Clinical Trials List
Protocol NumberC31008
NCT Number(ClinicalTrials.gov Identfier)NCT03370302
2018-06-01 - 2020-05-31
Phase I
Terminated1
ICD-10D75.9
Disease of blood and blood-forming organs, unspecified
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
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Trial Applicant
IQVIA RDS Taiwan Ltd.
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Sponsor
Millennium Pharmaceutical, Inc
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Chiun Hsu Division of Hematology & Oncology
- 林季宏 Division of Hematology & Oncology
- JHE-CYUAN GUO Division of Hematology & Oncology
- YEN-SHEN LU Division of Hematology & Oncology
- 廖斌志 Division of Hematology & Oncology
- Jih-Hsiang Lee Division of Hematology & Oncology
- James Chih-Hsin Yang Division of Hematology & Oncology
- 張端瑩 Division of Hematology & Oncology
- Ying-Chun Shen Division of Hematology & Oncology
- Chih-Hung Hsu Division of Hematology & Oncology
- Wei-Wu Chen Division of Hematology & Oncology
- 徐偉勛 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Condition/Disease
Advanced Nonhematological Malignancies
Objectives
Primary Objectives:
• To evaluate safety and tolerability and to determine RP2D of TAK-228 administered daily (QD arm) or weekly
(QW arm) to East Asian patients with advanced nonhematological malignancies
• To characterize PK of TAK-228 in East Asian patients with advanced nonhematological malignancies
Secondary Objectives:
• To evaluate preliminary anti-tumor activity of TAK-228
Test Drug
TAK-228
Active Ingredient
TAK-228
Dosage Form
capsule
Dosage
1,3 and 5
Endpoints
Main Criteria for Evaluation and Analyses:
Primary:
• The number and percentage of patients with Treatment-emergent AEs (TEAEs).
• The number and percentage of patients with Grade 3 or higher TEAEs.
• The number and percentage of patients with serious TEAEs.
• Number of patients with DLTs during Cycle 1.
• The number and percentage of patients with TEAEs leading to study drug discontinuation.
• TAK-228 Cmax, tmax, and AUC on Cycle 1 Days 1 and 15.
Secondary:
• Clinical benefit rate defined as the proportion of patients with a best overall response of complete response
(CR), partial response (PR) or stable disease (SD) (SD of any duration).
Exploratory:
• Accumulation ratio ([Cycle 1 Day 15]/[Cycle 1 Day 1]) of TAK-228 Cmax and AUC.
• TAK-228 t1/2, CL/F, and Vz/F on Cycle 1 Days 1 and 15.
• TAK-228 Ctrough in QD and QW Arms.
• Germline polymorphisms in genes encoding drug-metabolizing enzymes and/or transporters involved in the
metabolism or disposition of TAK-228.
Primary:
• The number and percentage of patients with Treatment-emergent AEs (TEAEs).
• The number and percentage of patients with Grade 3 or higher TEAEs.
• The number and percentage of patients with serious TEAEs.
• Number of patients with DLTs during Cycle 1.
• The number and percentage of patients with TEAEs leading to study drug discontinuation.
• TAK-228 Cmax, tmax, and AUC on Cycle 1 Days 1 and 15.
Secondary:
• Clinical benefit rate defined as the proportion of patients with a best overall response of complete response
(CR), partial response (PR) or stable disease (SD) (SD of any duration).
Exploratory:
• Accumulation ratio ([Cycle 1 Day 15]/[Cycle 1 Day 1]) of TAK-228 Cmax and AUC.
• TAK-228 t1/2, CL/F, and Vz/F on Cycle 1 Days 1 and 15.
• TAK-228 Ctrough in QD and QW Arms.
• Germline polymorphisms in genes encoding drug-metabolizing enzymes and/or transporters involved in the
metabolism or disposition of TAK-228.
Inclution Criteria
Main Criteria for Inclusion:
1. Patients of the primary East Asian ethnicity (ie, Japanese, Korean, or Chinese) aged 18 years or older (if local
regulation requires a minimum age for informed consent of more than 18 years, then patients must be the minimum
age or older per the local regulation) when written study informed consent is obtained.
