Dose Escalation Study of MLN0128 in Combination With Paclitaxel, With/Without Trastuzumab, in Subjects With Advanced Solid Malignancies

Sponsor

Millennium Pharmaceuticals, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT01351350

Collaborator

(none)

Enrollment

Locations

Arms

78.6

Actual Duration (Months)

22.7

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Malignancies Hematologic Malignancies	Drug: MLN0128 Drug: paclitaxel Drug: trastuzumab	Phase 1

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

Study Design

Study Type:

Interventional

Actual Enrollment :

68 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I, Open Label, Dose Escalation Study of Oral Administration of MLN0128 in Combination With Paclitaxel, With/Without Trastuzumab, in Subjects With Advanced Solid Malignancies

Actual Study Start Date :

Feb 28, 2011

Actual Primary Completion Date :

Sep 15, 2017

Actual Study Completion Date :

Sep 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MLN0128P 30 mg QW MLN0128 and paclitaxel (MLN0128P): MLN0128 30 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.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion
Experimental: MLN0128P 40 mg QW MLN0128 40 mg, capsule, orally, once a week (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.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion
Experimental: MLN0128P 6 mg QD×3d QW MLN0128 6 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 the Dose Escalation Phase.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion
Experimental: MLN0128P 7 mg QD×3d QW MLN0128 7 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 the Dose Escalation Phase.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion
Experimental: MLN0128P 8 mg QD×3d QW 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 the Dose Escalation Phase.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion
Experimental: MLN0128P 9 mg QD×3d QW MLN0128 9 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 the Dose Escalation Phase.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion
Experimental: MLN0128P 10 mg QD×3d QW MLN0128 10 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 the Dose Escalation Phase.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion
Experimental: MLN0128P 7 mg QD×5d QW 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.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion
Experimental: MLN0128P 8 mg QD×3d QW HER2- 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.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion
Experimental: MLN0128PH 8 mg QD×3d QW HER2+ 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.	Drug: MLN0128 MLN0128 capsules Drug: paclitaxel paclitaxel intravenous infusion Drug: trastuzumab trastuzumab intravenous infusion

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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.
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.
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel [Cycles 1 and 2: 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]
AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 exclusion criteria. The study center will determine if you meet all of the criteria.

Site personnel will explain the trial in detail and answer any question you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, site personnel will explain the reasons

Contacts and Locations

Locations

	City	State	Country	Postal Code
1	Fort Myers	Florida	United States	33905
2	Oklahoma City	Oklahoma	United States	73104
3	Nashville	Tennessee	United States	37203

Sponsors and Collaborators

Millennium Pharmaceuticals, Inc.

Investigators

Study Director: Medical Director, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

More Information

Publications

None provided.

Responsible Party:

Millennium Pharmaceuticals, Inc.

ClinicalTrials.gov Identifier:

NCT01351350

Other Study ID Numbers:

INK128-003
U1111-1181-8192

First Posted:

May 10, 2011

Last Update Posted:

Aug 8, 2019

Last Verified:

Jun 1, 2019

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Millennium Pharmaceuticals, Inc.

Solid tumor, mTORC1/2 inhibitors, HER2

Additional relevant MeSH terms:

Neoplasms

Hematologic Neoplasms

Paclitaxel

Trastuzumab

Study Results

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 Detail	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.

Arm/Group Title	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 QD×3d QW HER2+ Plus Trastuzumab
Arm/Group Description	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).	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).	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).	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).	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).
Period Title: Overall Study
STARTED	8	29	11	13	7
Treated	8	29	10	13	7
Dose-escalation Evaluable	7	23	10	0	0
COMPLETED	0	0	0	0	0
NOT COMPLETED	8	29	11	13	7

