ng/mL | Standard Deviation 878.39 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 1917.3 ng/mL | Standard Deviation 528.32 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 1492.7 ng/mL | Standard Deviation 558.14 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 1338.7 ng/mL | Standard Deviation 617.94 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 1750.0 ng/mL | Standard Deviation 183.85 |
Secondary
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).
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)
Population: Response evaluable population was defined as all participants who were randomized and had measurable disease according to RECIST or assessable disease by CA-125 criteria, who received at least 1 dose of any study drug, and who had at least 1 available post-Baseline response assessment as per either RECIST or CA-125 criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 1: Combined Best Overall Response Rate (ORR) in Participants With Recurrent Ovarian Cancer or Breast Cancer | 47 percentage of participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 1: Combined Best Overall Response Rate (ORR) in Participants With Recurrent Ovarian Cancer or Breast Cancer | 55 percentage of participants |
Secondary
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).
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)
Population: Response evaluable population was defined as all participants who were randomized and had measurable disease according to RECIST or assessable disease by CA-125 criteria, who received at least 1 dose of any study drug, and who had at least 1 available post-Baseline response assessment as per either RECIST or CA-125 criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Combined Best Overall Response Rate (ORR) | 60 percentage of participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Combined Best Overall Response Rate (ORR) | 52 percentage of participants |
Secondary
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.
Time frame: Up to data-cut off: 12 August 2014 (approximately 24 months)
Population: Participants from Response evaluable population, all participants who were randomized and had measurable disease according to RECIST 1.1 or assessable disease by CA-125 criteria, who received at least 1 dose of any study drug, and who had at least 1 available post-Baseline response assessment per RECIST 1.1 or CA-125 criteria, who were responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Duration of Response (DOR) | 201 days |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Duration of Response (DOR) | 169 days |
Secondary
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.
Time frame: First dose to 30 days past last dose (Up to 27 Months)
Population: Safety population was defined as all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 73 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 30 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 66 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 19 participants |
Secondary
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.
Time frame: First dose to 30 days past last dose (Up to 27 Months)
Population: Safety population was defined as all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Neutrophil count decreased | 14 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Alanine aminotransferase increased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Blood creatinine increased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Gamma-glutamyltransferase increased | 0 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | White blood cell count decreased | 6 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Blood alkaline phosphatase increased | 2 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Troponin T increased | 0 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Lymphocyte count decreased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Platelet count decreased | 2 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Blood magnesium decreased | 0 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | International normalised ratio increased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Aspartate aminotransferase increased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Blood albumin decreased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Haemoglobin decreased | 3 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Blood albumin decreased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Haemoglobin decreased | 1 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Blood magnesium decreased | 3 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Troponin T increased | 1 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Neutrophil count decreased | 4 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | White blood cell count decreased | 1 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Lymphocyte count decreased | 1 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Aspartate aminotransferase increased | 3 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Alanine aminotransferase increased | 4 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Gamma-glutamyltransferase increased | 1 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Blood alkaline phosphatase increased | 2 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Blood creatinine increased | 2 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | Platelet count decreased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Laboratory Values | International normalised ratio increased | 0 participants |
Secondary
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.
Time frame: First dose to 30 days past last dose (Up to 27 Months)
Population: Safety population was defined as all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Vital Sign Findings | Pyrexia | 15 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Vital Sign Findings | Heart rate increased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Vital Sign Findings | Blood pressure increased | 1 participants |
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Number of Participants With Clinically Significant Vital Sign Findings | Weight decreased | 8 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Vital Sign Findings | Weight decreased | 2 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Vital Sign Findings | Pyrexia | 8 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Vital Sign Findings | Blood pressure increased | 0 participants |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Number of Participants With Clinically Significant Vital Sign Findings | Heart rate increased | 0 participants |
Secondary
Phase 2: Overall Survival (OS)
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)
Population: mITT Population was defined as all participants who were randomized and received at least 1 dose of any study drug. For a participant that is alive, OS will be censored at the last known date.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Overall Survival (OS) | NA days |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Overall Survival (OS) | NA days |
Secondary
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.
