Advanced Nonhematological Neoplasms
Conditions
Keywords
Drug therapy
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.
Detailed description
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.
Interventions
DRUGTAK-228
TAK-228 Capsules.
Sponsors
Calithera Biosciences, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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: 1. Serum creatinine \<1.5\*ULN. 2. Creatinine clearance based on the Cockcroft-Gault estimate \>=40 milliliter per minute (mL/min). 3. Creatinine clearance based on urine collection (12- or 24-hour) \>=40 mL/min. 4. Metabolic: Glycosylated hemoglobin (hemoglobin A1c \[HbA1c\]) \<=7%, fasting serum glucose \<=130 milligram per deciliter (mg/dL), and fasting triglycerides \<=300 mg/dL.
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | — |
| 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) | — |
| 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 | 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 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. |
| 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 | Baseline up to Day 28 in Cycle 1 (Cycle length= 28 days) | 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. |
| 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) | — |
| 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) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) | Baseline Up to 1 Year 7 Months | 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. |
Countries
Japan, South Korea, Taiwan
Participant flow
Recruitment details
Participants took part in the study at 4 investigative sites in Japan, South Korea and Taiwan from 17 January 2018 to 28 August 2019.
Pre-assignment details
Participants with advanced nonhematological malignancies were enrolled in Dose Escalation and Expansion Phase to receive TAK-228 in 1 of the 2 schedules: once daily (QD) or once weekly (QW). Further enrollment in QW schedule was stopped and study was terminated before QW expansion because more favorable safety profile were observed in QD schedule.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg TAK-228 2 milligram (mg), milled capsule, orally, once daily, on an empty stomach in a 28-day treatment cycle until disease progression, unacceptable toxicity, or withdrawal of consent. | 3 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg TAK-228 3 mg, milled capsule, orally, once daily, on an empty stomach in a 28-day treatment cycle until disease progression, unacceptable toxicity, or withdrawal of consent. | 6 |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg TAK-228 4 mg, milled capsule, orally, once daily, on an empty stomach in a 28-day treatment cycle until disease progression, unacceptable toxicity, or withdrawal of consent. | 7 |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg TAK-228 3 mg, milled capsule, orally, once daily, on an empty stomach in each 28-day treatment cycle until disease progression, unacceptable toxicity, or withdrawal of consent. | 6 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg TAK-228 20 mg, milled capsule, orally, once weekly, on an empty stomach in a 28-day treatment cycle until disease progression, unacceptable toxicity, or withdrawal of consent. | 3 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg TAK-228 30 mg milled, capsule, orally, once weekly, on an empty stomach in a 28-day treatment cycle until disease progression, unacceptable toxicity, or withdrawal of consent. | 3 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Dose Escalation Phase | Adverse Event | 1 | 0 | 2 | 0 | 0 | 0 |
| Dose Escalation Phase | Other | 0 | 1 | 1 | 0 | 0 | 0 |
| Dose Escalation Phase | Progressive Disease | 2 | 4 | 2 | 0 | 3 | 1 |
| Dose Escalation Phase | Withdrawal by Subject | 0 | 1 | 2 | 0 | 0 | 2 |
| Dose Expansion Phase | Progressive Disease | 0 | 0 | 0 | 6 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 10.59 | 54.0 years STANDARD_DEVIATION 12.49 | 57.0 years STANDARD_DEVIATION 6.93 | 56.3 years STANDARD_DEVIATION 11.5 | 58.7 years STANDARD_DEVIATION 10.36 | 55.8 years STANDARD_DEVIATION 12.59 | 69.0 years STANDARD_DEVIATION 5.2 |
| Asian Sub-Category Chinese | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants |
| Asian Sub-Category Japanese | 17 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants |
| Asian Sub-Category Korean | 8 Participants | 2 Participants | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 3 Participants | 3 Participants | 6 Participants | 7 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 164.30 centimeter (cm) STANDARD_DEVIATION 8.96 | 160.73 centimeter (cm) STANDARD_DEVIATION 8.923 | 170.47 centimeter (cm) STANDARD_DEVIATION 12.003 | 162.42 centimeter (cm) STANDARD_DEVIATION 10.619 | 162.64 centimeter (cm) STANDARD_DEVIATION 5.839 | 167.05 centimeter (cm) STANDARD_DEVIATION 10.135 | 163.80 centimeter (cm) STANDARD_DEVIATION 10 |
| Region of Enrollment Japan | 17 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants |
| Region of Enrollment Korea, Republic Of | 8 Participants | 2 Participants | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Taiwan, Province Of China | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 12 Participants | 2 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 16 Participants | 1 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 2 Participants |
| Smoking Classification Moderate Smoker (6-20 Cigarettes/ day) | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Smoking Classification Never Smoked | 26 Participants | 3 Participants | 2 Participants | 6 Participants | 6 Participants | 6 Participants | 3 Participants |
| Smoking Classification Unknown | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Weight | 62.84 kilogram (kg) STANDARD_DEVIATION 12.08 | 63.43 kilogram (kg) STANDARD_DEVIATION 10.001 | 61.43 kilogram (kg) STANDARD_DEVIATION 6.3 | 61.87 kilogram (kg) STANDARD_DEVIATION 17.49 | 62.09 kilogram (kg) STANDARD_DEVIATION 11.982 | 64.87 kilogram (kg) STANDARD_DEVIATION 13.958 | 63.33 kilogram (kg) STANDARD_DEVIATION 11.201 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 7 / 7 | 6 / 6 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 2 / 6 | 3 / 7 | 1 / 6 | 2 / 3 | 1 / 3 |
Outcome results
Primary
AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1 | 143.6467 ng*hr/mL | Geometric Coefficient of Variation 51.931 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1 | 204.3414 ng*hr/mL | Geometric Coefficient of Variation 36.134 |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1 | 320.7879 ng*hr/mL | Geometric Coefficient of Variation 44.795 |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1 | 192.1438 ng*hr/mL | Geometric Coefficient of Variation 41.892 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1 | 1636.7944 ng*hr/mL | Geometric Coefficient of Variation 49.906 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1 | 2010.7676 ng*hr/mL | Geometric Coefficient of Variation 53.638 |
Primary
AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1 | 123.6468 ng*hr/mL | Geometric Coefficient of Variation 54.137 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1 | 175.6252 ng*hr/mL | Geometric Coefficient of Variation 45.734 |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1 | 306.5602 ng*hr/mL | Geometric Coefficient of Variation 39.279 |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1 | 173.5642 ng*hr/mL | Geometric Coefficient of Variation 44.339 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1 | 1471.9032 ng*hr/mL | Geometric Coefficient of Variation 45.692 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1 | 1839.6167 ng*hr/mL | Geometric Coefficient of Variation 52.905 |
Primary
AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15
Time frame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15 | 220.1116 ng*hr/mL | Geometric Coefficient of Variation 47.966 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15 | 240.1012 ng*hr/mL | Geometric Coefficient of Variation 38.261 |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15 | 322.9544 ng*hr/mL | Geometric Coefficient of Variation 51.178 |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15 | 276.9650 ng*hr/mL | Geometric Coefficient of Variation 74.314 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15 | 1590.2451 ng*hr/mL | Geometric Coefficient of Variation 38.77 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15 | 2690.2403 ng*hr/mL | Geometric Coefficient of Variation 45.633 |
Primary
Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The pharmacokinetic (PK) analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1 | 23.83 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 9.6 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1 | 41.35 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 29.6 |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1 | 55.25 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 26.2 |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1 | 41.78 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 23.7 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1 | 252.29 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 75.2 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1 | 268.61 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 57.8 |
Primary
Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15
Time frame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15 | 31.07 ng/mL | Geometric Coefficient of Variation 48.6 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15 | 46.85 ng/mL | Geometric Coefficient of Variation 31.6 |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15 | 52.68 ng/mL | Geometric Coefficient of Variation 47.2 |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15 | 45.02 ng/mL | Geometric Coefficient of Variation 44.5 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15 | 182.75 ng/mL | Geometric Coefficient of Variation 70.5 |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15 | 364.58 ng/mL | Geometric Coefficient of Variation 37.1 |
Primary
Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 1
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: PK analysis set: Participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. This outcome measure was planned to be assessed only in Daily Dosing arms. Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 1 | 131.0311 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 43.269 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 1 | 192.2467 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 32.263 |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 1 | 295.5497 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 41.724 |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 1 | 177.9464 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 38.813 |
Primary
Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 15
Time frame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: PK analysis set: Participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. This outcome measure was planned to be assessed only in Daily Dosing arms. Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 15 | 221.0132 ng*hr/mL | Geometric Coefficient of Variation 47.912 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 15 | 250.4458 ng*hr/mL | Geometric Coefficient of Variation 29.806 |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 15 | 341.1219 ng*hr/mL | Geometric Coefficient of Variation 44.219 |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 15 | 278.5369 ng*hr/mL | Geometric Coefficient of Variation 74.527 |
Primary
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.
