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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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ClinicalTrials.gov Identifier: NCT01351350
Recruitment Status : Completed
First Posted : May 10, 2011
Last Update Posted : February 26, 2018
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 subjects into 2 arms in parallel:

  • Arm A will consist of HER2-/unknown cancer subjects receiving MLN0128+paclitaxel
  • Arm B will consist of HER2+ cancer participants receiving MLN0128+paclitaxel plus weekly trastuzumab

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

U.S. FDA Resources

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 patients 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 patients 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 1-28 ]
    The MTD is the highest dose level at which the patient tolerates 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 1-28 ]
    A 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 patients at undue safety risk • Patients 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 22 months) ]
    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.


Secondary Outcome Measures :
  1. 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 22 months) ]
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A 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.

  2. Cmax: Maximum Observed Plasma Concentration for MLN0128 [ Time Frame: Cycle 1 and 2: Day 1 or 2 ]
  3. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 [ Time Frame: Cycle 1 and 2: Day 1 or 2 ]
  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: Cycle 1 and 2: Day 1 or 2 ]
  7. Cmax: Maximum Observed Plasma Concentration for Paclitaxel [ Time Frame: Cycle 1 and 2: Day 1 ]
  8. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel [ Time Frame: Cycle 1 and 2: Day 1 ]
  9. Terminal Phase Elimination Half-life (T1/2) for Paclitaxel [ Time Frame: Cycle 1 Day 1 ]
  10. AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for Paclitaxel [ Time Frame: Cycle 1 Day 1 ]
  11. AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours 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.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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 subjects 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 subjects will be enrolled
  • For expansion phase (Arm B) - HER2+ cancer subjects 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
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
Study Director: Medical Director Millennium Pharmaceuticals, Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01351350     History of Changes
Other Study ID Numbers: INK128-003
U1111-1181-8192 ( Other Identifier: WHO )
First Posted: May 10, 2011    Key Record Dates
Last Update Posted: February 26, 2018
Last Verified: February 2018

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:
Neoplasms
Paclitaxel
Albumin-Bound Paclitaxel
Trastuzumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action