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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).	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).	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).	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).	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).	Total of all reporting groups
Overall Participants	8	29	10	13	7	67
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.3 (14.34)	62.9 (9.57)	58.1 (14.70)	54.2 (14.46)	58.1 (8.03)	59.3 (12.07)
Sex: Female, Male (Count of Participants)
Female	5 62.5%	14 48.3%	7 70%	6 46.2%	6 85.7%	38 56.7%
Male	3 37.5%	15 51.7%	3 30%	7 53.8%	1 14.3%	29 43.3%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	0 0%	1 3.4%	0 0%	1 7.7%	1 14.3%	3 4.5%
Not Hispanic or Latino	8 100%	28 96.6%	10 100%	12 92.3%	6 85.7%	64 95.5%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	1 3.4%	0 0%	0 0%	0 0%	1 1.5%
Asian	0 0%	0 0%	0 0%	1 7.7%	0 0%	1 1.5%
Black or African American	0 0%	1 3.4%	0 0%	2 15.4%	0 0%	3 4.5%
White	8 100%	27 93.1%	10 100%	10 76.9%	7 100%	62 92.5%
Region of Enrollment (Count of Participants)
United States	8 100%	29 100%	10 100%	13 100%	7 100%	67 100%

Outcome Measures

1. Primary Outcome

Title	Dose Escalation Phase: Maximum Tolerated Dose (MTD)
Description	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

Outcome Measure Data

Analysis Population Description
Safety Population included all participants who received at least one dose of study drug.

Arm/Group Title	Dose Escalation
Arm/Group Description	Participants from the Dose Escalation Phase who received at least 1 dose of study medication. MLN0128 6,7,8,9 or10 mg QD×3d QW, 30 or 40 mg QW, or 7 mg QD×5d QW of a 4-week cycle in combination with paclitaxel (80 mg/m^2) on Days 1, 8, and 15 of Cycle 1.
Measure Participants	40
Number [mg (QD×3d QW)]	8

2. Primary Outcome

Title	Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT)
Description	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

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 30 mg QW	MLN0128P 40 mg QW	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 8 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW	MLN0128P 7 mg QD×5d QW
Arm/Group Description	MLN0128 30 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 MTD was established.	MLN0128 40 mg, capsule, orally, once a week (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 MTD was established.	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.	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).
Measure Participants	5	2	3	3	3	5	9	10
Number [participants]	0 0%	2 6.9%	0 0%	0 0%	0 0%	2 3%	2 NaN	2 NaN

3. Primary Outcome

Title	Objective Response Rate (ORR)
Description	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)

Outcome Measure Data

Analysis Population Description
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/Group Title	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
Arm/Group Description	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).	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).	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).	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).	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).
Measure Participants	8	22	9	10	5
Number [percentage of participants]	0 0%	9 31%	44 440%	10 76.9%	20 285.7%

4. Secondary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for MLN0128
Description	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

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 30 mg QW	MLN0128P 40 mg QW	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 8 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW	MLN0128P 7 mg QD×5d QW
Arm/Group Description	MLN0128 30 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 MTD was established.	MLN0128 40 mg, capsule, orally, once a week (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 MTD was established.	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.	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).
Measure Participants	6	2	3	4	3	6	13	10
Cycle 1	245.0	345.5	26.7	31.1	41.8	34.2	100.0	53.5
Cycle 2	242.2	107.0	33.8	45.5	53.1	23.0	80.1	45.3

5. Secondary Outcome

Title	Cmin: Minimum Observed Plasma Concentration for MLN0128
Description	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

Outcome Measure Data

Analysis Population Description
Due to the change in planned analysis, minimum plasma concentration data was not collected.

Arm/Group Title	MLN0128P 30 mg QW	MLN0128P 40 mg QW	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 8 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW	MLN0128P 7 mg QD×5d QW
Arm/Group Description	MLN0128 30 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 MTD was established.	MLN0128 40 mg, capsule, orally, once a week (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 MTD was established.	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.	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).
Measure Participants	0	0	0	0	0	0	0	0

6. Secondary Outcome

Title	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128
Description	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

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 30 mg QW	MLN0128P 40 mg QW	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 8 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW	MLN0128P 7 mg QD×5d QW
Arm/Group Description	MLN0128 30 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 MTD was established.	MLN0128 40 mg, capsule, orally, once a week (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 MTD was established.	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.	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).
Measure Participants	6	2	3	4	3	6	13	10
Cycle 1	3.0	3.0	2.0	3.0	5.6	4.1	1.0	1.6
Cycle 2	2.0	4.0	4.0	2.0	1.0	5.5	2.0	2.7

