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

Study Overview
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Brief Summary
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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.

Detailed Description
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The drug being tested in this study is called TAK-228. TAK-228 is being tested to treat East Asian participants with advanced nonhematological malignancies for whom standard anticancer treatment is not available or is no longer effective. This study will assess the safety, tolerability, PK and will determine the RP2Ds of TAK-228. The study will enroll approximately 46 participants, including at least 6 Japanese participants at RP2D dose level. Participants will be assigned to one of the following treatment arms: TAK-228 Once Daily TAK-228 Once Weekly This multi-center trial will be conducted in South Korea, Taiwan, and Japan. The overall time to participate in this study is up to 12 months, unless in the opinion of the investigator and sponsor the participant would derive benefit from continued therapy beyond 12 months. Participants will be followed for 30 days after last dose of study drug for a follow-up assessment.

Official Title
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A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-228 (a Catalytic TORC1/2 Inhibitor) as Single Agent in Adult East Asian Patients With Advanced Nonhematological Malignancies

Conditions
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Advanced Nonhematological Neoplasms

Intervention / Treatment
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* Drug: TAK-228


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Metabolic: Glycosylated hemoglobin (hemoglobin A1c [HbA1c]) <=7%, fasting serum glucose <=130 milligram per deciliter (mg/dL), and fasting triglycerides <=300 mg/dL. Exclusion Criteria: 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. Baseline prolongation of the rate corrected QT interval (QTc) (example, repeated demonstration of QTc interval >480 millisecond [ms], or history of congenital long QT syndrome, or torsades de pointes). Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-228 Once Daily<br>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<br>* TAK-228 Capsules.<br>|
| Experimental: TAK-228 Once Weekly<br>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<br>* TAK-228 Capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) | The CBR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD). BOR was defined as the best response recorded after the first dose of study drug until subsequent therapy. As per Response Evaluation Criteria Solid Tumors (RECIST) version 1.1 guidelines, CR was defined as disappearance of all target lesions and non-target lesions, and normalization of tumor marker level. PR was defined as >= 30% decrease in the sum of the longest diameter (LD) of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression (PD). PD was defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | Baseline Up to 1 Year 7 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy