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

NCT01351350 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: INK128-003U1111-1181-8192
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 3

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.

Conditions

Advanced Solid Malignancies; Hematologic Malignancies

Keywords

Solid tumor, mTORC1/2 inhibitors, HER2

Outcome Measures

Primary Outcomes (4)

• 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.

  Cycle 1: Days 1 to 28

• 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.

  Cycle 1: Days 1 to 28

• 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.

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

• 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.

  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 Outcomes (15)

• Cmax: Maximum Observed Plasma Concentration for MLN0128

  Cycles 1 and 2: Day 1 or 2

• Cmin: Minimum Observed Plasma Concentration for MLN0128

  Cycles 1 and 2: Day 1 or 2

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

  Cycles 1 and 2: Day 1 or 2

• 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

Study Arms (10)

MLN0128P 30 mg QW

EXPERIMENTAL

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; Drug: paclitaxel

MLN0128P 40 mg QW

EXPERIMENTAL

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; Drug: paclitaxel

MLN0128P 6 mg QD×3d QW

EXPERIMENTAL

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; Drug: paclitaxel

MLN0128P 7 mg QD×3d QW

EXPERIMENTAL

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; Drug: paclitaxel

MLN0128P 8 mg QD×3d QW

EXPERIMENTAL

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; Drug: paclitaxel

MLN0128P 9 mg QD×3d QW

EXPERIMENTAL

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; Drug: paclitaxel

MLN0128P 10 mg QD×3d QW

EXPERIMENTAL

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; Drug: paclitaxel

MLN0128P 7 mg QD×5d QW

EXPERIMENTAL

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; Drug: paclitaxel

MLN0128P 8 mg QD×3d QW HER2-

EXPERIMENTAL

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; Drug: paclitaxel

MLN0128PH 8 mg QD×3d QW HER2+

EXPERIMENTAL

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; Drug: paclitaxel; Drug: trastuzumab

Interventions

MLN0128 DRUG

MLN0128 capsules

MLN0128P 10 mg QD×3d QW; MLN0128P 30 mg QW; MLN0128P 40 mg QW; MLN0128P 6 mg QD×3d QW; MLN0128P 7 mg QD×3d QW; MLN0128P 7 mg QD×5d QW; MLN0128P 8 mg QD×3d QW; MLN0128P 8 mg QD×3d QW HER2-; MLN0128P 9 mg QD×3d QW; MLN0128PH 8 mg QD×3d QW HER2+

paclitaxel DRUG

paclitaxel intravenous infusion

MLN0128P 10 mg QD×3d QW; MLN0128P 30 mg QW; MLN0128P 40 mg QW; MLN0128P 6 mg QD×3d QW; MLN0128P 7 mg QD×3d QW; MLN0128P 7 mg QD×5d QW; MLN0128P 8 mg QD×3d QW; MLN0128P 8 mg QD×3d QW HER2-; MLN0128P 9 mg QD×3d QW; MLN0128PH 8 mg QD×3d QW HER2+

trastuzumab DRUG

trastuzumab intravenous infusion

MLN0128PH 8 mg QD×3d QW HER2+

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (3)

Unknown Facility

Fort Myers, Florida, 33905, United States

Location

Unknown Facility

Oklahoma City, Oklahoma, 73104, United States

Location

Unknown Facility

Nashville, Tennessee, 37203, United States

Location

Related Publications (1)

• 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.

  PMID: 28601972 DERIVED

MeSH Terms

Conditions

Hematologic Neoplasms

Interventions

sapanisertib; Paclitaxel; Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Medical Director, Clinical Science
• Organization: Takeda

trialdisclosures@takeda.com

+1-866-835-2233

Study Officials

• Medical Director

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2011
• First Posted: May 10, 2011
• Study Start: February 28, 2011
• Primary Completion: September 15, 2017
• Study Completion: September 15, 2017
• Last Updated: August 8, 2019
• Results First Posted: August 8, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will share

Locations

US (3)