Advanced Nonhematologic MalignanciesPhase 1NCT01899053

A Safety and Pharmacokinetic Study of TAK-228 in Combination With TAK-117 in Adult Participants With Advanced Nonhematologic Malignancies

A Phase 1 study testing TAK-228 and TAK-117 in people with Advanced Nonhematologic Malignancies, run by Millennium Pharmaceuticals, Inc. at 5 sites in 3 countries.

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

Who is it for?: Ages 18 years and older
Conditions the study is for: Advanced Nonhematologic Malignancies
What is being tested?: TAK-228 and TAK-117
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 101 participants
Where: 5 sitesin 3 countries
Study dates: 28 Jun 2013to 30 Apr 2018
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

Male or female participants 18 years or older
Participants must have a diagnosis and documented disease progression of a solid tumor malignancy, excluding primary brain tumor, for which standard, curative, or life prolonging treatment does not exist or is no longer effective
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Female participants who are postmenopausal for at least 1 year prior to screening. For women of child-bearing potential agree to practice 2 effective methods of contraception or agree to practice true abstinence
Male participants must agree to practice effective barrier contraception during the entire study treatment period and through 30 days after last dose of study drug or practice true abstinence
Voluntary written consent

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Suitable venous access
Participants must have a block of banked tumor tissue and/or fresh tumor tissue or at least 10 unstained slides available to be sent to the central laboratory
Clinical laboratory values as specified in the protocol
Participants must have radiographically or clinically evaluable tumor

Who cannot join

Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug
Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment
Treatment with any investigational products within 30 days before the first dose of study drug
Previous treatment with TAK-117 and/or TAK-228; previous treatment with dual mTORC1/2 or dual PI3K-mTOR inhibitors
Failed to have recovered from the reversible effects of previous anticancer therapies
Have received systemic corticosteroid (inhalers are allowed) within 7 days before the first administration of study drug

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Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of study drug
Diagnosis of diabetes mellitus
Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection
Known human immunodeficiency virus (HIV) infection
Cardiovascular conditions as defined in the protocol
A requirement for positive inotropic support (excluding digoxin) or serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation) within 1 year before screening
Participants who are taking proton pump inhibitors within 7 days of the first dose or who require treatment with proton pump inhibitors during the trial or those who are taking histamine-2 (H2) receptor antagonists within 24 hours of the first dose
Participants who received previous therapy with PI3K inhibitors or rapalogs will be allowed in the study if all other inclusion/exclusion criteria are met
Diagnosis of primary brain tumor or symptomatic brain metastasis. Participants with brain metastases must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs)

Trial locations and contacts

5 sites in 3 countries.

Country

City, postcode or hospital

5 sites in 3 countries

United States3 sites

Study site
Boston, Massachusetts
Study site
Nashville, Tennessee
Study site
San Antonio, Texas

Other trials in United States

Spain1 site

Study site
Barcelona

Other trials in Spain

United Kingdom1 site

Study site
Sutton

Other trials in United Kingdom

About this study

Official title: A Multicenter, Open-label, Phase 1b Study of MLN0128 (an Oral mTORC1/2 Inhibitor) in Combination With MLN1117 (an Oral PI3Kα Inhibitor) in Adult Patients With Advanced Nonhematologic Malignancies

The purpose of this study was to evaluate the safety and to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and dosing schedules of oral TAK-228+TAK-117. It also evaluated the single- and multiple-dose plasma pharmacokinetics (PK) of TAK-228+TAK-117 in participants with advanced nonhematologic malignancies.

Read the detailed description

The drug being tested in this study was TAK-228. TAK-228 was tested to evaluate the safety, pharmacokinetics and efficacy, of TAK-228 in combination with TAK-117 when administered to adult participants with advanced nonhematologic malignancies.

The study enrolled 101 patients. The study consisted of 2 phases: an escalation stage followed by an expansion stage. Participants in escalation stage were assigned to the following treatment arms:

Dose escalation treatment arm A: TAK-228 2 or 4 mg capsule
Dose escalation treatment arm B: TAK-228 3, 4, 6 or 8 mg capsule
Dose escalation treatment arm C: TAK-228 3 mg capsule

Upon completion of the escalation stage, 1 combination treatment regimen was selected for further safety, tolerability, pharmacokinetics, and mutual drug-drug interaction characterization in the expansion stage. During treatment, participants in both stages received TAK-228 and TAK-117 capsules at prespecified doses in repeated 28-day cycles.

This multi-center trial conducted in the United States, United Kingdom and Spain. The overall time to participate in this study was approximately 68 weeks. Participants made multiple visits to the clinic, and a final visit after 30 days after last dose of study drug.

Conditions: Advanced Nonhematologic Malignancies
Being tested: TAK-228, TAK-117
Keywords: Drug Therapy, TAK-228, TAK-117

What participants receive

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

TAK-228Drug
Also called MLN0128, INK128 or Sapanisertib
TAK-228 Capsules
TAK-117Drug
Also called MLN1117
TAK-117 Capsules

Study groups in NCT01899053
Study group	Role	What they receive
Dose Escalation Treatment Arm A	Experimental	TAK-228 2 or 4 mg, capsule (milled or unmilled), orally, once daily every day (QD), and TAK-117 100, 200 or 300 mg, capsule, orally, once on Monday, Wednesday and Friday each week (MWF QW) for up to 13 cycles (each cycle was 28 days), up to approximately 52 weeks. Receives: Drug: TAK-228; Drug: TAK-117
Dose Escalation Treatment Arm B	Experimental	TAK-228 3, 4, 6 or 8 mg, capsule (milled or unmilled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 100 or 200 mg, capsule, orally, once on MTuW QW for up to 9 cycles (each cycle was 28 days), up to approximately 38.7 weeks. Receives: Drug: TAK-228; Drug: TAK-117
Dose Escalation Treatment Arm C	Experimental	TAK-228 3 mg, capsule (milled or unmilled), orally, once on MTuW QW, and TAK-117 300 or 400 mg, capsule, orally, once on MTuW QW for up to 17 cycles (each cycle was 28 days), up to approximately 64.3 weeks. Receives: Drug: TAK-228; Drug: TAK-117
Drug-Drug Interaction (DDI) Expansion Cohort	Experimental	TAK-228 4 mg, capsule (milled), orally, once on MTuW QW except on Days 15, 16 and 17 of Cycle 1, and TAK-117 200 mg, capsule, orally, once on MTuW QW except on Days 1, 2 and 3 of Cycle 1 for up to 8 cycles (each cycle was 28 days), up to approximately 31.4 weeks. Receives: Drug: TAK-228; Drug: TAK-117

What is being measured

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

Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs)
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 TEAE is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above-mentioned criteria.
Measured: From Baseline to 30 days after the last dose of study drug (Up to approximately 68 weeks)
Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort
Accumulation ratio was based on AUC(0-24) between Cycle 1 Day 24 and Cycle 1 Day 1 (e.g. AUC(0-24) [Cycle 1 Day 24]/ AUC(0-24) [Cycle1 Day 1].
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort
Accumulation ratio was based on AUC(0-24) between Cycle 1 Day 24 and Cycle 1 Day 1 (e.g. AUC(0-24) [Cycle 1 Day 24]/ AUC(0-24) [Cycle1 Day 1].
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Measured: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Cmax: Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-228 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Terminal Phase Elimination Half-life (T1/2) for TAK-228 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-228 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Peak to Trough Ratio for TAK-228 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Cmax: Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-117 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Terminal Phase Elimination Half-life (T1/2) for TAK-117 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-117 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Peak to Trough Ratio for TAK-117 in DDI Expansion Cohort
Measured: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose

Secondary outcomes (2)

Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
ORR defined as the percentage of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT or MRI. CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter (LD) of target lesions. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD since the treatment started.
Measured: Baseline, Days 22 up to Day 28 of Cycle and every even-numbered cycle until disease progression or EOS (Up to approximately 68 weeks)
Duration of Response (DOR)
The DOR is defined as the time from the date of first documented response of CR/PR to the first documented progressive disease (PD), or censored at the last response assessment date that is SD or better for a participant that has not progressed. 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: Baseline, Days 22 up to Day 28 of Cycle and every even-numbered cycle until disease progression or EOS (Up to approximately 68 weeks)

Timeline

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

28 Jun 201330 Apr 2018

First posted15 Jul 2013 (estimated)
Study start28 Jun 2013
Primary completion31 Jan 2017
Study completion30 Apr 2018

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.
Other trials for Advanced Nonhematologic 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: 101 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01899053
Sponsor's protocol ID: C32001
Other IDs: 2013-000466-11
Status last verified: Oct 2019
First submitted: 10 Jul 2013
Last updated: 30 Oct 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 for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com 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.

Study at a glance

From the registry record, last updated by the sponsor on 30 Oct 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Multicenter, Open-label, Phase 1b Study of MLN0128 (an Oral mTORC1/2 Inhibitor) in Combination With MLN1117 (an Oral PI3Kα Inhibitor) in Adult Patients With Advanced Nonhematologic Malignancies
ClinicalTrials.gov ID: NCT01899053
Acronym / sponsor ID: C32001
Conditions: Advanced Nonhematologic Malignancies
Keywords: Drug Therapy, TAK-228, TAK-117
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 101 participants (actual)
Lead sponsor: Millennium Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
Study start: 28 Jun 2013 (actual)
Primary completion: 31 Jan 2017 (actual)
Study completion: 30 Apr 2018 (actual)
First posted: 15 Jul 2013 (estimated)
Results: Posted 30 Oct 2019

Clinical summary

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

Detailed description

The study enrolled 101 patients. The study consisted of 2 phases: an escalation stage followed by an expansion stage. Participants in escalation stage were assigned to the following treatment arms:

Dose escalation treatment arm A: TAK-228 2 or 4 mg capsule
Dose escalation treatment arm B: TAK-228 3, 4, 6 or 8 mg capsule
Dose escalation treatment arm C: TAK-228 3 mg capsule

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 4

Arm	Type	Receives
Dose Escalation Treatment Arm A	Experimental	Drug: TAK-228, Drug: TAK-117TAK-228 2 or 4 mg, capsule (milled or unmilled), orally, once daily every day (QD), and TAK-117 100, 200 or 300 mg, capsule, orally, once on Monday, Wednesday and Friday each week (MWF QW) for up to 13 cycles (each cycle was 28 days), up to approximately 52 weeks.
Dose Escalation Treatment Arm B	Experimental	Drug: TAK-228, Drug: TAK-117TAK-228 3, 4, 6 or 8 mg, capsule (milled or unmilled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 100 or 200 mg, capsule, orally, once on MTuW QW for up to 9 cycles (each cycle was 28 days), up to approximately 38.7 weeks.
Dose Escalation Treatment Arm C	Experimental	Drug: TAK-228, Drug: TAK-117TAK-228 3 mg, capsule (milled or unmilled), orally, once on MTuW QW, and TAK-117 300 or 400 mg, capsule, orally, once on MTuW QW for up to 17 cycles (each cycle was 28 days), up to approximately 64.3 weeks.
Drug-Drug Interaction (DDI) Expansion Cohort	Experimental	Drug: TAK-228, Drug: TAK-117TAK-228 4 mg, capsule (milled), orally, once on MTuW QW except on Days 15, 16 and 17 of Cycle 1, and TAK-117 200 mg, capsule, orally, once on MTuW QW except on Days 1, 2 and 3 of Cycle 1 for up to 8 cycles (each cycle was 28 days), up to approximately 31.4 weeks.

Who may qualify

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

Key inclusion criteria (10 listed)

Male or female participants 18 years or older
Participants must have a diagnosis and documented disease progression of a solid tumor malignancy, excluding primary brain tumor, for which standard, curative, or life prolonging treatment does not exist or is no longer effective
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Female participants who are postmenopausal for at least 1 year prior to screening. For women of child-bearing potential agree to practice 2 effective methods of contraception or agree to practice true abstinence
Male participants must agree to practice effective barrier contraception during the entire study treatment period and through 30 days after last dose of study drug or practice true abstinence

Key exclusion criteria (15 listed)

Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug
Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment
Treatment with any investigational products within 30 days before the first dose of study drug
Previous treatment with TAK-117 and/or TAK-228; previous treatment with dual mTORC1/2 or dual PI3K-mTOR inhibitors
Failed to have recovered from the reversible effects of previous anticancer therapies

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
TAK-228Also: MLN0128, INK128 or SapanisertibTAK-228 Capsules	Drug	Dose Escalation Treatment Arm A, Dose Escalation Treatment Arm B, Dose Escalation Treatment Arm C, Drug-Drug Interaction (DDI) Expansion Cohort
TAK-117Also: MLN1117TAK-117 Capsules	Drug	Dose Escalation Treatment Arm A, Dose Escalation Treatment Arm B, Dose Escalation Treatment Arm C, Drug-Drug Interaction (DDI) Expansion Cohort

