A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) of TAK-228 as Single Agent in Adult East Asian Participants With Advanced Nonhematological Malignancies

NCT03370302 | Terminated Phase 1 Results

• 5 other identifiers: C31008U1111-1202-4296106606463920170270241JapicCTI-183822
• Study Type: interventional
• Target: 28
• Locations: 3 countries
• Sites: 4

Brief Summary

The purpose of this study is to evaluate the safety and tolerability, recommended phase 2 dose (RP2D), and to characterize PK of TAK-228 administered once daily or once weekly to East Asian participants with advanced nonhematological malignancies.

Conditions

Advanced Nonhematological Neoplasms

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (16)

• Number of Participants With Treatment Emergent Adverse Events (TEAEs)

  Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)

• Number of Participants With Grade 3 or Higher TEAEs

  Adverse event (AE) Grades were evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), version 4.03. Grade 1 scaled as Mild; Grade 2 scaled as Moderate; Grade 3 scaled as severe or medically significant but not immediately life-threatening; Grade 4 scaled as life-threatening consequences; and Grade 5 scaled as death related to AE.

  Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)

• Number of Participants With Serious TEAEs

  Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)

• Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1

  Toxicity was evaluated according to NCI CTCAE version 4.03. DLT was defined as any of the following occurred events within the first 28 days of the administration of TAK-228 that were considered by investigator to be possibly related to therapy: Grade \>=3 nonhematologic toxicity except for inadequately treated Grade 3 nausea and/or vomiting and diarrhea, Grade 3 hyperglycemia lasting \<=14 days, Grade 3 rash lasting \<=3 days; Grade 3 thrombocytopenia with hemorrhage or requiring platelet transfusion; Grade 3 anemia requiring blood transfusion; Grade 4 neutropenia lasting \>7 days; Grade \>=3 neutropenia of any duration with fever \>=38.5 degree celsius and/or systemic infection; Any other \>=Grade 4 hematologic toxicity; Inability to administer at least 75 percent (%) of planned doses of TAK-228 within Cycle 1 due to treatment-related toxicity and any clinically significant occurrence that the investigators and sponsor agreed would place participants at an undue safety risk.

  Baseline up to Day 28 in Cycle 1 (Cycle length= 28 days)

• Number of Participants With TEAEs Leading to Study Drug Discontinuation

  Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)

• Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1

  Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

• Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15

  Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

• Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1

  Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

• Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15

  Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

• Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 1

  Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

• Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 15

  Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

• Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 1

  Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

• Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 15

  Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

• AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1

  Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

• AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15

  Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

• AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1

  Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

Secondary Outcomes (1)

• Clinical Benefit Rate (CBR)

  Baseline Up to 1 Year 7 Months

Study Arms (2)

TAK-228 Once Daily

EXPERIMENTAL

TAK-228, milled capsule, orally, once daily, on an empty stomach in a 28-day treatment cycle for up to 12 months or until disease progression or unacceptable toxicity or withdrawal of consent with a starting dose of 2 milligram (mg) in Cohort 1. Dose escalation will follow a standard 3+3 schema. If 2 mg, once daily, is safe and tolerable, then the dose will be escalated to 4 mg, once daily, until RP2D is determined.

Drug: TAK-228

TAK-228 Once Weekly

EXPERIMENTAL

TAK-228, milled capsule, orally, once weekly, on an empty stomach in Cycle 1 of a 28-day treatment cycle and following a light meal from Cycle 2 for up to 12 months or until disease progression or unacceptable toxicity or withdrawal of consent with a starting dose of 20 mg in Cohort 1. Dose escalation will follow a standard 3+3 schema. If 20 mg, once weekly, is safe and tolerable, then the dose will be escalated to 30 mg, once weekly, until RP2D is determined.

Drug: TAK-228

Interventions

TAK-228 DRUG

TAK-228 Capsules.

