Advanced Solid Malignancies, Hematologic Malignancies
Conditions
Keywords
Solid tumor, mTORC1/2 inhibitors, HER2
Brief summary
This is a Phase I, open label, dose escalation study of oral administration of MLN0128 in combination with paclitaxel, with/without trastuzumab, in participants with advanced solid malignancies.
Detailed description
This is a Phase I, open-label study consisting of a dose escalation phase in advanced solid malignancies to determine the maximum tolerated dose (MTD) of oral administration of MLN0128 in 1 or more dosing schedules, combined with paclitaxel on Days 1, 8 and 15 of each cycle, followed by an expansion phase for further safety and preliminary efficacy. Once the MTD is determined for each of the dosing schedules evaluated, a dose and schedule will be selected for the expansion phase, which may enroll participants into 2 arms in parallel: * Arm A will consist of HER2- unknown cancer participants receiving MLN0128+paclitaxel * Arm B will consist of HER2+ cancer participants receiving MLN0128+paclitaxel plus weekly trastuzumab
Interventions
DRUGMLN0128
MLN0128 capsules
DRUGpaclitaxel
paclitaxel intravenous infusion
DRUGtrastuzumab
trastuzumab intravenous infusion
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Voluntary written consent * Locally advanced or metastatic solid tumors with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Ability to swallow oral medications * For women of child-bearing potential, negative serum or urine pregnancy test within 14 days prior to the first study drug administration and use of physician-approved method of birth control from 30 days prior to 30 days following the last study drug administration * Male participants must be surgically sterile or must agree to use physician-approved contraception during the study and for 30 days following the last study drug administration * Clinical laboratory values as specified in the protocol * For expansion phase (Arm A) - HER2-/unknown participants will be enrolled * For expansion phase (Arm B) - HER2+ cancer participants will be enrolled
Exclusion criteria
* Diagnosis of primary brain tumor * Have received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug * Known impaired cardiac function or clinically significant cardiac disease * Known treatment with systemic corticosteroid within one week prior to the first administration of study drug * Diabetes mellitus * Human immunodeficiency virus (HIV) infection * Known active cardiovascular disease condition as specified in protocol * Pregnancy (positive serum or urine pregnancy test) or breast feeding * Malabsorption due to prior gastrointestinal (GI) surgery, GI disease * Other clinically significant co-morbidities Please note that there are additional inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Phase: Maximum Tolerated Dose (MTD) | Cycle 1: Days 1 to 28 | MTD is the highest dose level at which the participants tolerate treatment without dose-limiting toxicities during the first cycle (28 days) of therapy. |
| Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | Cycle 1: Days 1 to 28 | DLT was defined as any of the following occurring during Cycle 1 (Days 1-28) and attributable to MLN0128P: Grade ≥ 3 nonhematologic toxicity; Grade 3 thrombocytopenia with hemorrhage; Grade 4 neutropenia lasting \> 7 days in the absence of growth factor support; Grade 4 neutropenia of any duration associated with fever 38.5 degrees C and/or infection; Any other Grade 4 hematologic toxicity; Inability to administer at least 75 % of doses of MLN0128 within Cycle 1 due to drug-related toxicity; Any clinically significant occurrence which the investigators and sponsor agree would place participants at undue safety risk; Participants who experienced an adverse event (AE) that met the definition for a DLT. |
| Objective Response Rate (ORR) | At screening and thereafter every 2 cycles of treatment until disease progression (Up to 65.8 weeks) | ORR was defined as the percentage of participants with Complete Response (CR) and Partial Response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Each cycle was a 28 day cycle. CR was defined as the disappearance of all target lesions and for non-target lesions, the disappearance of all non-target lesions and normalization of tumor marker level. PR was defined of at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. |
| Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 91.4 weeks) | 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | — |
| AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | — |
| AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycles 1 and 2: Day 1 or 2 | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 30 and 40 mg QW arms. |
| Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycles 1 and 2: Day 1 | — |
| Cmin: Minimum Observed Plasma Concentration for Paclitaxel | Cycles 1 and 2: Day 1 or 2 | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. |
| AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel | Cycle 1 Day 1 | — |
| Terminal Phase Elimination Half-life (T1/2) for Paclitaxel | Cycle 1 Day 1 | — |
| AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel | Cycle 1 Day 1 | — |
| AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel | Cycle 1 Day 1 | — |
| CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | Cycle 1 Day 1 | — |
| Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | Cycle 1 Day 1 | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycles 1 and 2: Day 1 | — |
| Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycles 1 and 2: Day 1 or 2 | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. |
| Cmin: Minimum Observed Plasma Concentration for MLN0128 | Cycles 1 and 2: Day 1 or 2 | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycles 1 and 2: Day 1 or 2 | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i.e., C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at three investigative sites in the United States from 28 February 2011 to 15 Sep 2017.