7. Secondary Outcome

Title	Terminal Phase Elimination Half-life (T1/2) for MLN0128
Description
Time Frame	Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW
Arm/Group Description	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.
Measure Participants	2	2
Mean (Full Range) [hours]	6.6	7.2

8. Secondary Outcome

Title	AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128
Description
Time Frame	Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW
Arm/Group Description	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.
Measure Participants	2	2
Mean (Full Range) [ng*hr/mL]	206.5	286.0

9. Secondary Outcome

Title	AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128
Description	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

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 30 mg QW	MLN0128P 40 mg QW	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 8 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW
Arm/Group Description	MLN0128 30 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 MTD was established.	MLN0128 40 mg, capsule, orally, once a week (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 MTD was established.	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.
Measure Participants	6	2	3	4	3	6	13
Cycle 1	753.7	1325.0	104.4	121.7	139.9	146.2	347.0
Cycle 2	883.6	505.0	106.8	174.0	210.3	72.6	283.9

10. Secondary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Paclitaxel
Description
Time Frame	Cycles 1 and 2: Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 30 mg QW	MLN0128P 40 mg QW	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 8 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW	MLN0128P 7 mg QD×5d QW
Arm/Group Description	MLN0128 30 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 MTD was established.	MLN0128 40 mg, capsule, orally, once a week (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 MTD was established.	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.	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).
Measure Participants	5	2	3	4	3	6	13	10
Cycle 1, Day 1	2538.0	2355.0	1933.3	1942.5	1620.0	3798.3	2906.9	1637.7
Cycle 2, Day 1	3462.5	1500.0	1200.3	1550.0	3103.3	1602.3	2964.0	1765.7

11. Secondary Outcome

Title	Cmin: Minimum Observed Plasma Concentration for Paclitaxel
Description	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

Outcome Measure Data

Analysis Population Description
Due to the change in planned analysis, minimum plasma concentration data was not collected.

Arm/Group Title	MLN0128P 30 mg QW	MLN0128P 40 mg QW	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 8 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW	MLN0128P 7 mg QD×5d QW
Arm/Group Description	MLN0128 30 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 MTD was established.	MLN0128 40 mg, capsule, orally, once a week (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 MTD was established.	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.	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).
Measure Participants	0	0	0	0	0	0	0	0

12. Secondary Outcome

Title	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel
Description
Time Frame	Cycles 1 and 2: Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 30 mg QW	MLN0128P 40 mg QW	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 8 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW	MLN0128P 7 mg QD×5d QW
Arm/Group Description	MLN0128 30 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 MTD was established.	MLN0128 40 mg, capsule, orally, once a week (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 MTD was established.	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.	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).
Measure Participants	5	2	3	4	3	6	13	10
Cycle 1, Day 1	1.1	1.1	1.1	1.2	1.2	1.1	1.1	1.5
Cycle 2, Day 1	1.1	1.2	1.6	1.4	1.2	1.2	1.0	1.1

13. Secondary Outcome

Title	Terminal Phase Elimination Half-life (T1/2) for Paclitaxel
Description
Time Frame	Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW
Arm/Group Description	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.
Measure Participants	2	3	5	2
Mean (Full Range) [hours]	10.0	9.1	9.6	9.3

14. Secondary Outcome

Title	AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel
Description
Time Frame	Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW
Arm/Group Description	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.
Measure Participants	2	3	5	2
Mean (Full Range) [ng*hr/mL]	4590.0	4790.0	5002.0	5485.0

15. Secondary Outcome

Title	AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel
Description
Time Frame	Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 30 mg QW	MLN0128P 40 mg QW	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 8 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW	MLN0128P 7 mg QD×5d QW
Arm/Group Description	MLN0128 30 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 MTD was established.	MLN0128 40 mg, capsule, orally, once a week (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 MTD was established.	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.	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).
Measure Participants	6	2	3	4	3	6	13	10
Mean (Full Range) [ng*hr/mL]	3198.3	3515.0	2620.0	3157.5	2683.3	5315.0	3683.8	2657.0

