Advanced Nonhematological NeoplasmsPhase 1NCT03370302

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

A Phase 1 study testing TAK-228 in people with Advanced Nonhematological Neoplasms, run by Calithera Biosciences, Inc at 4 sites in 3 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Advanced Nonhematological Neoplasms
What is being tested?: TAK-228
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 28 participants
Where: 4 sitesin 3 countries
Study dates: 17 Jan 2018to 28 Aug 2019
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

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Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
Screening clinical laboratory values as specified below:
Bone marrow reserve consistent with absolute neutrophil count (ANC) >=2000 per cubic millimeter (/mm^3), platelet count >=125,000/mm^3, and hemoglobin >=10 gram per deciliter (g/dL) without transfusion in the last 4 weeks.
Note: Prophylactic transfusions of blood products or any prophylactic use of hematopoietic growth factors (such as erythropoietin, thrombopoietin, granulocyte colony stimulating factor [G-CSF], and granulocyte macrophage colony stimulating factor [GM-CSF]) is not permitted during the screening period.
Hepatic: Total bilirubin less than or equal to (<=) 1.5*upper limit of normal (ULN), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) <=2.5*ULN (<=5*ULN if their elevation can be reasonably ascribed to the presence of hepatocellular carcinoma, biliary tract cancer, or metastatic disease in liver).
Adequate renal function, defined as meeting any 1 of the following criteria:
Serum creatinine <1.5*ULN.
Creatinine clearance based on the Cockcroft-Gault estimate >=40 milliliter per minute (mL/min).
Creatinine clearance based on urine collection (12- or 24-hour) >=40 mL/min.
Metabolic: Glycosylated hemoglobin (hemoglobin A1c [HbA1c]) <=7%, fasting serum glucose <=130 milligram per deciliter (mg/dL), and fasting triglycerides <=300 mg/dL.

Who cannot join

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.

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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.

Trial locations and contacts

4 sites in 3 countries.

Country

City, postcode or hospital

4 sites in 3 countries

Japan2 sites

National Cancer Center Hospital
Chūōku, Tokyo-To, 104-0045
National Cancer Center Hospital East
Kashiwa-shi, Chiba, 277-8577

Other trials in Japan

South Korea1 site

Asan Medical Center
Seoul, 05505

Other trials in South Korea

Taiwan1 site

National Taiwan-University Hospital
Taipei, 100

Other trials in Taiwan

About this study

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

Read the 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.

Conditions: Advanced Nonhematological Neoplasms
Being tested: TAK-228
Keywords: Drug therapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

TAK-228Drug
TAK-228 Capsules.

Study groups in NCT03370302
Study group	Role	What they receive
TAK-228 Once Daily	Experimental	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. Receives: Drug: TAK-228
TAK-228 Once Weekly	Experimental	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. Receives: Drug: TAK-228

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Measured: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
Number of Participants With Grade 3 or Higher TEAEs
Adverse event (AE) Grades were evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), version 4.03. Grade 1 scaled as Mild; Grade 2 scaled as Moderate; Grade 3 scaled as severe or medically significant but not immediately life-threatening; Grade 4 scaled as life-threatening consequences; and Grade 5 scaled as death related to AE.
Measured: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
Number of Participants With Serious TEAEs
Measured: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1
Toxicity was evaluated according to NCI CTCAE version 4.03. DLT was defined as any of the following occurred events within the first 28 days of the administration of TAK-228 that were considered by investigator to be possibly related to therapy: Grade >=3 nonhematologic toxicity except for inadequately treated Grade 3 nausea and/or vomiting and diarrhea, Grade 3 hyperglycemia lasting <=14 days, Grade 3 rash lasting <=3 days; Grade 3 thrombocytopenia with hemorrhage or requiring platelet transfusion; Grade 3 anemia requiring blood transfusion; Grade 4 neutropenia lasting >7 days; Grade >=3 neutropenia of any duration with fever >=38.5 degree celsius and/or systemic infection; Any other >=Grade 4 hematologic toxicity; Inability to administer at least 75 percent (%) of planned doses of TAK-228 within Cycle 1 due to treatment-related toxicity and any clinically significant occurrence that the investigators and sponsor agreed would place participants at an undue safety risk.
Measured: Baseline up to Day 28 in Cycle 1 (Cycle length= 28 days)
Number of Participants With TEAEs Leading to Study Drug Discontinuation
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

Secondary outcomes (1)

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.
Measured: Baseline Up to 1 Year 7 Months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

17 Jan 201828 Aug 2019

First posted12 Dec 2017
Study start17 Jan 2018
Primary completion28 Aug 2019
Study completion28 Aug 2019

Why it stopped: More favorable safety profile was observed in QD schedule, therefore further enrollment in QW schedule was terminated.

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Advanced Nonhematological NeoplasmsStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Other
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 28 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03370302
Sponsor's protocol ID: C31008
Other IDs: U1111-1202-4296, 1066064639, 20170270241, JapicCTI-183822
Status last verified: Feb 2023
First submitted: 7 Dec 2017
Last updated: 8 Feb 2023
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Yes: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Publications

Shimizu T, Kuboki Y, Lin CC, Yonemori K, Yanai T, Faller DV, Dobler L, Gupta N, Sedarati F, Kim KP. A Phase 1 Study of Sapanisertib (TAK-228) in East Asian Patients with Advanced Nonhematological Malignancies. Target Oncol. 2022 Jan;17(1):15-24. doi: 10.1007/s11523-021-00855-w. Epub 2021 Nov 29.
PubMed 34843044