Pre-assignment details
Participants with advanced solid malignancies enrolled in the dose escalation phase to establish MTD: MLN0128 6,7,8,9,10 mg QDx3d QW, 7mg QDx5d QW or 30, 40 mg QW. The expansion phase enrolled participants in either A: HER2- cancer participants, MLN0128 at MTD+paclitaxel or B: HER2+ cancer participants, MLN0128 at MTD+paclitaxel+trastuzumab.
Participants by arm
| Arm | Count |
|---|---|
| MLN0128P 30 or 40 mg QW MLN0128 and paclitaxel (MLN0128P): MLN0128 30 or 40 mg, capsule, orally, once weekly (QW) + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 15.3 weeks). | 8 |
| MLN0128P 6, 7, 8, 9 or 10 mg QD×3d QW MLN0128 and paclitaxel (MLN0128P): MLN0128 6 , 7, 8, 9 or 10 mg, capsule, orally, once daily (QD) 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase until MTD was established (Up to 87.4 weeks). | 29 |
| MLN0128P 7 mg QD×5d QW MLN0128 and paclitaxel (MLN0128P): MLN0128 7 mg, capsule, orally, once daily 5 days on/2 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase until MTD was established (Up 65.4 weeks). | 10 |
| Expansion Cohort MLN0128P 8 mg QD×3d QW HER2- MLN0128 and paclitaxel (MLN0128P): MLN0128 8 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in human epidermal growth factor receptor 2 negative (HER-) cancer participants until disease progression or unacceptable toxicity for up to 1 year in the Expansion Phase (Up to 61.6 weeks). | 13 |
| Expansion Cohort MLN0128PH 8mg QDx3d QW HER2+ Plus Trastuzumab MLN0128 + paclitaxel + trastuzumab (MLN0128PH): MLN0128 8 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 plus trastuzumab 4 mg/kg loading dose on Day 1 followed by 2 mg/kg, intravenous each week of a 4-week cycle in HER+ cancer participants until disease progression or unacceptable toxicity for up to 1 year in the Expansion Phase (Up to 23.4 weeks). | 7 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 10 | 1 | 2 | 0 |
| Overall Study | Disease Progression | 5 | 13 | 6 | 8 | 5 |
| Overall Study | Enrolled but not Treated | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Participant Decision | 2 | 6 | 3 | 3 | 2 |
Baseline characteristics
| Characteristic | MLN0128P 30 or 40 mg QW | MLN0128P 6, 7, 8, 9 or 10 mg QD×3d QW | MLN0128P 7 mg QD×5d QW | Expansion Cohort MLN0128P 8 mg QD×3d QW HER2- | Expansion Cohort MLN0128PH 8mg QDx3d QW HER2+ Plus Trastuzumab | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 57.3 years STANDARD_DEVIATION 14.34 | 62.9 years STANDARD_DEVIATION 9.57 | 58.1 years STANDARD_DEVIATION 14.7 | 54.2 years STANDARD_DEVIATION 14.46 | 58.1 years STANDARD_DEVIATION 8.03 | 59.3 years STANDARD_DEVIATION 12.07 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 8 Participants | 28 Participants | 10 Participants | 12 Participants | 6 Participants | 64 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 27 Participants | 10 Participants | 10 Participants | 7 Participants | 62 Participants |
| Region of Enrollment United States | 8 Participants | 29 Participants | 10 Participants | 13 Participants | 7 Participants | 67 Participants |
| Sex: Female, Male Female | 5 Participants | 14 Participants | 7 Participants | 6 Participants | 6 Participants | 38 Participants |
| Sex: Female, Male Male | 3 Participants | 15 Participants | 3 Participants | 7 Participants | 1 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 8 | 2 / 29 | 2 / 10 | 2 / 13 | 1 / 7 |
| other Total, other adverse events | 8 / 8 | 29 / 29 | 10 / 10 | 13 / 13 | 7 / 7 |
| serious Total, serious adverse events | 5 / 8 | 12 / 29 | 6 / 10 | 4 / 13 | 3 / 7 |
Outcome results
Primary
Dose Escalation Phase: Maximum Tolerated Dose (MTD)
MTD is the highest dose level at which the participants tolerate treatment without dose-limiting toxicities during the first cycle (28 days) of therapy.