Time frame: Up to data-cut off: 12 August 2014 (approximately 24 months)
Population: mITT Population was defined as all participants who were randomized and received at least 1 dose of any study drug. For a participant that has not progressed, TTP is censored at the last response assessment that is SD or better
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Phase 2: Time to Disease Progression (TTP) | 204 days |
| Alisertib (Phase 1 - Breast Cancer) | Phase 2: Time to Disease Progression (TTP) | 142 days |
Secondary
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
Population: PK analysis set for paclitaxel was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration time data to permit noncompartmental PK analysis. Number analyzed is the number of participants with evaluable data at the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 17.2 hour | Standard Deviation 4.2 |
| Alisertib + Paclitaxel (Phase 1) | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 17.0 hour | Standard Deviation 3.63 |
| Alisertib (Phase 1 - Breast Cancer) | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 17.5 hour | Standard Deviation 1.87 |
| Alisertib (Phase 1 - Breast Cancer) | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 16.2 hour | Standard Deviation 5.05 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 17.3 hour | Standard Deviation 4.16 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 17.3 hour | Standard Deviation 5.23 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 13.9 hour | Standard Deviation 4.68 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 16.5 hour | Standard Deviation 4.32 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 16.8 hour | Standard Deviation 6.83 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 13.3 hour | Standard Deviation 5.59 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 18.4 hour | Standard Deviation 8.7 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | t½: Terminal Half-Life for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 14.6 hour | Standard Deviation 2.19 |
Secondary
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
Population: PK analysis set for alisertib was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 1 | 3.0 hour | Full Range 189.59 |
| Alisertib + Paclitaxel (Phase 1) | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 3 | 2.2 hour | Full Range 228.46 |
| Alisertib (Phase 1 - Breast Cancer) | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 1 | 3.1 hour | Full Range 312.1 |
| Alisertib (Phase 1 - Breast Cancer) | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 3 | 3.0 hour | Full Range 280.95 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 1 | 2.6 hour | Full Range 392.17 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 3 | 3.5 hour | Full Range 268.23 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 1 | 2.5 hour | Full Range 466.51 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 3 | 2.0 hour | Full Range 820.54 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 1 | 3.0 hour | Full Range 607.7 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 3 | 2.0 hour | Full Range 955.31 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 1 | 2.0 hour | Full Range 515.65 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1 | Cycle 1, Day 3 | 2.0 hour | Full Range 947.33 |
Secondary
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
Population: PK analysis set for paclitaxel was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration time data to permit noncompartmental PK analysis. Number analyzed is the number of participants with evaluable data at the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 313.444 liter | Standard Deviation 118.6593 |
| Alisertib + Paclitaxel (Phase 1) | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 391.364 liter | Standard Deviation 64.3137 |
| Alisertib (Phase 1 - Breast Cancer) | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 283.200 liter | Standard Deviation 121.1123 |
| Alisertib (Phase 1 - Breast Cancer) | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 310.800 liter | Standard Deviation 86.9235 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 413.500 liter | Standard Deviation 242.5376 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 330.000 liter | Standard Deviation 208.8851 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 377.000 liter | Standard Deviation 118.965 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 357.000 liter | Standard Deviation 158.1834 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 372.600 liter | Standard Deviation 180.7332 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 433.909 liter | Standard Deviation 179.7757 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 460.500 liter | Standard Deviation 103.9447 |
Secondary
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
Population: PK analysis set for paclitaxel was defined as all participants in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration time data to permit noncompartmental PK analysis. Number analyzed is the number of participants with evaluable data at the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel (Phase 1) | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 705.000 liter | Standard Deviation 179.0223 |
| Alisertib + Paclitaxel (Phase 1) | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 829.364 liter | Standard Deviation 156.606 |
| Alisertib (Phase 1 - Breast Cancer) | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 663.200 liter | Standard Deviation 321.307 |
| Alisertib (Phase 1 - Breast Cancer) | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 721.600 liter | Standard Deviation 203.8021 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 694.000 liter | Standard Deviation 352.1534 |
| Alisertib 20 mg BID + Paclitaxel 60 mg/m^2 | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 865.500 liter | Standard Deviation 388.2016 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 850.500 liter | Standard Deviation 291.0401 |
| Alisertib 30 mg BID + Paclitaxel 60 mg/m^2 | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 777.250 liter | Standard Deviation 103.7027 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 2, Day 1 | 733.000 liter | Standard Deviation 208.4898 |
| Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 872.727 liter | Standard Deviation 328.6202 |
| Alisertib 50 mg BID + Paclitaxel 60 mg/m^2 | Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1 | Cycle 1, Day 1 | 956.500 liter | Standard Deviation 188.7975 |
Other Pre-specified
Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes
Time frame: Up to 24 Months
Population: This Outcome Measure was originally registered as a Secondary but this Outcome Measure was Exploratory and no data was collected.