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
Sponsor
Millennium Pharmaceuticals, Inc. (Industry)
Overall Status
Terminated
CT.gov ID
NCT03370302
Collaborator
(none)
28
4
2
19.3
7
0.4
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
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.
Study Design
Study Type:
Interventional
Actual Enrollment
:
28 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
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
Actual Study Start Date
:
Jan 17, 2018
Actual Primary Completion Date
:
Aug 28, 2019
Actual Study Completion Date
:
Aug 28, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: TAK-228
TAK-228 Capsules.
|
| Experimental: 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. |
Drug: TAK-228
TAK-228 Capsules.
|
Outcome Measures
Primary Outcome Measures
- 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)]
- 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
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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 (/mm3), platelet count >=125,000/mm3, 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 (<=) 1.5upper limit of normal (ULN), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) <=2.5ULN (<=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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Cancer Center Hospital East | Kashiwa-shi | Chiba-Ken | Japan | 277-8577 |
| 2 | National Cancer Center Hospital | Chuo-ku | Tokyo-To | Japan | 104-0045 |
| 3 | Asan Medical Center | Seoul | Korea, Republic of | 05505 | |
| 4 | National Taiwan-University Hospital | Taipei | Taiwan | 100 |
Sponsors and Collaborators
- Millennium Pharmaceuticals, Inc.
Investigators
- Study Director: Medical Director, Millennium Pharmaceuticals, Inc.
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT03370302
Other Study ID Numbers:
- C31008
- U1111-1202-4296
- 1066064639
- 20170270241
- JapicCTI-183822
First Posted:
Dec 12, 2017
Last Update Posted:
May 11, 2021
Last Verified:
Apr 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Millennium Pharmaceuticals, Inc.
Additional relevant MeSH terms:
Study Results
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 Detail | 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. |
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Period Title: Dose Escalation Phase | ||||||
| STARTED | 3 | 6 | 7 | 0 | 3 | 3 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 3 | 6 | 7 | 0 | 3 | 3 |
| Period Title: Dose Escalation Phase | ||||||
| STARTED | 0 | 0 | 0 | 6 | 0 | 0 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 6 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | Total |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | Total of all reporting groups |
| Overall Participants | 3 | 6 | 7 | 6 | 3 | 3 | 28 |
| Age (years) [Mean (Standard Deviation) ] | |||||||
| Mean (Standard Deviation) [years] |
69.0
(5.20)
|
55.8
(12.59)
|
58.7
(10.36)
|
56.3
(11.5)
|
57.0
(6.93)
|
54.0
(12.49)
|
58
(10.59)
|
| Sex: Female, Male (Count of Participants) | |||||||
| Female |
1
33.3%
|
2
33.3%
|
3
42.9%
|
3
50%
|
1
33.3%
|
2
66.7%
|
12
42.9%
|
| Male |
2
66.7%
|
4
66.7%
|
4
57.1%
|
3
50%
|
2
66.7%
|
1
33.3%
|
16
57.1%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||||||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
3
100%
|
6
100%
|
7
100%
|
6
100%
|
3
100%
|
3
100%
|
28
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (Count of Participants) | |||||||
| Japan |
3
100%
|
4
66.7%
|
3
42.9%
|
3
50%
|
3
100%
|
1
33.3%
|
17
60.7%
|
| Taiwan, Province Of China |
0
0%
|
1
16.7%
|
1
14.3%
|
1
16.7%
|
0
0%
|
0
0%
|
3
10.7%
|
| Korea, Republic Of |
0
0%
|
1
16.7%
|
3
42.9%
|
2
33.3%
|
0
0%
|
2
66.7%
|
8
28.6%
|
| Height (centimeter (cm)) [Mean (Standard Deviation) ] | |||||||
| Mean (Standard Deviation) [centimeter (cm)] |
163.80
(10.000)
|
167.05
(10.135)
|
162.64
(5.839)
|
162.42
(10.619)
|
170.47
(12.003)
|
160.73
(8.923)
|
164.30
(8.96)
|
| Weight (kilogram (kg)) [Mean (Standard Deviation) ] | |||||||
| Mean (Standard Deviation) [kilogram (kg)] |
63.33
(11.201)
|
64.87
(13.958)
|
62.09
(11.982)
|
61.87
(17.490)
|
61.43
(6.300)
|
63.43
(10.001)
|
62.84
(12.08)
|
| Smoking Classification (Count of Participants) | |||||||
| Never Smoked |
3
100%
|
6
100%
|
6
85.7%
|
6
100%
|
2
66.7%
|
3
100%
|
26
92.9%
|
| Moderate Smoker (6-20 Cigarettes/ day) |
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
0
0%
|
0
0%
|
1
3.6%
|
| Unknown |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
0
0%
|
1
3.6%
|
| Asian Sub-Category (Count of Participants) | |||||||
| Japanese |
3
100%
|
4
66.7%
|
3
42.9%
|
3
50%
|
3
100%
|
1
33.3%
|
17
60.7%
|
| Korean |
0
0%
|
1
16.7%
|
3
42.9%
|
2
33.3%
|
0
0%
|
2
66.7%
|
8
28.6%
|
| Chinese |
0
0%
|
1
16.7%
|
1
14.3%
|
1
16.7%
|
0
0%
|
0
0%
|
3
10.7%
|
Outcome Measures
| Title | Number of Participants With Treatment Emergent Adverse Events (TEAEs) |
|---|---|
| Description | |
| Time Frame | Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety analysis set included all participants who received at least 1 dose of study drug. |