Time frame: Cycle 1: Days 1 to 28
Population: Safety Population included all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation | Dose Escalation Phase: Maximum Tolerated Dose (MTD) | 8 mg (QD×3d QW) |
Primary
Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT)
DLT was defined as any of the following occurring during Cycle 1 (Days 1-28) and attributable to MLN0128P: Grade ≥ 3 nonhematologic toxicity; Grade 3 thrombocytopenia with hemorrhage; Grade 4 neutropenia lasting \> 7 days in the absence of growth factor support; Grade 4 neutropenia of any duration associated with fever 38.5 degrees C and/or infection; Any other Grade 4 hematologic toxicity; Inability to administer at least 75 % of doses of MLN0128 within Cycle 1 due to drug-related toxicity; Any clinically significant occurrence which the investigators and sponsor agree would place participants at undue safety risk; Participants who experienced an adverse event (AE) that met the definition for a DLT.
Time frame: Cycle 1: Days 1 to 28
Population: Dose-Escalation evaluable population included participants who received ≥ 75% of planned doses of MLN0128 in Cycle 1 or stopped study drug before receiving 75% of doses because of study drug-related AEs (considered as DLT).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation | Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | 0 participants |
| MLN0128P 40 mg QW | Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | 2 participants |
| MLN0128P 6 mg QD×3d QW | Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | 0 participants |
| MLN0128P 7 mg QD×3d QW | Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | 0 participants |
| MLN0128P 8 mg QD×3d QW | Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | 0 participants |
| MLN0128P 9 mg QD×3d QW | Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | 2 participants |
| MLN0128P 10 mg QD×3d QW | Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | 2 participants |
| MLN0128P 7 mg QD×5d QW | Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | 2 participants |
Primary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants with Complete Response (CR) and Partial Response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Each cycle was a 28 day cycle. CR was defined as the disappearance of all target lesions and for non-target lesions, the disappearance of all non-target lesions and normalization of tumor marker level. PR was defined of at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions.
Time frame: At screening and thereafter every 2 cycles of treatment until disease progression (Up to 65.8 weeks)
Population: Full Analysis Set (FAS) included all participants who received 1 or more doses of MLN0128 and have adequate baseline and post-baseline data collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation | Objective Response Rate (ORR) | 0 percentage of participants |
| MLN0128P 40 mg QW | Objective Response Rate (ORR) | 9 percentage of participants |
| MLN0128P 6 mg QD×3d QW | Objective Response Rate (ORR) | 44 percentage of participants |
| MLN0128P 7 mg QD×3d QW | Objective Response Rate (ORR) | 10 percentage of participants |
| MLN0128P 8 mg QD×3d QW | Objective Response Rate (ORR) | 20 percentage of participants |
Primary
Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug
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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event 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 of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 91.4 weeks)
Population: All Subjects as Treated (ASaT) population consisted of all enrolled participants who received at least 1 dose of MLN0128, was used in the safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 100 percentage of participants |
| Dose Escalation | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 63 percentage of participants |
| Dose Escalation | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 25 percentage of participants |
| Dose Escalation | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 13 percentage of participants |
| MLN0128P 40 mg QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 100 percentage of participants |
| MLN0128P 40 mg QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 34 percentage of participants |
| MLN0128P 40 mg QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 41 percentage of participants |
| MLN0128P 40 mg QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 7 percentage of participants |
| MLN0128P 6 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 10 percentage of participants |
| MLN0128P 6 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 60 percentage of participants |
| MLN0128P 6 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 20 percentage of participants |
| MLN0128P 6 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 100 percentage of participants |
| MLN0128P 7 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 100 percentage of participants |
| MLN0128P 7 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 31 percentage of participants |
| MLN0128P 7 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 15 percentage of participants |
| MLN0128P 7 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 15 percentage of participants |
| MLN0128P 8 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 0 percentage of participants |
| MLN0128P 8 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 14 percentage of participants |
| MLN0128P 8 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 43 percentage of participants |
| MLN0128P 8 mg QD×3d QW | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events(SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 100 percentage of participants |
Secondary
AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel
Time frame: Cycle 1 Day 1
Population: PK population consisted of all participants enrolled during the Dose Escalation phase of the study who received at least 1 dose of paclitaxel and had sufficient concentration-time data to calculate 1 or more PK parameters. AUC0-24 data is only available for participants in the MLN0128P 6,7,9 and 10 mg QD×3d QW arms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Escalation | AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel | 3583.3 ng*hr/mL |
| MLN0128P 40 mg QW | AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel | 4332.5 ng*hr/mL |
| MLN0128P 6 mg QD×3d QW | AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel | 6415.0 ng*hr/mL |
| MLN0128P 7 mg QD×3d QW | AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel | 5135.0 ng*hr/mL |
Secondary
AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128
Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 30 and 40 mg QW arms.