Primary outcome

Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs)
Time frame: From Baseline to 30 days after the last dose of study drug (Up to approximately 68 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 TEAE is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above-mentioned criteria.
Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
RAC: Accumulation Ratio for TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Accumulation ratio was based on AUC(0-24) between Cycle 1 Day 24 and Cycle 1 Day 1 (e.g. AUC(0-24) [Cycle 1 Day 24]/ AUC(0-24) [Cycle1 Day 1].
Peak to Trough Ratio for TAK-228 After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-117 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Terminal Phase Elimination Half-life (T1/2) After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
RAC: Accumulation Ratio for TAK-117 in the Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Accumulation ratio was based on AUC(0-24) between Cycle 1 Day 24 and Cycle 1 Day 1 (e.g. AUC(0-24) [Cycle 1 Day 24]/ AUC(0-24) [Cycle1 Day 1].
Peak to Trough Ratio After Single-dose and Multiple-dose of TAK-117 in Dose Escalation Cohort
Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose
Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Cmax: Maximum Observed Plasma Concentration for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Terminal Phase Elimination Half-life (T1/2) for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Peak to Trough Ratio for TAK-228 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 10 predose and at multiple timepoints (up to 24 hours) postdose
Tmax: Time to Reach the Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Cmax: Maximum Observed Plasma Concentration for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Terminal Phase Elimination Half-life (T1/2) for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
CL/F: Apparent Clearance After Extravascular Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose
Peak to Trough Ratio for TAK-117 in DDI Expansion Cohort
Time frame: Cycle 1, Day 3 predose and at multiple timepoints (up to 8 hours) postdose; Cycle 1, Day 17 predose and at multiple timepoints (up to 24 hours) postdose

2 secondary outcomes

Objective Response Rate (ORR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Time frame: Baseline, Days 22 up to Day 28 of Cycle and every even-numbered cycle until disease progression or EOS (Up to approximately 68 weeks)
Duration of Response (DOR)
Time frame: Baseline, Days 22 up to Day 28 of Cycle and every even-numbered cycle until disease progression or EOS (Up to approximately 68 weeks)

Results and safety

Results posted to the registry on 30 Oct 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
Dose Escalation Treatment Arm A: Cohort 1A	7	0
Dose Escalation Treatment Arm A: Cohort 2A	3	0
Dose Escalation Treatment Arm A: Cohort 3A	7	0
Dose Escalation Treatment Arm A: Cohort 3A (Milled)	3	0
Dose Escalation Treatment Arm A: Cohort 4A	6	0
Dose Escalation Treatment Arm B: Cohort 1B	3	0
Dose Escalation Treatment Arm B: Cohort 2B	3	0
Dose Escalation Treatment Arm B: Cohort 3B	3	0
Dose Escalation Treatment Arm B: Cohort 3B (Milled)	6	0
Dose Escalation Treatment Arm B: Cohort 4B	3	0
Dose Escalation Treatment Arm B: Cohort 5B (Milled)	16	0
Dose Escalation Treatment Arm C: Cohort 1C	7	0
Dose Escalation Treatment Arm C: Cohort 2C (Milled)	14	0
Drug-Drug Interaction (DDI) Expansion Cohort (Milled)	20	0

Primary outcome: Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs)

Time frame: From Baseline to 30 days after the last dose of study drug (Up to approximately 68 weeks). Count of participants. Unit: Participants

Measure	Dose Escalation Treatment Arm A: Cohort 1A n = 7	Dose Escalation Treatment Arm A: Cohort 2A n = 3	Dose Escalation Treatment Arm A: Cohort 3A n = 7	Dose Escalation Treatment Arm A: Cohort 3A (Milled) n = 3	Dose Escalation Treatment Arm A: Cohort 4A n = 6	Dose Escalation Treatment Arm B: Cohort 1B n = 3	Dose Escalation Treatment Arm B: Cohort 2B n = 3	Dose Escalation Treatment Arm B: Cohort 3B n = 3	Dose Escalation Treatment Arm B: Cohort 3B (Milled) n = 6	Dose Escalation Treatment Arm B: Cohort 4B n = 3	Dose Escalation Treatment Arm B: Cohort 5B (Milled) n = 16	Dose Escalation Treatment Arm C: Cohort 1C n = 7	Dose Escalation Treatment Arm C: Cohort 2C (Milled) n = 14	Drug-Drug Interaction (DDI) Expansion Cohort (Milled) n = 20
AEs	7	3	7	3	5	3	3	3	6	3	16	7	14	19
SAEs	2	0	1	1	1	0	1	1	1	1	4	4	6	9

Population analysed: Safety population consisted of all enrolled participants who received at least 1 dose of any study drug.

Primary outcome: Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort

Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose. Median (Full Range). Unit: hour

Measure	Dose Escalation Treatment Arm A: Cohort 1A n = 7	Dose Escalation Treatment Arm A: Cohort 2A n = 3	Dose Escalation Treatment Arm A: Cohort 3A n = 7	Dose Escalation Treatment Arm A: Cohort 3A (Milled) n = 3	Dose Escalation Treatment Arm A: Cohort 4A n = 6	Dose Escalation Treatment Arm B: Cohort 1B n = 3	Dose Escalation Treatment Arm B: Cohort 2B n = 3	Dose Escalation Treatment Arm B: Cohort 3B n = 3	Dose Escalation Treatment Arm B: Cohort 3B (Milled) n = 6	Dose Escalation Treatment Arm B: Cohort 4B n = 3	Dose Escalation Treatment Arm B: Cohort 5B (Milled) n = 16	Dose Escalation Treatment Arm C: Cohort 1C n = 7	Dose Escalation Treatment Arm C: Cohort 2C (Milled) n = 14
Cycle 1, Day 1	1.000 (0.50 to 4.00)	1.000 (0.97 to 1.03)	1.000 (0.50 to 4.07)	2.050 (0.53 to 2.07)	1.033 (1.00 to 2.08)	2.083 (1.97 to 4.02)	1.000 (0.48 to 1.07)	1.067 (1.03 to 8.12)	1.358 (0.50 to 4.00)	1.067 (0.98 to 3.83)	1.000 (0.50 to 2.15)	0.725 (0.43 to 2.08)	0.983 (0.47 to 4.17)
Cycle 1, Day 24	1.000 (0.50 to 2.00)	0.758 (0.48 to 1.03)	1.400 (0.45 to 4.08)	–	2.000 (0.92 to 2.25)	4.000 (1.00 to 4.12)	1.408 (1.00 to 1.82)	0.617 (0.48 to 2.00)	0.925 (0.50 to 2.15)	4.000 (4.000 to 4.000)	1.033 (0.47 to 2.30)	2.083 (1.95 to 4.87)	1.017 (0.50 to 7.03)

Population analysed: Pharmacokinetic (PK) population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Primary outcome: Cmax: Maximum Observed Plasma Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort

Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose. Mean (Standard Deviation). Unit: ng/mL

Measure	Dose Escalation Treatment Arm A: Cohort 1A n = 7	Dose Escalation Treatment Arm A: Cohort 2A n = 3	Dose Escalation Treatment Arm A: Cohort 3A n = 7	Dose Escalation Treatment Arm A: Cohort 3A (Milled) n = 3	Dose Escalation Treatment Arm A: Cohort 4A n = 6	Dose Escalation Treatment Arm B: Cohort 1B n = 3	Dose Escalation Treatment Arm B: Cohort 2B n = 3	Dose Escalation Treatment Arm B: Cohort 3B n = 3	Dose Escalation Treatment Arm B: Cohort 3B (Milled) n = 6	Dose Escalation Treatment Arm B: Cohort 4B n = 3	Dose Escalation Treatment Arm B: Cohort 5B (Milled) n = 16	Dose Escalation Treatment Arm C: Cohort 1C n = 7	Dose Escalation Treatment Arm C: Cohort 2C (Milled) n = 14
Cycle 1, Day 1	24.63 (7.355)	39.73 (7.853)	25.80 (8.188)	28.67 (3.702)	18.26 (8.610)	21.69 (29.273)	48.90 (28.157)	33.30 (16.301)	53.10 (7.257)	53.53 (29.788)	42.17 (11.495)	27.53 (11.665)	26.51 (12.788)
Cycle 1, Day 24	27.78 (6.632)	53.55 (2.192)	29.45 (9.746)	–	13.75 (6.938)	37.36 (49.078)	46.10 (17.253)	72.43 (13.094)	61.58 (14.894)	17.1 (0)	50.68 (12.055)	17.75 (4.865)	35.59 (18.415)

Population analysed: PK population consisted of all participants enrolled in the study who received at least 1 dose of TAK-228 and TAK-117 and had sufficient concentration-time data to calculate 1 or more PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

