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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

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

28

A total of 28 patients were enrolled in Study C31008 and received at least 1 dose of study drug: 22 subjects (3 subjects received 2 mg, 6 subjects received 3 mg, and 7 subjects received 4 mg in the dose escalation cohort, 6 subjects received 3 mg in the dose expansion cohort) in the daily dosing schedule (QD) arm, 6 subjects (3 subjects received 20 mg or 30 mg, respectively in the dose escalation cohort) in the weekly dosing schedule (QW) arm. All subjects discontinued study treatment. The most common reason for study treatment discontinuation were PD; 14 subjects (64%) in QD arm, 4 subjects (67%) in QW arm.

DLTs and maximum tolerated dose (MTD): DLTs were reported only in the 4 mg QD cohort, which included stomatitis (2 subjects), gastrointestinal inflammation, gingivitis, and acute myocardial infarction (1 subject). On the basis of these DLTs, the MTD for TAK-228 given in the QD treatment regimen was established as 3 mg QD in East Asian patients enrolled in this study. No DLT was observed in the QW treatment regimen. The MTD was not reached and RP2D in East Asian patients was selected 30 mg QW in the same as that in Western patients. TEAEs: All subjects in both arms reported at least 1 TEAE. The most commonly reported (>=20%) preferred terms in the QD arm were stomatitis, decreased appetite and nausea, hyperglycaemia, fatigue and weight decreased, aspartate aminotransferase increased, platelet count decreased, anaemia, rash maculo-papular, and vomiting. The most commonly reported (>=20%) preferred terms in the QW arm were nausea, blood alkaline phosphatase increased, hyperglycaemia, alanine aminotransferase increased, aspartate aminotransferase increased, decreased appetite, vomiting, weight decreased, blood bilirubin increased, fatigue, gamma-glutamyltransferase increased, hiccups, and stomatitis. There were no noteworthy trends in common TEAEs across dose levels and the different dosing schedules. Fourteen subjects (64%) in the QD arm and 4 subjects (67%) in the QW arm reported at least 1 Grade 3 or higher TEAE. TEAEs of Grade 3 or higher (>1 subject in any cohort) were nausea, stomatitis and lymphocyte count decreased and rash maculo-papular in the QD arm, and gamma-glutamyltransferase increased in the QW arm. Deaths, Other SAEs, and Study Drug Discontinuation Due to AE: There was no on-study death observed during the study. Six subjects (27%) in the QD arm and 3 subjects (50%) in the QW arm experienced at least 1 SAE. All SAEs occurred in a single subject in each arm. The SAEs were genital herpes, sepsis, acute myocardial infarction, jaundice cholestatic, cerebrovascular accident and renal impairment in the QD arm, and malignant neoplasm progression, metastases to central nervous system, enteritis and cholangitis acute in the QW arm. TEAEs resulting in study drug discontinuation, dose reduction or dose interruption and Grade 3 or higher TEAE appeared to occur more frequently at higher dose compared with lower dose in QD dosing (No trend was confirmed at weekly dosing due to the small number of subjects). No clinical meaningful changes were observed in laboratory values, vital signs, ECG and other safety evaluations.

Safety Results: Refer to Adverse Event Section Pharmacokinetic Results: TAK-228 exhibited rapid absorption following oral administration, with a median tmax ranging from 0.5 to 2.6 hours across all doses in both arms. TAK-228 exposures generally increased in a dose-dependent manner. TAK-228 did not accumulate in plasma to any appreciable extent with QD and QW administration in any of the dose levels. The PK of TAK-228 was consistent during both PK assessment periods (Cycle 1 Day 1 and Cycle 1 Day 15) at all dose levels. TAK-228 administered on a QW schedule exhibited consistent PK, with a dose-dependent increase in plasma exposure between the 20 and 30 mg doses.