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 7 | 6 | 3 | 3 |
| Count of Participants [Participants] |
3
100%
|
6
100%
|
7
100%
|
6
100%
|
3
100%
|
3
100%
|
| Title | Number of Participants With Grade 3 or Higher TEAEs |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety analysis set included all participants who received at least 1 dose of study drug. |
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 7 | 6 | 3 | 3 |
| Count of Participants [Participants] |
1
33.3%
|
2
33.3%
|
6
85.7%
|
5
83.3%
|
3
100%
|
1
33.3%
|
| Title | Number of Participants With Serious TEAEs |
|---|---|
| Description | |
| Time Frame | Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety analysis set included all participants who received at least 1 dose of study drug. |
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 7 | 6 | 3 | 3 |
| Count of Participants [Participants] |
0
0%
|
2
33.3%
|
3
42.9%
|
1
16.7%
|
2
66.7%
|
1
33.3%
|
| Title | Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1 |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 6 | 3 | 3 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
3
42.9%
|
0
0%
|
0
0%
|
| Title | Number of Participants With TEAEs Leading to Study Drug Discontinuation |
|---|---|
| Description | |
| Time Frame | Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety analysis set included all participants who received at least 1 dose of the study drug. |
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 7 | 6 | 3 | 3 |
| Count of Participants [Participants] |
1
33.3%
|
0
0%
|
2
28.6%
|
0
0%
|
0
0%
|
1
33.3%
|
| Title | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacokinetic (PK) analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. |
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 7 | 6 | 3 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)] |
23.83
(9.6)
|
41.35
(29.6)
|
55.25
(26.2)
|
41.78
(23.7)
|
252.29
(75.2)
|
268.61
(57.8)
|
| Title | Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 4 | 6 | 3 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
31.07
(48.6)
|
46.85
(31.6)
|
52.68
(47.2)
|
45.02
(44.5)
|
182.75
(70.5)
|
364.58
(37.1)
|
| Title | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. |
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 7 | 6 | 3 | 3 |
| Median (Full Range) [hours] |
0.870
|
0.990
|
1.000
|
0.500
|
0.470
|
1.970
|
| Title | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 4 | 6 | 3 | 3 |
| Median (Full Range) [hours] |
1.000
|
0.965
|
1.500
|
1.000
|
2.630
|
2.000
|
| Title | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 6 | 6 |
| Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter (ng*hr/mL)] |
131.0311
(43.269)
|
192.2467
(32.263)
|
295.5497
(41.724)
|
177.9464
(38.813)
|
| Title | Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 15 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 4 | 6 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL] |
221.0132
(47.912)
|
250.4458
(29.806)
|
341.1219
(44.219)
|
278.5369
(74.527)
|
| Title | Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 3 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL] |
1636.7580
(49.907)
|
2010.5661
(53.631)
|
| Title | Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 15 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 3 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL] |
1860.7705
(42.989)
|
2958.0487
(47.602)
|
| Title | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. |
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 7 | 6 | 3 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL] |
123.6468
(54.137)
|
175.6252
(45.734)
|
306.5602
(39.279)
|
173.5642
(44.339)
|
1471.9032
(45.692)
|
1839.6167
(52.905)
|
| Title | AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 4 | 6 | 3 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL] |
220.1116
(47.966)
|
240.1012
(38.261)
|
322.9544
(51.178)
|
276.9650
(74.314)
|
1590.2451
(38.770)
|
2690.2403
(45.633)
|
| Title | AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 6 | 6 | 3 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL] |
143.6467
(51.931)
|
204.3414
(36.134)
|
320.7879
(44.795)
|
192.1438
(41.892)
|
1636.7944
(49.906)
|
2010.7676
(53.638)
|
| Title | Clinical Benefit Rate (CBR) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety set includes all participants who received at least 1 dose of study drug. |
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 6 | 7 | 6 | 3 | 3 |
| Number [Percentage of participants] |
33
1100%
|
50
833.3%
|
57
814.3%
|
33
550%
|
67
2233.3%
|
67
2233.3%
|
Adverse Events
| Time Frame | TEAEs are AEs that started after the first dose of study drug and no more than 30 days after the last dose of study drug (up to Cycle 12 Day 58) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. | |||||||||||
| Arm/Group Title | Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | ||||||
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | ||||||
All Cause Mortality |
||||||||||||
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
Serious Adverse Events |
||||||||||||
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 2/6 (33.3%) | 3/7 (42.9%) | 1/6 (16.7%) | 2/3 (66.7%) | 1/3 (33.3%) | ||||||
| Cardiac disorders | ||||||||||||
| Acute myocardial infarction | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Enteritis | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Hepatobiliary disorders | ||||||||||||
| Jaundice cholestatic | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Cholangitis acute | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Infections and infestations | ||||||||||||
| Genital Herpes | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Sepsis | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
| Malignant neoplasm progression | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Metastases to central nervous system | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Nervous system disorders | ||||||||||||
| Cerebrovascular accident | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Renal and urinary disorders | ||||||||||||
| Renal impairment | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
Other (Not Including Serious) Adverse Events |
||||||||||||
| Dose Escalation, Daily Dosing Arm: TAK-228 2 mg | Dose Escalation, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Daily Dosing Arm: TAK-228 4 mg | Dose Expansion, Daily Dosing Arm: TAK-228 3 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg | Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/3 (100%) | 6/6 (100%) | 7/7 (100%) | 6/6 (100%) | 3/3 (100%) | 3/3 (100%) | ||||||
| Blood and lymphatic system disorders | ||||||||||||
| Anaemia | 0/3 (0%) | 1/6 (16.7%) | 3/7 (42.9%) | 1/6 (16.7%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Neutropenia | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Cardiac disorders | ||||||||||||
| Palpitations | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Ear and labyrinth disorders | ||||||||||||
| Vertigo | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Eye disorders | ||||||||||||
| Retinal haemorrhage | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Vision blurred | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Stomatitis | 0/3 (0%) | 5/6 (83.3%) | 4/7 (57.1%) | 5/6 (83.3%) | 1/3 (33.3%) | 1/3 (33.3%) | ||||||
| Vomiting | 0/3 (0%) | 2/6 (33.3%) | 3/7 (42.9%) | 2/6 (33.3%) | 0/3 (0%) | 3/3 (100%) | ||||||
| Constipation | 1/3 (33.3%) | 1/6 (16.7%) | 2/7 (28.6%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Diarrhoea | 1/3 (33.3%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Gastrointestinal inflammation | 0/3 (0%) | 0/6 (0%) | 2/7 (28.6%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Abdominal distension | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Dyspepsia | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Gastritis | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Gastrooesophageal reflux disease | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Gingival pain | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Haematochezia | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Nausea | 3/3 (100%) | 2/6 (33.3%) | 4/7 (57.1%) | 2/6 (33.3%) | 3/3 (100%) | 3/3 (100%) | ||||||
| Angular cheilitis | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Epigastric discomfort | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Abdominal pain | 0/3 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 1/6 (16.7%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| General disorders | ||||||||||||
| Fatigue | 1/3 (33.3%) | 1/6 (16.7%) | 3/7 (42.9%) | 2/6 (33.3%) | 1/3 (33.3%) | 1/3 (33.3%) | ||||||
| Pyrexia | 1/3 (33.3%) | 1/6 (16.7%) | 0/7 (0%) | 2/6 (33.3%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Malaise | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Oedema peripheral | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Hepatobiliary disorders | ||||||||||||
| Cholangitis | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Infections and infestations | ||||||||||||
| Rash pustular | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Cystitis bacterial | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Gingivitis | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Large intestine infection | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Nasopharyngitis | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Paronychia | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Pneumonia | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Skin infection | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Tooth infection | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Urinary tract infection | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Hordeolum | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Periodontitis | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Investigations | ||||||||||||
| Weight decreased | 1/3 (33.3%) | 3/6 (50%) | 3/7 (42.9%) | 0/6 (0%) | 2/3 (66.7%) | 1/3 (33.3%) | ||||||
| Aspartate aminotransferase increased | 1/3 (33.3%) | 2/6 (33.3%) | 1/7 (14.3%) | 2/6 (33.3%) | 2/3 (66.7%) | 1/3 (33.3%) | ||||||
