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

Primary Purpose

Advanced Solid Malignancies, Hematologic Malignancies

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

MLN0128

paclitaxel

trastuzumab

About this trial

This is an interventional treatment trial for Advanced Solid Malignancies focused on measuring Solid tumor, mTORC1/2 inhibitors, HER2

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm Type

Experimental

Arm Label

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

MLN0128P 8 mg QD×3d QW HER2-

MLN0128PH 8 mg QD×3d QW HER2+

Arm Description

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

Secondary Outcome Measures

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.

Cmin: Minimum Observed Plasma Concentration for MLN0128

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.

Terminal Phase Elimination Half-life (T1/2) for MLN0128

AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128

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

Cmax: Maximum Observed Plasma Concentration for Paclitaxel

Cmin: Minimum Observed Plasma Concentration for Paclitaxel

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel

Terminal Phase Elimination Half-life (T1/2) for Paclitaxel

AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel

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

AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel

CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel

Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel

Full Information

NCT ID

NCT01351350

First Posted

February 21, 2011

Last Updated

June 28, 2019

Sponsor

Millennium Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01351350

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2019

Overall Recruitment Status

Completed

Study Start Date

February 28, 2011 (Actual)

Primary Completion Date

September 15, 2017 (Actual)

Study Completion Date

September 15, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Millennium Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Advanced Solid Malignancies, Hematologic Malignancies

Keywords

Solid tumor, mTORC1/2 inhibitors, HER2

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

68 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MLN0128P 30 mg QW

Arm Type

Experimental

Arm Description

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.

Arm Title

MLN0128P 40 mg QW

Arm Type

Experimental

Arm Description

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.

Arm Title

MLN0128P 6 mg QD×3d QW

Arm Type

Experimental

Arm Description

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.

Arm Title

MLN0128P 7 mg QD×3d QW

Arm Type

Experimental

Arm Description

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.

Arm Title

MLN0128P 8 mg QD×3d QW

Arm Type

Experimental

Arm Description

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.

Arm Title

MLN0128P 9 mg QD×3d QW

Arm Type

Experimental

Arm Description

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.

Arm Title

MLN0128P 10 mg QD×3d QW

Arm Type

Experimental

Arm Description

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.

Arm Title

MLN0128P 7 mg QD×5d QW

Arm Type

Experimental

Arm Description

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.

Arm Title

MLN0128P 8 mg QD×3d QW HER2-

Arm Type

Experimental

Arm Description

Arm Title

MLN0128PH 8 mg QD×3d QW HER2+

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

MLN0128

Intervention Description

MLN0128 capsules

Intervention Type

Drug

Intervention Name(s)

paclitaxel

Intervention Description

paclitaxel intravenous infusion

Intervention Type

Drug

Intervention Name(s)

trastuzumab

Intervention Description

trastuzumab intravenous infusion

Primary Outcome Measure Information:

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

Title

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

Description

Time Frame

Cycle 1: Days 1 to 28

Title

Objective Response Rate (ORR)

Description

Time Frame

At screening and thereafter every 2 cycles of treatment until disease progression (Up to 65.8 weeks)

Title

Description

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)

Secondary Outcome Measure Information:

Title

Cmax: Maximum Observed Plasma Concentration for MLN0128

Description

Time Frame

Cycles 1 and 2: Day 1 or 2

Title

Cmin: Minimum Observed Plasma Concentration for MLN0128

Description

Time Frame

Cycles 1 and 2: Day 1 or 2

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

Title

Terminal Phase Elimination Half-life (T1/2) for MLN0128

Time Frame

Cycle 1 Day 1

Title

AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128

Time Frame

Cycle 1 Day 1

Title

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

Description

Time Frame

Cycles 1 and 2: Day 1 or 2

Title

Cmax: Maximum Observed Plasma Concentration for Paclitaxel

Time Frame

Cycles 1 and 2: Day 1

Title

Cmin: Minimum Observed Plasma Concentration for Paclitaxel

Description

Time Frame

Cycles 1 and 2: Day 1 or 2

Title

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel

Time Frame

Cycles 1 and 2: Day 1

Title

Terminal Phase Elimination Half-life (T1/2) for Paclitaxel

Time Frame

Cycle 1 Day 1

Title

AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel

Time Frame

Cycle 1 Day 1

Title

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

Time Frame

Cycle 1 Day 1

Title

AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel

Time Frame

Cycle 1 Day 1

Title

CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel

Time Frame

Cycle 1 Day 1

Title

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Millennium Pharmaceuticals, Inc.

Official's Role

Study Director

Facility Information:

City

Fort Myers

State/Province

Florida

ZIP/Postal Code

33905

Country

United States

City

Oklahoma City

State/Province

Oklahoma

ZIP/Postal Code

73104

Country

United States

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37203

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Citations:

PubMed Identifier

28601972

Citation

Burris HA 3rd, Kurkjian CD, Hart L, Pant S, Murphy PB, Jones SF, Neuwirth R, Patel CG, Zohren F, Infante JR. TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. Cancer Chemother Pharmacol. 2017 Aug;80(2):261-273. doi: 10.1007/s00280-017-3343-4. Epub 2017 Jun 10.

Results Reference

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

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