16. Secondary Outcome

Title	AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel
Description
Time Frame	Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW
Arm/Group Description	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.
Measure Participants	3	4	6	2
Mean (Full Range) [ng*hr/mL]	3583.3	4332.5	6415.0	5135.0

17. Secondary Outcome

Title	CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Description
Time Frame	Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW
Arm/Group Description	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.
Measure Participants	2	3	5	2
Mean (Full Range) [L/hr]	36.2	34.8	31.2	25.8

18. Secondary Outcome

Title	Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Description
Time Frame	Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description
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/Group Title	MLN0128P 6 mg QD×3d QW	MLN0128P 7 mg QD×3d QW	MLN0128P 9 mg QD×3d QW	MLN0128P 10 mg QD×3d QW
Arm/Group Description	MLN0128 6 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.	MLN0128 7 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 the Dose Escalation Phase until MTD was established.	MLN0128 9 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 the Dose Escalation Phase until MTD was established.	MLN0128 10 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 the Dose Escalation Phase until MTD was established.
Measure Participants	2	3	5	2
Mean (Full Range) [L]	313.5	262.0	252.2	150.0

19. Primary Outcome

Title	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
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A 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)

Outcome Measure Data

Analysis Population Description
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/Group Title	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
Arm/Group Description	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).	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).	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).	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).	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).
Measure Participants	8	29	10	13	7
TEAE	100 1250%	100 344.8%	100 1000%	100 769.2%	100 1428.6%
SAE	63 787.5%	41 141.4%	60 600%	31 238.5%	43 614.3%
Fatal AEs within 30 Days of Last Dose Study Drug	25 312.5%	7 24.1%	20 200%	15 115.4%	14 200%
AEs Resulting in Discontinuation of MLN0128	13 162.5%	34 117.2%	10 100%	15 115.4%	0 0%

Adverse Events

	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 QD×3d QW HER2+ Plus Trastuzumab
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)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. According to the protocol analysis planned, data was collected as per the dosing schedule.