Time frame: Baseline up to Day 28 in Cycle 1 (Cycle length= 28 days)
Population: The DLT-evaluable set included participants who had received at least 75% of planned doses of TAK-228 in Cycle 1 unless interrupted by treatment-related events and had sufficient follow-up data considered by sponsor and investigator to determine whether DLT occurred.This outcome measure was planned to be assessed only in the dose escalation phase.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 0 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 0 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 3 Participants |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 0 Participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 | 0 Participants |
Primary
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.
Time frame: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
Population: The safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Number of Participants With Grade 3 or Higher TEAEs | 1 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Number of Participants With Grade 3 or Higher TEAEs | 2 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Number of Participants With Grade 3 or Higher TEAEs | 6 Participants |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Number of Participants With Grade 3 or Higher TEAEs | 5 Participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Number of Participants With Grade 3 or Higher TEAEs | 3 Participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Number of Participants With Grade 3 or Higher TEAEs | 1 Participants |
Primary
Number of Participants With Serious TEAEs
Time frame: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
Population: The safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Number of Participants With Serious TEAEs | 0 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Number of Participants With Serious TEAEs | 2 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Number of Participants With Serious TEAEs | 3 Participants |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Number of Participants With Serious TEAEs | 1 Participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Number of Participants With Serious TEAEs | 2 Participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Number of Participants With Serious TEAEs | 1 Participants |
Primary
Number of Participants With TEAEs Leading to Study Drug Discontinuation
Time frame: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
Population: The safety analysis set included all participants who received at least 1 dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Number of Participants With TEAEs Leading to Study Drug Discontinuation | 1 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Number of Participants With TEAEs Leading to Study Drug Discontinuation | 0 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Number of Participants With TEAEs Leading to Study Drug Discontinuation | 2 Participants |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Number of Participants With TEAEs Leading to Study Drug Discontinuation | 0 Participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Number of Participants With TEAEs Leading to Study Drug Discontinuation | 0 Participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Number of Participants With TEAEs Leading to Study Drug Discontinuation | 1 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Time frame: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
Population: The safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 6 Participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 6 Participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1 | 0.870 hours |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1 | 0.990 hours |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1 | 1.000 hours |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1 | 0.500 hours |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1 | 0.470 hours |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1 | 1.970 hours |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15
Time frame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Here overall number of participants analyzed are participants who were available for this outcome measure assessment at given time period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15 | 1.000 hours |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15 | 0.965 hours |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15 | 1.500 hours |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15 | 1.000 hours |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15 | 2.630 hours |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15 | 2.000 hours |
Primary
Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 1
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. This outcome measure was planned to be assessed only in the Weekly Dosing arms.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 1 | 1636.7580 ng*hr/mL | Geometric Coefficient of Variation 49.907 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 1 | 2010.5661 ng*hr/mL | Geometric Coefficient of Variation 53.631 |
Primary
Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 15
Time frame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
Population: The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. This outcome measure was planned to be assessed only in the Weekly Dosing arms.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 15 | 1860.7705 ng*hr/mL | Geometric Coefficient of Variation 42.989 |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 15 | 2958.0487 ng*hr/mL | Geometric Coefficient of Variation 47.602 |
Secondary
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.
Time frame: Baseline Up to 1 Year 7 Months
Population: The safety set includes all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Clinical Benefit Rate (CBR) | 33 Percentage of participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Clinical Benefit Rate (CBR) | 50 Percentage of participants |
| Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Clinical Benefit Rate (CBR) | 57 Percentage of participants |
| Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Clinical Benefit Rate (CBR) | 33 Percentage of participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Clinical Benefit Rate (CBR) | 67 Percentage of participants |
| Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Clinical Benefit Rate (CBR) | 67 Percentage of participants |