Primary outcome: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Observed Quantifiable Concentration After Single-dose and Multiple-dose of TAK-228 in the Dose Escalation Cohort

Time frame: Cycle 1: Days 1 and 24 predose and at multiple timepoints (up to 24 hours) postdose. Mean (Standard Deviation). Unit: ng*hr/mL

Measure	Dose Escalation Treatment Arm A: Cohort 1A n = 7	Dose Escalation Treatment Arm A: Cohort 2A n = 3	Dose Escalation Treatment Arm A: Cohort 3A n = 7	Dose Escalation Treatment Arm A: Cohort 3A (Milled) n = 3	Dose Escalation Treatment Arm A: Cohort 4A n = 6	Dose Escalation Treatment Arm B: Cohort 1B n = 3	Dose Escalation Treatment Arm B: Cohort 2B n = 3	Dose Escalation Treatment Arm B: Cohort 3B n = 3	Dose Escalation Treatment Arm B: Cohort 3B (Milled) n = 6	Dose Escalation Treatment Arm B: Cohort 4B n = 3	Dose Escalation Treatment Arm B: Cohort 5B (Milled) n = 16	Dose Escalation Treatment Arm C: Cohort 1C n = 7	Dose Escalation Treatment Arm C: Cohort 2C (Milled) n = 14
Cycle 1, Day 1	120.888 (36.1184)	247.361 (156.0211)	138.929 (37.3727)	230.983 (14.6292)	109.622 (45.6613)	126.062 (120.8204)	303.897 (152.5659)	287.283 (268.7088)	351.602 (122.6407)	382.588 (250.2623)	249.341 (128.4868)	168.408 (103.9245)	160.670 (90.6815)
Cycle 1, Day 24	206.418 (169.5373)	208.389 (78.6461)	200.762 (56.1368)	–	115.884 (50.7913)	203.836 (120.1336)	410.604 (265.8768)	535.365 (256.8762)	331.286 (133.7879)	305.97 (0)	317.111 (151.6045)	132.058 (71.7154)	211.792 (100.9091)

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: Baseline up to 30 days after the last dose of study drug (Up to approximately 68 weeks). Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Dose Escalation Treatment Arm A: Cohort 1A	2 of 7 (28.6%)	6 of 7 (85.7%)	0 of 7
Dose Escalation Treatment Arm A: Cohort 2A	0 of 3 (0%)	3 of 3 (100%)	0 of 3
Dose Escalation Treatment Arm A: Cohort 3A	1 of 7 (14.3%)	7 of 7 (100%)	1 of 7
Dose Escalation Treatment Arm A: Cohort 3A (Milled)	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
Dose Escalation Treatment Arm A: Cohort 4A	1 of 6 (16.7%)	5 of 6 (83.3%)	1 of 6
Dose Escalation Treatment Arm B: Cohort 1B	0 of 3 (0%)	3 of 3 (100%)	0 of 3
Dose Escalation Treatment Arm B: Cohort 2B	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
Dose Escalation Treatment Arm B: Cohort 3B	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
Dose Escalation Treatment Arm B: Cohort 3B (Milled)	1 of 6 (16.7%)	6 of 6 (100%)	0 of 6
Dose Escalation Treatment Arm B: Cohort 4B	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
Dose Escalation Treatment Arm B: Cohort 5B (Milled)	4 of 16 (25%)	16 of 16 (100%)	2 of 16
Dose Escalation Treatment Arm C: Cohort 1C	4 of 7 (57.1%)	7 of 7 (100%)	0 of 7
Dose Escalation Treatment Arm C: Cohort 2C (Milled)	6 of 14 (42.9%)	13 of 14 (92.9%)	0 of 14
Drug-Drug Interaction (DDI) Expansion Cohort (Milled)	9 of 20 (45%)	19 of 20 (95%)	2 of 20

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 30 Oct 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: Yes. Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com 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.

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 Monitor study director

Millennium Pharmaceuticals, Inc.

5 sites in 3 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing TAK-228 and TAK-117 in people with Advanced Nonhematologic Malignancies, run by Millennium Pharmaceuticals, Inc. at 5 sites in 3 countries.

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 10 inclusion and 15 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 30 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States, Spain, United Kingdom. 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 30 Oct 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?

Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Event (TEAEs) and Serious Adverse Events (SAEs) (time frame: From Baseline to 30 days after the last dose of study drug (Up to approximately 68 weeks)). The study lists 27 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 NCT01899053.

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 30 Oct 2019.