Arm/Group Title	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 QD×3d QW HER2+ Plus Trastuzumab
Arm/Group Description	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).		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).		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).		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).		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).
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/8 (25%)		2/29 (6.9%)		2/10 (20%)		2/13 (15.4%)		1/7 (14.3%)
Serious Adverse Events
	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 QD×3d QW HER2+ Plus Trastuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/8 (62.5%)		12/29 (41.4%)		6/10 (60%)		4/13 (30.8%)		3/7 (42.9%)
Blood and lymphatic system disorders
Neutropenia	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Cardiac disorders
Myocardial infarction	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Gastrointestinal disorders
Oesophageal ulcer	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Vomiting	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Small intestinal obstruction	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Stomatitis	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Diarrhoea	0/8 (0%)		1/29 (3.4%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Diverticular perforation	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Intestinal obstruction	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Lower gastrointestinal haemorrhage	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Enterocutaneous fistula	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Haematemesis	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Abdominal pain upper	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
General disorders
Fatigue	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Non-cardiac chest pain	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Disease Progression	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Infections and infestations
Pneumonia	1/8 (12.5%)		2/29 (6.9%)		2/10 (20%)		2/13 (15.4%)		0/7 (0%)
Sepsis	1/8 (12.5%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Device related infection	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Gastroenteritis	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Urinary tract infection	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Injury, poisoning and procedural complications
Wound	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Metabolism and nutrition disorders
Dehydration	0/8 (0%)		3/29 (10.3%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Failure to thrive	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Musculoskeletal and connective tissue disorders
Bone pain	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Laryngeal cancer	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Oesophageal carcinoma	1/8 (12.5%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Neoplasm Progression	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Endometrial cancer	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Nervous system disorders
Cerebrovascular accident	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Psychiatric disorders
Confusional state	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Renal and urinary disorders
Haematuria	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Reproductive system and breast disorders
Female genital tract fistula	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Pneumothorax spontaneous	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Pulmonary embolism	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Tracheal obstruction extrinsic	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Vascular disorders
Embolism	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Deep vein thrombosis	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	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 QD×3d QW HER2+ Plus Trastuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		29/29 (100%)		10/10 (100%)		13/13 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Anaemia	4/8 (50%)		12/29 (41.4%)		3/10 (30%)		4/13 (30.8%)		2/7 (28.6%)
Leukopenia	1/8 (12.5%)		3/29 (10.3%)		2/10 (20%)		2/13 (15.4%)		1/7 (14.3%)
Thrombocytopenia	3/8 (37.5%)		2/29 (6.9%)		3/10 (30%)		1/13 (7.7%)		2/7 (28.6%)
Iron deficiency anaemia	0/8 (0%)		1/29 (3.4%)		1/10 (10%)		1/13 (7.7%)		0/7 (0%)
Neutropenia	2/8 (25%)		8/29 (27.6%)		4/10 (40%)		3/13 (23.1%)		0/7 (0%)
Cardiac disorders
Tachycardia	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Angina pectoris	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Ear and labyrinth disorders
Hypoacusis	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Ear pain	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Tinnitus	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Vertigo	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Endocrine disorders
Cushingoid	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Hypothyroidism	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Eye disorders
Vision blurred	1/8 (12.5%)		1/29 (3.4%)		1/10 (10%)		0/13 (0%)		1/7 (14.3%)
Visual impairment	1/8 (12.5%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Dry eye	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Orbital Oedema	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Photophobia	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Photopsia	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Gastrointestinal disorders