TAK-228 Once Daily; TAK-228 Once Weekly

Eligibility Criteria

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

You may qualify if:

• With advanced nonhematologic malignancies, with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy. History of brain metastasis may be allowed if all of the following criteria are met:
• Brain metastases have been treated.
• There is no evidence of progression or hemorrhage after treatment.
• Steroid has been discontinued for \>=4 weeks before the first dose of study drug.
• There is no ongoing requirement for steroids or anti-epileptic drugs.
• Received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or metastatic disease.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
• Screening clinical laboratory values as specified below:
• Bone marrow reserve consistent with absolute neutrophil count (ANC) \>=2000 per cubic millimeter (/mm\^3), platelet count \>=125,000/mm\^3, and hemoglobin \>=10 gram per deciliter (g/dL) without transfusion in the last 4 weeks.
• Note: Prophylactic transfusions of blood products or any prophylactic use of hematopoietic growth factors (such as erythropoietin, thrombopoietin, granulocyte colony stimulating factor \[G-CSF\], and granulocyte macrophage colony stimulating factor \[GM-CSF\]) is not permitted during the screening period.
• Hepatic: Total bilirubin less than or equal to (\<=) 1.5\*upper limit of normal (ULN), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \<=2.5\*ULN (\<=5\*ULN if their elevation can be reasonably ascribed to the presence of hepatocellular carcinoma, biliary tract cancer, or metastatic disease in liver).
• Adequate renal function, defined as meeting any 1 of the following criteria:
• Serum creatinine \<1.5\*ULN.
• Creatinine clearance based on the Cockcroft-Gault estimate \>=40 milliliter per minute (mL/min).
• Creatinine clearance based on urine collection (12- or 24-hour) \>=40 mL/min.

You may not qualify if:

• Diagnosis of primary brain tumor.
• Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression.
• Failed to recover from the reversible effects of prior anticancer therapies with the exception of alopecia, and after-effects associated with prior tyrosine kinase inhibitor therapy, such as hair depigmentation, hypothyroidism, and/or splinter hemorrhage.
• Initiation of hematopoietic growth factors within 1 week before the first dose of study drug.
• Manifestations of malabsorption caused by prior gastrointestinal surgery, gastrointestinal disease, or for some other reason that may alter the absorption of TAK-228. In addition, participants with enteric stomata are also excluded.
• Poorly controlled diabetes mellitus defined as Hemoglobin A1c (HbA1c) greater than (\>) 7%; participants with a history of transient glucose intolerance caused by corticosteroid administration are allowed if all other eligibility criteria are met.
• Known human immunodeficiency virus infection.
• Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis C virus (HCV) infection. Note: Participants who have isolated positive hepatitis B core antibody (HBcAb) and/or hepatitis B surface antibody (HBsAb) (that is, in the setting of negative HBsAg) may be enrolled but must have an undetectable hepatitis B virus (HBV) viral load. Participants who have positive hepatitis C virus antibody (HCVAb) may be enrolled but must have an undetectable HCV viral load.
• Significant active cardiovascular or pulmonary disease before the first dose of study drug, including:
• Uncontrolled hypertension (that is, systolic blood pressure \>180 millimeter of mercury \[mmHg\]; diastolic blood pressure \>95 mmHg).
• Pulmonary hypertension.
• Uncontrolled asthma or oxygen saturation less than (\<) 90% by pulse oximetry on room air.
• Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention; or history of valve replacement.
• Medically significant (symptomatic) bradycardia.
• History of arrhythmia requiring an implantable cardiac defibrillator.

Sponsors & Collaborators

• Calithera Biosciences, Inc: lead

Study Sites (4)

National Cancer Center Hospital East

Kashiwa-shi, Chiba, 277-8577, Japan

Location

National Cancer Center Hospital

Chūōku, Tokyo-To, 104-0045, Japan

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

National Taiwan-University Hospital

Taipei, 100, Taiwan

Location

Related Publications (1)

• Shimizu T, Kuboki Y, Lin CC, Yonemori K, Yanai T, Faller DV, Dobler L, Gupta N, Sedarati F, Kim KP. A Phase 1 Study of Sapanisertib (TAK-228) in East Asian Patients with Advanced Nonhematological Malignancies. Target Oncol. 2022 Jan;17(1):15-24. doi: 10.1007/s11523-021-00855-w. Epub 2021 Nov 29.

  PMID: 34843044 DERIVED

MeSH Terms

Interventions

sapanisertib

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: December 7, 2017
• First Posted: December 12, 2017
• Study Start: January 17, 2018
• Primary Completion: August 28, 2019
• Study Completion: August 28, 2019
• Last Updated: February 8, 2023
• Results First Posted: September 9, 2020

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Locations

KR (1); TW (1); JP (2)