2. Patients 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
3. Received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or metastatic disease.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
5. Screening clinical laboratory values as specified below:
• Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥2000/mm3
, platelet count
≥125,000/mm3
, and hemoglobin ≥10 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 ≤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 mL/min.
- Creatinine clearance based on urine collection (12- or 24-hour) ≥40 mL/min.
• Metabolic: Glycosylated hemoglobin (HbA1c) ≤7%, fasting serum glucose ≤130 mg/dL, and fasting
triglycerides ≤300 mg/dL.
6. Female patients who:
• Are postmenopausal (natural amenorrhea, not caused by other medical reasons) for at least 1 year before the
screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1
additional effective (barrier) method at the same time, from the time of signing the informed consent through
90 days after the last dose of study drug, OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], condoms only,
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
• Agree to practice effective barrier contraception during the entire study treatment period and through 120 days
after the last dose of study drug, OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner],
condoms only, withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of
contraception.)
7. Ability to swallow oral medications.
8. Voluntary written consent obtained before performance of any study-related procedure not part of standard
medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to
future medical care.
1. Patients of the primary East Asian ethnicity (ie, Japanese, Korean, or Chinese) aged 18 years or older (if local
regulation requires a minimum age for informed consent of more than 18 years, then patients must be the minimum
age or older per the local regulation) when written study informed consent is obtained.
2. Patients 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
3. Received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or metastatic disease.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
5. Screening clinical laboratory values as specified below:
• Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥2000/mm3
, platelet count
≥125,000/mm3
, and hemoglobin ≥10 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 ≤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 mL/min.
- Creatinine clearance based on urine collection (12- or 24-hour) ≥40 mL/min.
• Metabolic: Glycosylated hemoglobin (HbA1c) ≤7%, fasting serum glucose ≤130 mg/dL, and fasting
triglycerides ≤300 mg/dL.
6. Female patients who:
• Are postmenopausal (natural amenorrhea, not caused by other medical reasons) for at least 1 year before the
screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1
additional effective (barrier) method at the same time, from the time of signing the informed consent through
90 days after the last dose of study drug, OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], condoms only,
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
• Agree to practice effective barrier contraception during the entire study treatment period and through 120 days
after the last dose of study drug, OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner],
condoms only, withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of
contraception.)
7. Ability to swallow oral medications.
8. Voluntary written consent obtained before performance of any study-related procedure not part of standard
medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to
future medical care.
Exclusion Criteria
Main Criteria for Exclusion:
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
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. Received prior cancer therapy or other investigational therapy within 2 weeks before the first dose of study drug.
For prior therapies with a half-life longer than 3 days, the interval must be at least 28 days before the first dose of
study drug.
5. Initiation of hematopoietic growth factors within 1 week before the first dose of study drug.
6. Requirement of systemic corticosteroid treatment within 7 days before receiving the first dose of TAK-228.
Inhalers and low-dose glucocorticoids for replacement therapy are allowed.
7. 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, patients with enteric stomata are also excluded.
8. Poorly controlled diabetes mellitus defined as HbA1c >7%; patients with a history of transient glucose intolerance
caused by corticosteroid administration are allowed if all other eligibility criteria are met.
9. Other clinically significant comorbidities, such as uncontrolled pulmonary disease (eg, severe chronic obstructive
pulmonary disease with hypoxemia, interstitial lung disease, radiation induced lung injury), active central nervous
system disease, active infection, or any other condition that could compromise the patient’s safety and
participation in the study per protocol.
10. Known human immunodeficiency virus infection.
11. Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis C virus (HCV)
infection.
Note: Patients who have isolated positive hepatitis B core antibody (HBcAb) and/or hepatitis B surface antibody
(HBsAb) may be enrolled but must have an undetectable hepatitis B virus (HBV) viral load. Patients who have
positive hepatitis C virus antibody (HCVAb) may be enrolled but must have an undetectable HCV viral load.
12. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening
period or a positive urine pregnancy test on Cycle 1 Day 1 before the first dose of the study drug.
(Note: Female patients who are lactating will be excluded, even if they discontinue breastfeeding.)
13. History of any of the following within the last 6 months before the first dose of study drug:
• Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures.
• Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures.
• Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including
atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
• Placement of a pacemaker for control of rhythm.
• New York Heart Association Class III or IV heart failure.
• Pulmonary embolism.
14. Significant active cardiovascular or pulmonary disease before the first dose of study drug, including:
• Uncontrolled hypertension (ie, systolic blood pressure >180 mmHg; diastolic blood pressure >95 mmHg).
• Pulmonary hypertension.
• Uncontrolled asthma or oxygen saturation <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 [eg, repeated demonstration of QTc interval
>480 ms, or history of congenital long QT syndrome, or torsades de pointes]).
15. 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. Patients with nonmelanoma skin cancer or
carcinoma in situ of any type are not excluded if they have undergone complete resection.
16.Requirement of daily or chronic use of proton pump inhibitors (PPIs) and/or the use of a PPI within 7 days before receiving the first dose of TAK-228. Use of PPIs is prohibited during the study.
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
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. Received prior cancer therapy or other investigational therapy within 2 weeks before the first dose of study drug.
For prior therapies with a half-life longer than 3 days, the interval must be at least 28 days before the first dose of
study drug.
5. Initiation of hematopoietic growth factors within 1 week before the first dose of study drug.
6. Requirement of systemic corticosteroid treatment within 7 days before receiving the first dose of TAK-228.
Inhalers and low-dose glucocorticoids for replacement therapy are allowed.
7. 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, patients with enteric stomata are also excluded.
8. Poorly controlled diabetes mellitus defined as HbA1c >7%; patients with a history of transient glucose intolerance
caused by corticosteroid administration are allowed if all other eligibility criteria are met.
9. Other clinically significant comorbidities, such as uncontrolled pulmonary disease (eg, severe chronic obstructive
pulmonary disease with hypoxemia, interstitial lung disease, radiation induced lung injury), active central nervous
system disease, active infection, or any other condition that could compromise the patient’s safety and
participation in the study per protocol.
10. Known human immunodeficiency virus infection.
11. Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis C virus (HCV)
infection.
Note: Patients who have isolated positive hepatitis B core antibody (HBcAb) and/or hepatitis B surface antibody
(HBsAb) may be enrolled but must have an undetectable hepatitis B virus (HBV) viral load. Patients who have
positive hepatitis C virus antibody (HCVAb) may be enrolled but must have an undetectable HCV viral load.
12. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening
period or a positive urine pregnancy test on Cycle 1 Day 1 before the first dose of the study drug.
(Note: Female patients who are lactating will be excluded, even if they discontinue breastfeeding.)
13. History of any of the following within the last 6 months before the first dose of study drug:
• Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures.
• Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures.
• Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including
atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
• Placement of a pacemaker for control of rhythm.
• New York Heart Association Class III or IV heart failure.
• Pulmonary embolism.
14. Significant active cardiovascular or pulmonary disease before the first dose of study drug, including:
• Uncontrolled hypertension (ie, systolic blood pressure >180 mmHg; diastolic blood pressure >95 mmHg).
• Pulmonary hypertension.
• Uncontrolled asthma or oxygen saturation <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 [eg, repeated demonstration of QTc interval
>480 ms, or history of congenital long QT syndrome, or torsades de pointes]).
15. 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. Patients with nonmelanoma skin cancer or
carcinoma in situ of any type are not excluded if they have undergone complete resection.
16.Requirement of daily or chronic use of proton pump inhibitors (PPIs) and/or the use of a PPI within 7 days before receiving the first dose of TAK-228. Use of PPIs is prohibited during the study.
The Estimated Number of Participants
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Taiwan
3 participants
-
Global
36 participants