Nausea	4/8 (50%)		18/29 (62.1%)		6/10 (60%)		6/13 (46.2%)		6/7 (85.7%)
Constipation	3/8 (37.5%)		4/29 (13.8%)		2/10 (20%)		1/13 (7.7%)		3/7 (42.9%)
Dry mouth	1/8 (12.5%)		3/29 (10.3%)		1/10 (10%)		0/13 (0%)		1/7 (14.3%)
Oesophagitis	0/8 (0%)		3/29 (10.3%)		1/10 (10%)		0/13 (0%)		1/7 (14.3%)
Abdominal pain	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		5/13 (38.5%)		0/7 (0%)
Gastrooesophageal reflux disease	1/8 (12.5%)		2/29 (6.9%)		0/10 (0%)		1/13 (7.7%)		2/7 (28.6%)
Dyspepsia	1/8 (12.5%)		1/29 (3.4%)		2/10 (20%)		1/13 (7.7%)		3/7 (42.9%)
Gastritis	1/8 (12.5%)		1/29 (3.4%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Oral pain	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Retching	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Mouth ulceration	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Sensitivity of teeth	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		1/7 (14.3%)
Dysphagia	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Haematochezia	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Hyperchlorhydria	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Lip swelling	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Oesophageal obstruction	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Diarrhoea	3/8 (37.5%)		15/29 (51.7%)		6/10 (60%)		7/13 (53.8%)		4/7 (57.1%)
Vomiting	5/8 (62.5%)		10/29 (34.5%)		3/10 (30%)		7/13 (53.8%)		6/7 (85.7%)
Stomatitis	2/8 (25%)		13/29 (44.8%)		4/10 (40%)		5/13 (38.5%)		3/7 (42.9%)
Haemorrhoids	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Inguinal Hernia	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
General disorders
Asthenia	1/8 (12.5%)		11/29 (37.9%)		4/10 (40%)		4/13 (30.8%)		2/7 (28.6%)
Pyrexia	2/8 (25%)		4/29 (13.8%)		0/10 (0%)		3/13 (23.1%)		1/7 (14.3%)
Oedema peripheral	0/8 (0%)		3/29 (10.3%)		2/10 (20%)		2/13 (15.4%)		1/7 (14.3%)
Chills	1/8 (12.5%)		2/29 (6.9%)		1/10 (10%)		0/13 (0%)		1/7 (14.3%)
Pain	0/8 (0%)		2/29 (6.9%)		2/10 (20%)		2/13 (15.4%)		0/7 (0%)
Feeling jittery	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Puncture site haemorrhage	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Fatigue	4/8 (50%)		19/29 (65.5%)		8/10 (80%)		9/13 (69.2%)		4/7 (57.1%)
Non-cardiac chest pain	2/8 (25%)		0/29 (0%)		0/10 (0%)		2/13 (15.4%)		0/7 (0%)
Peripheral swelling	0/8 (0%)		1/29 (3.4%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Chest discomfort	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Chest pain	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Oedema	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Immune system disorders
Hypersensitivity	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Infections and infestations
Oral candidiasis	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Sinusitis	1/8 (12.5%)		2/29 (6.9%)		2/10 (20%)		1/13 (7.7%)		1/7 (14.3%)
Pharyngitis streptococcal	0/8 (0%)		1/29 (3.4%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Respiratory tract infection	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		2/13 (15.4%)		0/7 (0%)
Upper respiratory tract infection	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		2/13 (15.4%)		0/7 (0%)
Herpes zoster	1/8 (12.5%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		1/7 (14.3%)
Conjunctivitis	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Folliculitis	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Gastroenteritis viral	0/8 (0%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		0/7 (0%)
Pharyngitis	0/8 (0%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		0/7 (0%)
Tooth infection	0/8 (0%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		0/7 (0%)
Abscess neck	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Bronchitis	0/8 (0%)		0/29 (0%)		0/10 (0%)		2/13 (15.4%)		0/7 (0%)
Catheter site cellulitis	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Hordeolum	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Influenza	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Labyrinthitis	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Laryngitis	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Rhinitis	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Skin infection	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Tooth abscess	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Urinary tract infection	3/8 (37.5%)		5/29 (17.2%)		4/10 (40%)		4/13 (30.8%)		2/7 (28.6%)
Sepsis	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Viral upper respiratory tract infection	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Pneumonia	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Gastrointestinal viral infection	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Injury, poisoning and procedural complications
Fall	1/8 (12.5%)		2/29 (6.9%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Infusion related reaction	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		1/7 (14.3%)
Contusion	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Corneal abrasion	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Arhropod bite	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Ankle fracture	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Burn oral cavity	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Arthropod bite	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Investigations
Weight decreased	2/8 (25%)		6/29 (20.7%)		0/10 (0%)		5/13 (38.5%)		2/7 (28.6%)
Blood alkaline phosphatase increased	0/8 (0%)		2/29 (6.9%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Blood creatinine increased	0/8 (0%)		2/29 (6.9%)		3/10 (30%)		1/13 (7.7%)		1/7 (14.3%)
Low density lipoprotein increased	0/8 (0%)		1/29 (3.4%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
White blood cell count decreased	1/8 (12.5%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
White blood cells urine positive	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Blood triglycerides increased	2/8 (25%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Blood bilirubin increased	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
High density lipoprotein decreased	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Protein total decreased	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		2/13 (15.4%)		1/7 (14.3%)
Activated partial thromboplastin time prolonged	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Aspartate aminotransferase increased	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		1/7 (14.3%)
Blood cholosterol increased	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Blood chloride decreased	0/8 (0%)		0/29 (0%)		0/10 (0%)		2/13 (15.4%)		0/7 (0%)
Blood lactate dehydrogenase increased	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		1/7 (14.3%)
Alanine aminotransferase increased	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		1/7 (14.3%)
Blood chloride increased	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Blood urea increased	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Carbon dioxide increased	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Electrocardiogram abnormal	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
International normalised ratio increased	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Prothrombin time prolonged	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Weight increased	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Blood cholesterol increased	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	5/8 (62.5%)		14/29 (48.3%)		3/10 (30%)		3/13 (23.1%)		4/7 (57.1%)
Hypokalaemia	3/8 (37.5%)		8/29 (27.6%)		3/10 (30%)		4/13 (30.8%)		1/7 (14.3%)
Decreased appetite	2/8 (25%)		12/29 (41.4%)		7/10 (70%)		4/13 (30.8%)		4/7 (57.1%)
Hypomagnesaemia	2/8 (25%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		1/7 (14.3%)
Hypophosphataemia	2/8 (25%)		7/29 (24.1%)		3/10 (30%)		1/13 (7.7%)		1/7 (14.3%)
Hyperammonaemia	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Hypoalbuminaemia	1/8 (12.5%)		2/29 (6.9%)		0/10 (0%)		1/13 (7.7%)		1/7 (14.3%)
Hypocalcaemia	1/8 (12.5%)		2/29 (6.9%)		1/10 (10%)		0/13 (0%)		1/7 (14.3%)
Hypertriglyceridaemia	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Hypercalcaemia	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Hyponatraemia	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Hypophagia	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Fluid overload	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Hypoglycaemia	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Dehydration	4/8 (50%)		12/29 (41.4%)		2/10 (20%)		3/13 (23.1%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Myalgia	0/8 (0%)		4/29 (13.8%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Arthralgia	1/8 (12.5%)		2/29 (6.9%)		0/10 (0%)		4/13 (30.8%)		0/7 (0%)
Muscular weakness	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Musculoskeletal chest pain	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Back pain	1/8 (12.5%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Muscle spasms	0/8 (0%)		1/29 (3.4%)		1/10 (10%)		1/13 (7.7%)		1/7 (14.3%)
Neck pain	2/8 (25%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Pain in jaw	1/8 (12.5%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Musculoskeletal pain	2/8 (25%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Muscle tightness	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Pain in extremity	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Fistula	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Coccydynia	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Muscle twitching	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Nervous system disorders
Dizziness	0/8 (0%)		7/29 (24.1%)		1/10 (10%)		4/13 (30.8%)		2/7 (28.6%)
Peripheral sensory neuropathy	2/8 (25%)		5/29 (17.2%)		0/10 (0%)		3/13 (23.1%)		2/7 (28.6%)
Dysgeusia	0/8 (0%)		4/29 (13.8%)		1/10 (10%)		2/13 (15.4%)		1/7 (14.3%)
Headache	1/8 (12.5%)		4/29 (13.8%)		1/10 (10%)		3/13 (23.1%)		1/7 (14.3%)
Neuropathy peripheral	0/8 (0%)		2/29 (6.9%)		1/10 (10%)		5/13 (38.5%)		1/7 (14.3%)
Syncope	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Dysarthria	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Tremor	0/8 (0%)		1/29 (3.4%)		1/10 (10%)		0/13 (0%)		2/7 (28.6%)
Peripheral motor neuropathy	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Hyperaesthesia	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Paraesthesia	0/8 (0%)		0/29 (0%)		1/10 (10%)		2/13 (15.4%)		0/7 (0%)
Restless legs syndrome	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Somnolence	0/8 (0%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		0/7 (0%)
Amnesia	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Aphasia	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Hemiparesis	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Facial paralysis	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Migraine	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Visual field defect	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Psychiatric disorders
