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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01351350
Recruitment Status : Completed
First Posted : May 10, 2011
Results First Posted : August 8, 2019
Last Update Posted : August 8, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

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

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Study Type : Interventional  (Clinical Trial)
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 : February 28, 2011
Actual Primary Completion Date : September 15, 2017
Actual Study Completion Date : September 15, 2017

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Dose Escalation Phase: Maximum Tolerated Dose (MTD) [ Time Frame: 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.

  2. Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) [ Time Frame: 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.

  3. Objective Response Rate (ORR) [ Time Frame: 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.

  4. 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 [ 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) ]
    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 :
  1. Cmax: Maximum Observed Plasma Concentration for MLN0128 [ Time Frame: 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.

  2. Cmin: Minimum Observed Plasma Concentration for MLN0128 [ Time Frame: 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.

  3. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 [ Time Frame: 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.

  4. Terminal Phase Elimination Half-life (T1/2) for MLN0128 [ Time Frame: Cycle 1 Day 1 ]
  5. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 [ Time Frame: Cycle 1 Day 1 ]
  6. AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 [ Time Frame: 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.

  7. Cmax: Maximum Observed Plasma Concentration for Paclitaxel [ Time Frame: Cycles 1 and 2: Day 1 ]
  8. Cmin: Minimum Observed Plasma Concentration for Paclitaxel [ Time Frame: 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.

  9. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel [ Time Frame: Cycles 1 and 2: Day 1 ]
  10. Terminal Phase Elimination Half-life (T1/2) for Paclitaxel [ Time Frame: Cycle 1 Day 1 ]
  11. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel [ Time Frame: Cycle 1 Day 1 ]
  12. AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel [ Time Frame: Cycle 1 Day 1 ]
  13. AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel [ Time Frame: Cycle 1 Day 1 ]
  14. CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel [ Time Frame: Cycle 1 Day 1 ]
  15. 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01351350


Locations
Layout table for location information
United States, Florida
Fort Myers, Florida, United States, 33905
United States, Oklahoma
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Layout table for investigator information
Study Director: Medical Director Millennium Pharmaceuticals, Inc.
  Study Documents (Full-Text)

Documents provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Statistical Analysis Plan  [PDF] October 7, 2013
Study Protocol  [PDF] March 5, 2014


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01351350    
Other Study ID Numbers: INK128-003
U1111-1181-8192 ( Other Identifier: WHO )
First Posted: May 10, 2011    Key Record Dates
Results First Posted: August 8, 2019
Last Update Posted: August 8, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Solid tumor, mTORC1/2 inhibitors, HER2
Additional relevant MeSH terms:
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Neoplasms
Paclitaxel
Albumin-Bound Paclitaxel
Trastuzumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological