Advanced Solid MalignanciesPhase 1NCT01351350

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

A Phase 1 study testing MLN0128, paclitaxel and trastuzumab in people with Advanced Solid Malignancies and Hematologic Malignancies, run by Millennium Pharmaceuticals, Inc. at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Advanced Solid Malignancies, Hematologic Malignancies
What is being tested?: MLN0128, paclitaxel and trastuzumab
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 68 participants
Where: 3 sitesUnited States
Study dates: 28 Feb 2011to 15 Sep 2017
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

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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

Who cannot join

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

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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

Trial locations and contacts

3 sites in 1 country.

United States3 sites

Study site
Fort Myers, Florida, 33905
Study site
Nashville, Tennessee, 37203
Study site
Oklahoma City, Oklahoma, 73104

Other trials in United States

About this study

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

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.

Read the 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

Conditions: Advanced Solid Malignancies, Hematologic Malignancies
Being tested: MLN0128, paclitaxel, trastuzumab
Keywords: Solid tumor, mTORC1/2 inhibitors, HER2
Medical subject headings: Hematologic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

MLN0128Drug
MLN0128 capsules
paclitaxelDrug
paclitaxel intravenous infusion
trastuzumabDrug
trastuzumab intravenous infusion

Study groups in NCT01351350
Study group	Role	What they receive
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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: MLN0128; Drug: paclitaxel; Drug: trastuzumab

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
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.
Measured: Cycles 1 and 2: Day 1 or 2
Cmin: Minimum 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.
Measured: Cycles 1 and 2: Day 1 or 2
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.
Measured: Cycles 1 and 2: Day 1 or 2
Terminal Phase Elimination Half-life (T1/2) for MLN0128
Measured: Cycle 1 Day 1
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128
Measured: Cycle 1 Day 1
AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours 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, 30 and 40 mg QW arms.
Measured: Cycles 1 and 2: Day 1 or 2
Cmax: Maximum Observed Plasma Concentration for Paclitaxel
Measured: Cycles 1 and 2: Day 1
Cmin: Minimum Observed Plasma Concentration for Paclitaxel
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.
Measured: Cycles 1 and 2: Day 1 or 2
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel
Measured: Cycles 1 and 2: Day 1
Terminal Phase Elimination Half-life (T1/2) for Paclitaxel
Measured: Cycle 1 Day 1
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel
Measured: Cycle 1 Day 1
AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel
Measured: Cycle 1 Day 1
AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel
Measured: Cycle 1 Day 1
CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Measured: Cycle 1 Day 1
Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Measured: Cycle 1 Day 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

28 Feb 201115 Sep 2017

First posted10 May 2011 (estimated)
Study start28 Feb 2011
Primary completion15 Sep 2017
Study completion15 Sep 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Advanced Solid MalignanciesStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 68 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01351350
Sponsor's protocol ID: INK128-003
Other IDs: U1111-1181-8192
Status last verified: Jun 2019
First submitted: 21 Feb 2011
Last updated: 8 Aug 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: 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.

Publications

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.
PubMed 28601972

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Advanced Solid Malignancies trials

Study at a glance

From the registry record, last updated by the sponsor on 8 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT01351350
Acronym / sponsor ID: INK128-003
Conditions: Advanced Solid Malignancies, Hematologic Malignancies
Keywords: Solid tumor, mTORC1/2 inhibitors, HER2
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 68 participants (actual)
Lead sponsor: Millennium Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
Study start: 28 Feb 2011 (actual)
Primary completion: 15 Sep 2017 (actual)
Study completion: 15 Sep 2017 (actual)
First posted: 10 May 2011 (estimated)
Results: Posted 8 Aug 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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

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

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 10

Arm	Type	Receives
MLN0128P 30 mg QW	Experimental	Drug: MLN0128, Drug: paclitaxelMLN0128 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.
MLN0128P 40 mg QW	Experimental	Drug: MLN0128, Drug: paclitaxelMLN0128 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.
MLN0128P 6 mg QD×3d QW	Experimental	Drug: MLN0128, Drug: paclitaxelMLN0128 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.
MLN0128P 7 mg QD×3d QW	Experimental	Drug: MLN0128, Drug: paclitaxelMLN0128 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.
MLN0128P 8 mg QD×3d QW	Experimental	Drug: MLN0128, Drug: paclitaxelMLN0128 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.
MLN0128P 9 mg QD×3d QW	Experimental	Drug: MLN0128, Drug: paclitaxelMLN0128 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.
MLN0128P 10 mg QD×3d QW	Experimental	Drug: MLN0128, Drug: paclitaxelMLN0128 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.
MLN0128P 7 mg QD×5d QW	Experimental	Drug: MLN0128, Drug: paclitaxelMLN0128 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.
MLN0128P 8 mg QD×3d QW HER2-	Experimental	Drug: MLN0128, Drug: paclitaxelMLN0128 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.
MLN0128PH 8 mg QD×3d QW HER2+	Experimental	Drug: MLN0128, Drug: paclitaxel, Drug: trastuzumabMLN0128 + 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (9 listed)

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

Key exclusion criteria (12 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
MLN0128MLN0128 capsules	Drug	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+
paclitaxelpaclitaxel intravenous infusion	Drug	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+
trastuzumabtrastuzumab intravenous infusion	Drug	MLN0128PH 8 mg QD×3d QW HER2+

Primary outcome

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.
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.
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.
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.