Anxiety	1/8 (12.5%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		2/7 (28.6%)
Insomnia	1/8 (12.5%)		1/29 (3.4%)		2/10 (20%)		2/13 (15.4%)		2/7 (28.6%)
Claustrophobia	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Adjustment disorder with depressed mood	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Depression	0/8 (0%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		2/7 (28.6%)
Sleep disorder	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Confusional state	0/8 (0%)		3/29 (10.3%)		0/10 (0%)		2/13 (15.4%)		1/7 (14.3%)
Renal and urinary disorders
Dysuria	0/8 (0%)		2/29 (6.9%)		1/10 (10%)		0/13 (0%)		1/7 (14.3%)
Pollakiuria	0/8 (0%)		2/29 (6.9%)		1/10 (10%)		0/13 (0%)		1/7 (14.3%)
Proteinuria	1/8 (12.5%)		2/29 (6.9%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Nephrolithiasis	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Urine odour abnormal	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Haematuria	0/8 (0%)		4/29 (13.8%)		1/10 (10%)		2/13 (15.4%)		0/7 (0%)
Acute kidney injury	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/8 (25%)		6/29 (20.7%)		1/10 (10%)		2/13 (15.4%)		0/7 (0%)
Cough	1/8 (12.5%)		5/29 (17.2%)		1/10 (10%)		4/13 (30.8%)		0/7 (0%)
Oropharyngeal pain	0/8 (0%)		4/29 (13.8%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Epistaxis	0/8 (0%)		2/29 (6.9%)		1/10 (10%)		2/13 (15.4%)		0/7 (0%)
Productive cough	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		2/13 (15.4%)		1/7 (14.3%)
Chronic Obstructive Pulmonary Disease	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Dyspnoea exertional	1/8 (12.5%)		1/29 (3.4%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Haemoptysis	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Hypoxia	1/8 (12.5%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Rhinorrhoea	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Dysphonia	0/8 (0%)		0/29 (0%)		1/10 (10%)		2/13 (15.4%)		0/7 (0%)
Respiratory tract infection	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		2/13 (15.4%)		0/7 (0%)
Chronic respiratory failure	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Dyspnoea paroxysmal nocturnal	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Pharyngeal lesion	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Sinus congestion	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Lower respiratory tract congestion	0/8 (0%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		0/7 (0%)
Nasal congestion	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Paranasal Sinus discomfort	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Pleural effusion	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Sleep apnoea syndrome	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Wheezing	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Alopecia	1/8 (12.5%)		4/29 (13.8%)		3/10 (30%)		4/13 (30.8%)		1/7 (14.3%)
Rash	1/8 (12.5%)		4/29 (13.8%)		3/10 (30%)		5/13 (38.5%)		0/7 (0%)
Rash maculo-papular	1/8 (12.5%)		4/29 (13.8%)		1/10 (10%)		2/13 (15.4%)		3/7 (42.9%)
Rash macular	0/8 (0%)		3/29 (10.3%)		1/10 (10%)		1/13 (7.7%)		0/7 (0%)
Dermatitis acneiform	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Pruritus	1/8 (12.5%)		2/29 (6.9%)		2/10 (20%)		4/13 (30.8%)		0/7 (0%)
Rash erythematous	0/8 (0%)		2/29 (6.9%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Rash papular	0/8 (0%)		2/29 (6.9%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Dry skin	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		2/13 (15.4%)		0/7 (0%)
Erythema	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Hyperhidrosis	1/8 (12.5%)		1/29 (3.4%)		0/10 (0%)		0/13 (0%)		0/7 (0%)
Night sweats	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		2/13 (15.4%)		0/7 (0%)
Swelling face	1/8 (12.5%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Nail bed tenderness	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Rash pruritic	0/8 (0%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		1/7 (14.3%)
Skin ulcer	0/8 (0%)		0/29 (0%)		1/10 (10%)		0/13 (0%)		0/7 (0%)
Urticaria	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		1/7 (14.3%)
Hirsutism	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Nail disorder	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Skin disorder	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Skin hyperpigmentation	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Ecchymosis	0/8 (0%)		0/29 (0%)		0/10 (0%)		0/13 (0%)		1/7 (14.3%)
Vascular disorders
Flushing	1/8 (12.5%)		4/29 (13.8%)		2/10 (20%)		0/13 (0%)		0/7 (0%)
Hypotension	1/8 (12.5%)		4/29 (13.8%)		1/10 (10%)		1/13 (7.7%)		0/7 (0%)
Orthostatic hypotension	0/8 (0%)		1/29 (3.4%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)
Hot flush	0/8 (0%)		0/29 (0%)		1/10 (10%)		1/13 (7.7%)		0/7 (0%)
Hypertension	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		1/7 (14.3%)
Superior vena cava occlusion	0/8 (0%)		0/29 (0%)		0/10 (0%)		1/13 (7.7%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.

Results Point of Contact

Name/Title	Medical Director, Clinical Science
Organization	Takeda
Phone	+1-866-835-2233
Email	trialdisclosures@takeda.com

Responsible Party:

Millennium Pharmaceuticals, Inc.

ClinicalTrials.gov Identifier:

NCT01351350

Other Study ID Numbers:

INK128-003
U1111-1181-8192

First Posted:

May 10, 2011

Last Update Posted:

Aug 8, 2019

Last Verified:

Jun 1, 2019

Dose Escalation Study of MLN0128 in Combination With Paclitaxel, With/Without Trastuzumab, in Subjects With Advanced Solid Malignancies

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