Time frame: Cycles 1 and 2: Day 1 or 2
Population: PK population included all participants enrolled during Dose Escalation phase, received at least 1 dose of MLN0128 and had sufficient concentration-time data to calculate PK parameters. Here, number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Dose Escalation | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 1 | 753.7 ng*hr/mL |
| Dose Escalation | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 2 | 883.6 ng*hr/mL |
| MLN0128P 40 mg QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 1 | 1325.0 ng*hr/mL |
| MLN0128P 40 mg QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 2 | 505.0 ng*hr/mL |
| MLN0128P 6 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 1 | 104.4 ng*hr/mL |
| MLN0128P 6 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 2 | 106.8 ng*hr/mL |
| MLN0128P 7 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 1 | 121.7 ng*hr/mL |
| MLN0128P 7 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 2 | 174.0 ng*hr/mL |
| MLN0128P 8 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 1 | 139.9 ng*hr/mL |
| MLN0128P 8 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 2 | 210.3 ng*hr/mL |
| MLN0128P 9 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 1 | 146.2 ng*hr/mL |
| MLN0128P 9 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 2 | 72.6 ng*hr/mL |
| MLN0128P 10 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 1 | 347.0 ng*hr/mL |
| MLN0128P 10 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Cycle 2 | 283.9 ng*hr/mL |
Secondary
AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel
Time frame: Cycle 1 Day 1
Population: Participants from the PK population, all participants enrolled during the Dose Escalation phase of the study who received at least 1 dose of paclitaxel and had sufficient concentration-time data to calculate 1 or more PK parameters, with data available for analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Escalation | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel | 3198.3 ng*hr/mL |
| MLN0128P 40 mg QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel | 3515.0 ng*hr/mL |
| MLN0128P 6 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel | 2620.0 ng*hr/mL |
| MLN0128P 7 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel | 3157.5 ng*hr/mL |
| MLN0128P 8 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel | 2683.3 ng*hr/mL |
| MLN0128P 9 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel | 5315.0 ng*hr/mL |
| MLN0128P 10 mg QD×3d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel | 3683.8 ng*hr/mL |
| MLN0128P 7 mg QD×5d QW | AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel | 2657.0 ng*hr/mL |
Secondary
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128
Time frame: Cycle 1 Day 1
Population: PK population consisted of all participants enrolled during the Dose Escalation phase of the study who received at least 1 dose of MLN0128 and had sufficient concentration-time data to calculate 1 or more PK parameters. AUC∞ data is only available for 2 participants in each the MLN0128P 6 mg QD×3d QW and MLN0128P 7 mg QD×3d QW arms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Escalation | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | 206.5 ng*hr/mL |
| MLN0128P 40 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | 286.0 ng*hr/mL |
Secondary
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel
Time frame: Cycle 1 Day 1
Population: PK population consisted of all participants enrolled during the Dose Escalation phase of the study who received at least 1 dose of paclitaxel and had sufficient concentration-time data to calculate 1 or more PK parameters. AUC∞ data is only available for participants in the MLN0128P 6,7,9 and 10 mg QD×3d QW arms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Escalation | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel | 4590.0 ng*hr/mL |
| MLN0128P 40 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel | 4790.0 ng*hr/mL |
| MLN0128P 6 mg QD×3d QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel | 5002.0 ng*hr/mL |
| MLN0128P 7 mg QD×3d QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel | 5485.0 ng*hr/mL |
Secondary
CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Time frame: Cycle 1 Day 1
Population: PK population consisted of all participants enrolled during the Dose Escalation phase of the study who received at least 1 dose of paclitaxel and had sufficient concentration-time data to calculate 1 or more PK parameters. CL data is only available for participants in the MLN0128P 6,7,9 and 10 mg QD×3d QW arms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Escalation | CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | 36.2 L/hr |
| MLN0128P 40 mg QW | CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | 34.8 L/hr |
| MLN0128P 6 mg QD×3d QW | CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | 31.2 L/hr |
| MLN0128P 7 mg QD×3d QW | CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | 25.8 L/hr |
Secondary
Cmax: Maximum Observed Plasma Concentration for MLN0128
Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms.