15 secondary outcomes

Cmax: Maximum Observed Plasma Concentration for MLN0128
Time frame: Cycles 1 and 2: Day 1 or 2
Cmin: Minimum Observed Plasma Concentration for MLN0128
Time frame: Cycles 1 and 2: Day 1 or 2
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128
Time frame: Cycles 1 and 2: Day 1 or 2
Terminal Phase Elimination Half-life (T1/2) for MLN0128
Time frame: Cycle 1 Day 1
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128
Time frame: Cycle 1 Day 1
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
Cmax: Maximum Observed Plasma Concentration for Paclitaxel
Time frame: Cycles 1 and 2: Day 1
Cmin: Minimum Observed Plasma Concentration for Paclitaxel
Time frame: Cycles 1 and 2: Day 1 or 2
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel
Time frame: Cycles 1 and 2: Day 1
Terminal Phase Elimination Half-life (T1/2) for Paclitaxel
Time frame: Cycle 1 Day 1
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel
Time frame: Cycle 1 Day 1
AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel
Time frame: Cycle 1 Day 1
AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel
Time frame: Cycle 1 Day 1
CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Time frame: Cycle 1 Day 1
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

Results and safety

Results posted to the registry on 8 Aug 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
MLN0128P 30 or 40 mg QW	8	0
MLN0128P 6, 7, 8, 9 or 10 mg QD×3d QW	29	0
MLN0128P 7 mg QD×5d QW	11	0
Expansion Cohort MLN0128P 8 mg QD×3d QW HER2-	13	0
Expansion Cohort MLN0128PH 8mg QD×3d QW HER2+ Plus Trastuzumab	7	0

Primary outcome: Dose Escalation Phase: Maximum Tolerated Dose (MTD)

Time frame: Cycle 1: Days 1 to 28. Number. Unit: mg (QD×3d QW)

Measure	Dose Escalation n = 40
Value	8

Population analysed: Safety Population included all participants who received at least one dose of study drug.

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

Time frame: Cycle 1: Days 1 to 28. Number. Unit: participants

Measure	MLN0128P 30 mg QW n = 5	MLN0128P 40 mg QW n = 2	MLN0128P 6 mg QD×3d QW n = 3	MLN0128P 7 mg QD×3d QW n = 3	MLN0128P 8 mg QD×3d QW n = 3	MLN0128P 9 mg QD×3d QW n = 5	MLN0128P 10 mg QD×3d QW n = 9	MLN0128P 7 mg QD×5d QW n = 10
Value	0	2	0	0	0	2	2	2

Population analysed: Dose-Escalation evaluable population included participants who received ≥ 75% of planned doses of MLN0128 in Cycle 1 or stopped study drug before receiving 75% of doses because of study drug-related AEs (considered as DLT).

Primary outcome: Objective Response Rate (ORR)

Time frame: At screening and thereafter every 2 cycles of treatment until disease progression (Up to 65.8 weeks). Number. Unit: percentage of participants

Measure	MLN0128P 30 or 40 mg QW n = 8	MLN0128P 6, 7, 8, 9 or 10 mg QD×3d QW n = 22	MLN0128P 7 mg QD×5d QW n = 9	Expansion Cohort MLN0128P 8 mg QD×3d QW HER2- n = 10	Expansion Cohort MLN0128PH 8mg QDx3d QW HER2+ Plus Trastuzumab n = 5
Value	0	9	44	10	20

Population analysed: Full Analysis Set (FAS) included all participants who received 1 or more doses of MLN0128 and have adequate baseline and post-baseline data collected.

Primary outcome: 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). Number. Unit: percentage of participants

Measure	MLN0128P 30 or 40 mg QW n = 8	MLN0128P 6, 7, 8, 9 or 10 mg QD×3d QW n = 29	MLN0128P 7 mg QD×5d QW n = 10	Expansion Cohort MLN0128P 8 mg QD×3d QW HER2- n = 13	Expansion Cohort MLN0128PH 8mg QDx3d QW HER2+ Plus Trastuzumab n = 7
TEAE	100	100	100	100	100
SAE	63	41	60	31	43
Fatal AEs within 30 Days of Last Dose Study Drug	25	7	20	15	14
AEs Resulting in Discontinuation of MLN0128	13	34	10	15	0

Population analysed: All Subjects as Treated (ASaT) population consisted of all enrolled participants who received at least 1 dose of MLN0128, was used in the safety analyses.

15 secondary outcomes are reported in the full results.

Adverse events

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). Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
MLN0128P 30 or 40 mg QW	5 of 8 (62.5%)	8 of 8 (100%)	2 of 8
MLN0128P 6, 7, 8, 9 or 10 mg QD×3d QW	12 of 29 (41.4%)	29 of 29 (100%)	2 of 29
MLN0128P 7 mg QD×5d QW	6 of 10 (60%)	10 of 10 (100%)	2 of 10
Expansion Cohort MLN0128P 8 mg QD×3d QW HER2-	4 of 13 (30.8%)	13 of 13 (100%)	2 of 13
Expansion Cohort MLN0128PH 8mg QD×3d QW HER2+ Plus Trastuzumab	3 of 7 (42.9%)	7 of 7 (100%)	1 of 7

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 8 Aug 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 28601972Burris 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.
Individual participant dataSharing planned: Yes. 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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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Director study director

Millennium Pharmaceuticals, Inc.

3 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Aug 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Dose Escalation Phase: Maximum Tolerated Dose (MTD) (time frame: Cycle 1: Days 1 to 28). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01351350, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Aug 2019.