Study at a glance

From the registry record, last updated by the sponsor on 8 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT03370302
Acronym / sponsor ID: C31008
Conditions: Advanced Nonhematological Neoplasms
Keywords: Drug therapy
Phase: Phase 1
Study type: Interventional
Recruitment status: TerminatedReason stopped: More favorable safety profile was observed in QD schedule, therefore further enrollment in QW schedule was terminated.
Enrolment: 28 participants (actual)
Lead sponsor: Calithera Biosciences, IncIndustry (pharma, biotech, devices)
Study start: 17 Jan 2018 (actual)
Primary completion: 28 Aug 2019 (actual)
Study completion: 28 Aug 2019 (actual)
First posted: 12 Dec 2017 (actual)
Results: Posted 9 Sep 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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

Study design

Primary purpose: Other
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
TAK-228 Once Daily	Experimental	Drug: TAK-228TAK-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.
TAK-228 Once Weekly	Experimental	Drug: TAK-228TAK-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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (16 listed)

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:
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:
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.

Key exclusion criteria (17 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TAK-228TAK-228 Capsules.	Drug	TAK-228 Once Daily, TAK-228 Once Weekly

Primary outcome

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)
Number of Participants With Grade 3 or Higher 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)
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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)

1 secondary outcome

Clinical Benefit Rate (CBR)
Time frame: Baseline Up to 1 Year 7 Months

Results and safety

Results posted to the registry on 9 Sep 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Dose Escalation, Daily Dosing Arm: TAK-228 2 mg	3	0
Dose Escalation, Daily Dosing Arm: TAK-228 3 mg	6	0
Dose Escalation, Daily Dosing Arm: TAK-228 4 mg	7	0
Dose Expansion, Daily Dosing Arm: TAK-228 3 mg	0	0
Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg	3	0
Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg	3	0

Primary outcome: 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). Count of participants. Unit: Participants

Measure	Dose Escalation, Daily Dosing Arm: TAK-228 2 mg n = 3	Dose Escalation, Daily Dosing Arm: TAK-228 3 mg n = 6	Dose Escalation, Daily Dosing Arm: TAK-228 4 mg n = 7	Dose Expansion, Daily Dosing Arm: TAK-228 3 mg n = 6	Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg n = 3	Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg n = 3
Value	3	6	7	6	3	3

Population analysed: The safety analysis set included all participants who received at least 1 dose of study drug.

Primary outcome: Number of Participants With Grade 3 or Higher 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). Count of participants. Unit: Participants

Measure	Dose Escalation, Daily Dosing Arm: TAK-228 2 mg n = 3	Dose Escalation, Daily Dosing Arm: TAK-228 3 mg n = 6	Dose Escalation, Daily Dosing Arm: TAK-228 4 mg n = 7	Dose Expansion, Daily Dosing Arm: TAK-228 3 mg n = 6	Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg n = 3	Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg n = 3
Value	1	2	6	5	3	1

Population analysed: The safety analysis set included all participants who received at least 1 dose of study drug.

Primary outcome: 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). Count of participants. Unit: Participants

Measure	Dose Escalation, Daily Dosing Arm: TAK-228 2 mg n = 3	Dose Escalation, Daily Dosing Arm: TAK-228 3 mg n = 6	Dose Escalation, Daily Dosing Arm: TAK-228 4 mg n = 7	Dose Expansion, Daily Dosing Arm: TAK-228 3 mg n = 6	Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg n = 3	Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg n = 3
Value	0	2	3	1	2	1

Population analysed: The safety analysis set included all participants who received at least 1 dose of study drug.

Primary outcome: Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1

Time frame: Baseline up to Day 28 in Cycle 1 (Cycle length= 28 days). Count of participants. Unit: Participants

Measure	Dose Escalation, Daily Dosing Arm: TAK-228 2 mg n = 3	Dose Escalation, Daily Dosing Arm: TAK-228 3 mg n = 6	Dose Escalation, Daily Dosing Arm: TAK-228 4 mg n = 6	Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg n = 3	Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg n = 3
Value	0	0	3	0	0

Population analysed: 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.

1 secondary outcome is reported in the full results.

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). Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Dose Escalation, Daily Dosing Arm: TAK-228 2 mg	0 of 3 (0%)	3 of 3 (100%)	0 of 3
Dose Escalation, Daily Dosing Arm: TAK-228 3 mg	2 of 6 (33.3%)	6 of 6 (100%)	0 of 6
Dose Escalation, Daily Dosing Arm: TAK-228 4 mg	3 of 7 (42.9%)	7 of 7 (100%)	0 of 7
Dose Expansion, Daily Dosing Arm: TAK-228 3 mg	1 of 6 (16.7%)	6 of 6 (100%)	0 of 6
Dose Escalation, Weekly Dosing Arm: TAK-228 20 mg	2 of 3 (66.7%)	3 of 3 (100%)	0 of 3
Dose Escalation, Weekly Dosing Arm: TAK-228 30 mg	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 8 Feb 2023.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 34843044Shimizu T, Kuboki Y, Lin CC, Yonemori K, Yanai T, Faller DV, Dobler L, Gupta N, Sedarati F, Kim KP. A Phase 1 Study of Sapanisertib (TAK-228) in East Asian Patients with Advanced Nonhematological Malignancies. Target Oncol. 2022 Jan;17(1):15-24. doi: 10.1007/s11523-021-00855-w. Epub 2021 Nov 29.
Individual participant dataSharing planned: Yes. Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Director study director

Millennium Pharmaceuticals, Inc.

4 sites in 3 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing TAK-228 in people with Advanced Nonhematological Neoplasms, run by Calithera Biosciences, Inc at 4 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 8 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Japan, South Korea, Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). The study lists 16 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03370302, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Feb 2023.