Time frame: Cycles 1 and 2: Day 1 or 2
Population: Pharmacokinetic (PK) population included all participants enrolled during Dose Escalation phase, received at least 1 dose of MLN0128 and had sufficient concentration-time data to calculate PK parameters, with data available for Cmax. Here, number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Dose Escalation | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 | 245.0 ng/mL |
| Dose Escalation | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 | 242.2 ng/mL |
| MLN0128P 40 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 | 345.5 ng/mL |
| MLN0128P 40 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 | 107.0 ng/mL |
| MLN0128P 6 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 | 26.7 ng/mL |
| MLN0128P 6 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 | 33.8 ng/mL |
| MLN0128P 7 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 | 31.1 ng/mL |
| MLN0128P 7 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 | 45.5 ng/mL |
| MLN0128P 8 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 | 41.8 ng/mL |
| MLN0128P 8 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 | 53.1 ng/mL |
| MLN0128P 9 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 | 34.2 ng/mL |
| MLN0128P 9 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 | 23.0 ng/mL |
| MLN0128P 10 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 | 80.1 ng/mL |
| MLN0128P 10 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 | 100.0 ng/mL |
| MLN0128P 7 mg QD×5d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 | 53.5 ng/mL |
| MLN0128P 7 mg QD×5d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 | 45.3 ng/mL |
Secondary
Cmax: Maximum Observed Plasma Concentration for Paclitaxel
Time frame: Cycles 1 and 2: Day 1
Population: PK population included all participants enrolled during Dose Escalation phase, received at least 1 dose of paclitaxel and had sufficient concentration-time data to calculate PK parameters, with data available for Cmax. Here, number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Dose Escalation | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 1, Day 1 | 2538.0 ng/mL |
| Dose Escalation | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 2, Day 1 | 3462.5 ng/mL |
| MLN0128P 40 mg QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 1, Day 1 | 2355.0 ng/mL |
| MLN0128P 40 mg QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 2, Day 1 | 1500.0 ng/mL |
| MLN0128P 6 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 1, Day 1 | 1933.3 ng/mL |
| MLN0128P 6 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 2, Day 1 | 1200.3 ng/mL |
| MLN0128P 7 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 1, Day 1 | 1942.5 ng/mL |
| MLN0128P 7 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 2, Day 1 | 1550.0 ng/mL |
| MLN0128P 8 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 1, Day 1 | 1620.0 ng/mL |
| MLN0128P 8 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 2, Day 1 | 3103.3 ng/mL |
| MLN0128P 9 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 1, Day 1 | 3798.3 ng/mL |
| MLN0128P 9 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 2, Day 1 | 1602.3 ng/mL |
| MLN0128P 10 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 2, Day 1 | 2964.0 ng/mL |
| MLN0128P 10 mg QD×3d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 1, Day 1 | 2906.9 ng/mL |
| MLN0128P 7 mg QD×5d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 1, Day 1 | 1637.7 ng/mL |
| MLN0128P 7 mg QD×5d QW | Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 2, Day 1 | 1765.7 ng/mL |
Secondary
Cmin: Minimum Observed Plasma Concentration for MLN0128
Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms.
Time frame: Cycles 1 and 2: Day 1 or 2
Population: Due to the change in planned analysis, minimum plasma concentration data was not collected.
Secondary
Cmin: Minimum Observed Plasma Concentration for Paclitaxel
Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms.
Time frame: Cycles 1 and 2: Day 1 or 2
Population: Due to the change in planned analysis, minimum plasma concentration data was not collected.
