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

NCT01899053 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: C320012013-000466-11
• Study Type: interventional
• Target: 101
• Locations: 3 countries
• Sites: 5

Brief Summary

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.

Conditions

Advanced Nonhematologic Malignancies

Keywords

Drug Therapy; TAK-228; TAK-117

Outcome Measures

Primary Outcomes (27)

• 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.

  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

  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

  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

  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

  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

  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) \[Cycle1 Day 1\].

  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

  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

  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

  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

  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

  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

  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) \[Cycle1 Day 1\].

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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)

  Baseline, Days 22 up to Day 28 of Cycle and every even-numbered cycle until disease progression or EOS (Up to approximately 68 weeks)

Study Arms (4)

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.

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.

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.

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.

Drug: TAK-228; Drug: TAK-117

Interventions

TAK-228 DRUG

TAK-228 Capsules

Also known as: MLN0128, INK128 or Sapanisertib

Dose Escalation Treatment Arm A; Dose Escalation Treatment Arm B; Dose Escalation Treatment Arm C; Drug-Drug Interaction (DDI) Expansion Cohort

TAK-117 DRUG

TAK-117 Capsules

Also known as: MLN1117

Dose Escalation Treatment Arm A; Dose Escalation Treatment Arm B; Dose Escalation Treatment Arm C; Drug-Drug Interaction (DDI) Expansion Cohort

Eligibility Criteria

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

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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
• 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)

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (5)

Unknown Facility

Boston, Massachusetts, United States

Location

Unknown Facility

Nashville, Tennessee, United States

Location

Unknown Facility

San Antonio, Texas, United States

Location

Unknown Facility

Barcelona, Spain

Location

Unknown Facility

Sutton, United Kingdom

Location

MeSH Terms

Interventions

sapanisertib; serabelisib

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: July 10, 2013
• First Posted: July 15, 2013
• Study Start: June 28, 2013
• Primary Completion: January 31, 2017
• Study Completion: April 30, 2018
• Last Updated: October 30, 2019
• Results First Posted: October 30, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will share

Locations

US (3); ES (1); GB (1)