No subjects achieved a best overall response of CR or PR in both treatment arms and overall response rate (ORR) was 0%. Ten subjects (45%) in the QD arm and 4 subjects (67%) in the QW arm achieved SD, and 10 subjects (45%) in the QD arm and 2 subjects (33%) in the QW arm achieved PD. Three subjects who achieved SD were reported to be maintained SD for at least 6 months (3 mg QD, 4 mg QD and 20 mg QW in the escalation cohort). The clinical benefit rate of 45% in the QD arm and 67% in the QW arm was achieved. Brief Summary (Continued): Based on the results of Study C31008, the MTD and RP2D for QD regimen was established at 3 mg, which was lower than 4 mg that was established as RP2D in combination with either exemestane or fulvestrant in Western countries. DLTs were reported only in the 4 mg QD cohort. TAK-228 generally exhibited a rapid oral absorption when administered in each dose of the QD and the QW arms. Single-agent TAK-228 administered QD or QW exhibited linear PK. Although no subject achieved a CR or PR, the clinical benefit rate was 45% in the QD arm and 67% in the QW arm. A signal of moderate anti-tumor effect was shown with advanced non-hematologic malignancies.

No new safety signals were identified in this study. The safety profile of TAK-228 was acceptable, with no on-study deaths reported. Study drug was generally well-tolerated, and had a safety profile consistent with other TAK-228 studies.

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.

Takeda Pharmaceutical Company Limited

https://www.takeda.com/who-we-are/contact-us/

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Takeda Pharmaceutical Company Limited

https://www.takeda.com/who-we-are/contact-us/

+81-6-6204-2111

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completed

Jan. 17, 2018

Interventional

Open-label, Non-randomized, Parallel Assignment study

treatment purpose

1

1. 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.
2. Received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or metastatic disease.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
4. 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:
a) Serum creatinine <1.5*ULN.
b) Creatinine clearance based on the Cockcroft-Gault estimate >=40 milliliter per minute (mL/min).
c) Creatinine clearance based on urine collection (12- or 24-hour) >=40 mL/min.
d) Metabolic: Glycosylated hemoglobin (hemoglobin A1c [HbA1c]) <=7%, fasting serum glucose <=130 milligram per deciliter (mg/dL), and fasting triglycerides <=300 mg/dL.

1. Diagnosis of primary brain tumor.
2. Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression.
3. 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.
4. Initiation of hematopoietic growth factors within 1 week before the first dose of study drug.
5. 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.
6. 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.
7. Known human immunodeficiency virus infection.
8. 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.
9. 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).
10. 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.

Both

Advanced Nonhematological Neoplasms

investigational material(s)
Generic name etc : TAK-228
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : TAK-228 Once Daily: 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.
Generic name etc : TAK-228
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : TAK-228 Once Weekly: 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.

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

safety
Number of Participants with Treatment Emergent Adverse Events (TEAEs)
Timeframe; Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)

safety
Number of Participants with Grade 3 or Higher TEAEs
Timeframe; Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
Adverse Event (AE) Grades will be 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.

safety
Number of Participants with Serious TEAEs
Timeframe; Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)

safety
Number of Participants with Dose-limiting Toxicities (DLTs) during Cycle 1
Timeframe; Baseline up to Day 28 in Cycle 1 (Cycle length= 28 days)

safety
Number of Participants with TEAEs Leading to Study Drug Discontinuation
Timeframe; Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)

pharmacokinetics
Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1
Timeframe; Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15
Timeframe; Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1
Timeframe; Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15
Timeframe; Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
Daily Dosing Arms, AUC24: Area under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 1
Timeframe; Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
Daily Dosing Arms, AUC24: Area under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 15
Timeframe; Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
Weekly Dosing Arms,AUC 168: Area under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 1
Timeframe; Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
Weekly Dosing Arms, AUC 168: Area under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 15
Timeframe; Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1
Timeframe; Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15
Timeframe; Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

pharmacokinetics
AUCinfinity: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1
Timeframe; Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

efficacy
Clinical Benefit Rate
Timeframe; Baseline up to 1 Year 7 Months
The Clinical Benefit Rate (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.

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Jan. 15, 2018