Clinical trial NCT01351350: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Malignancies
Hematologic Malignancies
Keywords: Solid tumor, mTORC1/2 inhibitors, HER2
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-05-10
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Dose Escalation Phase: Maximum Tolerated Dose (MTD)
timeFrame: Cycle 1: Days 1 to 28
measure: Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT)
timeFrame: Cycle 1: Days 1 to 28
measure: Objective Response Rate (ORR)
timeFrame: At screening and thereafter every 2 cycles of treatment until disease progression (Up to 65.8 weeks)
measure: 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
timeFrame: 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:
measure: Cmax: Maximum Observed Plasma Concentration for MLN0128
timeFrame: Cycles 1 and 2: Day 1 or 2
measure: Cmin: Minimum Observed Plasma Concentration for MLN0128
timeFrame: Cycles 1 and 2: Day 1 or 2
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128
timeFrame: Cycles 1 and 2: Day 1 or 2
measure: Terminal Phase Elimination Half-life (T1/2) for MLN0128
timeFrame: Cycle 1 Day 1
measure: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128
timeFrame: Cycle 1 Day 1
measure: AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128
timeFrame: Cycles 1 and 2: Day 1 or 2
measure: Cmax: Maximum Observed Plasma Concentration for Paclitaxel
timeFrame: Cycles 1 and 2: Day 1
measure: Cmin: Minimum Observed Plasma Concentration for Paclitaxel
timeFrame: Cycles 1 and 2: Day 1 or 2
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel
timeFrame: Cycles 1 and 2: Day 1
measure: Terminal Phase Elimination Half-life (T1/2) for Paclitaxel
timeFrame: Cycle 1 Day 1
measure: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel
timeFrame: Cycle 1 Day 1
measure: AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel
timeFrame: Cycle 1 Day 1
measure: AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel
timeFrame: Cycle 1 Day 1
measure: CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
timeFrame: Cycle 1 Day 1
measure: Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
timeFrame: Cycle 1 Day 1
Other outcomes:
Locations:
city: Fort Myers
country: United States
state: Florida
city: Oklahoma City
country: United States
state: Oklahoma
city: Nashville
country: United States
state: Tennessee
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
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.