Secondary
Terminal Phase Elimination Half-life (T1/2) for MLN0128
Time frame: Cycle 1 Day 1
Population: PK population consisted of all participants enrolled during the Dose Escalation phase of the study who received at least 1 dose of MLN0128 and had sufficient concentration-time data to calculate 1 or more PK parameters. T1/2 data is only available for 2 participants in the MLN0128P 6 mg QD×3d QW and 2 participants in the MLN0128P 7 mg QD×3d QW arm.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Escalation | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | 6.6 hours |
| MLN0128P 40 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | 7.2 hours |
Secondary
Terminal Phase Elimination Half-life (T1/2) for Paclitaxel
Time frame: Cycle 1 Day 1
Population: PK population consisted of all participants enrolled during the Dose Escalation phase of the study who received at least 1 dose of paclitaxel and had sufficient concentration-time data to calculate 1 or more PK parameters. T1/2 data is only available for participants in the MLN0128P 6,7,9 and 10 mg QD×3d QW arms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Escalation | Terminal Phase Elimination Half-life (T1/2) for Paclitaxel | 10.0 hours |
| MLN0128P 40 mg QW | Terminal Phase Elimination Half-life (T1/2) for Paclitaxel | 9.1 hours |
| MLN0128P 6 mg QD×3d QW | Terminal Phase Elimination Half-life (T1/2) for Paclitaxel | 9.6 hours |
| MLN0128P 7 mg QD×3d QW | Terminal Phase Elimination Half-life (T1/2) for Paclitaxel | 9.3 hours |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128
Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i.e., C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms.
Time frame: Cycles 1 and 2: Day 1 or 2
Population: PK population included all participants enrolled during Dose Escalation phase, received at least 1 dose of MLN0128 and had sufficient concentration-time data to calculate PK parameters, with data available for Tmax. Here, number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 1 | 3.0 hours |
| Dose Escalation | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 2 | 2.0 hours |
| MLN0128P 40 mg QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 1 | 3.0 hours |
| MLN0128P 40 mg QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 2 | 4.0 hours |
| MLN0128P 6 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 1 | 2.0 hours |
| MLN0128P 6 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 2 | 4.0 hours |
| MLN0128P 7 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 1 | 3.0 hours |
| MLN0128P 7 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 2 | 2.0 hours |
| MLN0128P 8 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 1 | 5.6 hours |
| MLN0128P 8 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 2 | 1.0 hours |
| MLN0128P 9 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 1 | 4.1 hours |
| MLN0128P 9 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 2 | 5.5 hours |
| MLN0128P 10 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 2 | 2.0 hours |
| MLN0128P 10 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 1 | 1.0 hours |
| MLN0128P 7 mg QD×5d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 1 | 1.6 hours |
| MLN0128P 7 mg QD×5d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 2 | 2.7 hours |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel
Time frame: Cycles 1 and 2: Day 1
Population: PK population consisted of all participants enrolled during Dose Escalation phase of study who received at least 1 dose of MLN0128 or paclitaxel and had sufficient concentration-time data to calculate PK parameters for either compound. Here, number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 2, Day 1 | 1.1 hours |
| Dose Escalation | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 1, Day 1 | 1.1 hours |
| MLN0128P 40 mg QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 2, Day 1 | 1.2 hours |
| MLN0128P 40 mg QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 1, Day 1 | 1.1 hours |
| MLN0128P 6 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 2, Day 1 | 1.6 hours |
| MLN0128P 6 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 1, Day 1 | 1.1 hours |
| MLN0128P 7 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 1, Day 1 | 1.2 hours |
| MLN0128P 7 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 2, Day 1 | 1.4 hours |
| MLN0128P 8 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 2, Day 1 | 1.2 hours |
| MLN0128P 8 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 1, Day 1 | 1.2 hours |
| MLN0128P 9 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 1, Day 1 | 1.1 hours |
| MLN0128P 9 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 2, Day 1 | 1.2 hours |
| MLN0128P 10 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 1, Day 1 | 1.1 hours |
| MLN0128P 10 mg QD×3d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 2, Day 1 | 1.0 hours |
| MLN0128P 7 mg QD×5d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 2, Day 1 | 1.1 hours |
| MLN0128P 7 mg QD×5d QW | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel | Cycle 1, Day 1 | 1.5 hours |
Secondary
Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Time frame: Cycle 1 Day 1
Population: PK population consisted of all participants enrolled during the Dose Escalation phase of the study who received at least 1 dose of paclitaxel and had sufficient concentration-time data to calculate 1 or more PK parameters. Vss data is only available for participants in the MLN0128P 6,7,9 and 10 mg QD×3d QW arms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Escalation | Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | 313.5 L |
| MLN0128P 40 mg QW | Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | 262.0 L |
| MLN0128P 6 mg QD×3d QW | Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | 252.2 L |
| MLN0128P 7 mg QD×3d QW | Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | 150.0 L |