| Platelet count decreased | 0/3 (0%) | 1/6 (16.7%) | 2/7 (28.6%) | 3/6 (50%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Alanine aminotransferase increased | 0/3 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 2/6 (33.3%) | 2/3 (66.7%) | 1/3 (33.3%) | ||||||
| Lymphocyte count decreased | 0/3 (0%) | 2/6 (33.3%) | 0/7 (0%) | 2/6 (33.3%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| White blood cell count decreased | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 3/6 (50%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Gamma-glutamyltransferase increases | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 2/6 (33.3%) | 1/3 (33.3%) | 1/3 (33.3%) | ||||||
| Neutrophil count decreased | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 2/6 (33.3%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Blood cholesterol increased | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Blood creatinine phosphokinase increased | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Blood creatinine increased | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Weight increased | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Blood alkaline phosphatase increased | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 3/3 (100%) | 1/3 (33.3%) | ||||||
| Blood bilirubin increased | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | ||||||
| Haemoglobin increased | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Metabolism and nutrition disorders | ||||||||||||
| Decreased appetite | 2/3 (66.7%) | 1/6 (16.7%) | 4/7 (57.1%) | 4/6 (66.7%) | 2/3 (66.7%) | 1/3 (33.3%) | ||||||
| Hyperglycaemia | 0/3 (0%) | 2/6 (33.3%) | 4/7 (57.1%) | 3/6 (50%) | 3/3 (100%) | 1/3 (33.3%) | ||||||
| Hypokalaemia | 0/3 (0%) | 2/6 (33.3%) | 1/7 (14.3%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Dehydration | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Gout | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Hypertriglyceridaemia | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Hypoalbuminaemia | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Flank pain | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Myalgia | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Back pain | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
| Cancer pain | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Tumour pain | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Nervous system disorders | ||||||||||||
| Headache | 1/3 (33.3%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Cognitive disorder | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Post herpetic neuralgia | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Tremor | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Dizziness | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Psychiatric disorders | ||||||||||||
| Insomnia | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Renal and urinary disorders | ||||||||||||
| Renal impairment | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Proteinuria | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Reproductive system and breast disorders | ||||||||||||
| Vaginal haemorrhage | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Genital haemorrhage | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Productive cough | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Rhinitis allergic | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Hiccups | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | ||||||
| Laryngeal discomfort | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Skin and subcutaneous tissue disorders | ||||||||||||
| Rash maculo-papular | 1/3 (33.3%) | 0/6 (0%) | 2/7 (28.6%) | 2/6 (33.3%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Urticaria | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 2/6 (33.3%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Erythema | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 1/3 (33.3%) | ||||||
| Erythema multiforme | 0/3 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Pruritus | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Rash erythmatous | 0/3 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Dry skin | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Rash | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Seborrhoeic dermatitis | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 0/3 (0%) | 0/3 (0%) | ||||||
| Rash pruritic | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
| Eczema asteatotic | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/3 (33.3%) | 0/3 (0%) | ||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.
Results Point of Contact
| Name/Title | Medical Director |
|---|---|
| Organization | Takeda |
| Phone | +1-877-825-3327 |
| trialdisclosures@takeda.com |
Responsible Party:
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT03370302
Other Study ID Numbers:
- C31008
- U1111-1202-4296
- 1066064639
- 20170270241
- JapicCTI-183822
First Posted:
Dec 12, 2017
Last Update Posted:
May 11, 2021
Last Verified:
Apr 1, 2021