Clinical trial NCT03370302: 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
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Nonhematological Neoplasms
Keywords: Drug therapy
Lead sponsor: Calithera Biosciences, Inc
Sponsor class: INDUSTRY
First posted: 2017-12-12
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The purpose of this study is to evaluate the safety and tolerability, recommended phase 2 dose (RP2D), and to characterize PK of TAK-228 administered once daily or once weekly to East Asian participants with advanced nonhematological malignancies.

Detailed description: The drug being tested in this study is called TAK-228. TAK-228 is being tested to treat East Asian participants with advanced nonhematological malignancies for whom standard anticancer treatment is not available or is no longer effective. This study will assess the safety, tolerability, PK and will determine the RP2Ds of TAK-228.

The study will enroll approximately 46 participants, including at least 6 Japanese participants at RP2D dose level. Participants will be assigned to one of the following treatment arms:

* TAK-228 Once Daily
* TAK-228 Once Weekly

This multi-center trial will be conducted in South Korea, Taiwan, and Japan. The overall time to participate in this study is up to 12 months, unless in the opinion of the investigator and sponsor the participant would derive benefit from continued therapy beyond 12 months. Participants will be followed for 30 days after last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

1. With advanced nonhematologic malignancies, with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy. History of brain metastasis may be allowed if all of the following criteria are met:

   * Brain metastases have been treated.
   * There is no evidence of progression or hemorrhage after treatment.
   * Steroid has been discontinued for \>=4 weeks before the first dose of study drug.
   * There is no ongoing requirement for steroids or anti-epileptic drugs.
2. Received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or metastatic disease.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
4. Screening clinical laboratory values as specified below:

   * Bone marrow reserve consistent with absolute neutrophil count (ANC) \>=2000 per cubic millimeter (/mm\^3), platelet count \>=125,000/mm\^3, and hemoglobin \>=10 gram per deciliter (g/dL) without transfusion in the last 4 weeks.

Note: Prophylactic transfusions of blood products or any prophylactic use of hematopoietic growth factors (such as erythropoietin, thrombopoietin, granulocyte colony stimulating factor \[G-CSF\], and granulocyte macrophage colony stimulating factor \[GM-CSF\]) is not permitted during the screening period.

* Hepatic: Total bilirubin less than or equal to (\<=) 1.5\*upper limit of normal (ULN), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \<=2.5\*ULN (\<=5\*ULN if their elevation can be reasonably ascribed to the presence of hepatocellular carcinoma, biliary tract cancer, or metastatic disease in liver).
* Adequate renal function, defined as meeting any 1 of the following criteria:

  1. Serum creatinine \<1.5\*ULN.
  2. Creatinine clearance based on the Cockcroft-Gault estimate \>=40 milliliter per minute (mL/min).
  3. Creatinine clearance based on urine collection (12- or 24-hour) \>=40 mL/min.
  4. Metabolic: Glycosylated hemoglobin (hemoglobin A1c \[HbA1c\]) \<=7%, fasting serum glucose \<=130 milligram per deciliter (mg/dL), and fasting triglycerides \<=300 mg/dL.

Exclusion Criteria:

1. Diagnosis of primary brain tumor.
2. Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression.
3. Failed to recover from the reversible effects of prior anticancer therapies with the exception of alopecia, and after-effects associated with prior tyrosine kinase inhibitor therapy, such as hair depigmentation, hypothyroidism, and/or splinter hemorrhage.
4. Initiation of hematopoietic growth factors within 1 week before the first dose of study drug.
5. Manifestations of malabsorption caused by prior gastrointestinal surgery, gastrointestinal disease, or for some other reason that may alter the absorption of TAK-228. In addition, participants with enteric stomata are also excluded.
6. Poorly controlled diabetes mellitus defined as Hemoglobin A1c (HbA1c) greater than (\>) 7%; participants with a history of transient glucose intolerance caused by corticosteroid administration are allowed if all other eligibility criteria are met.
7. Known human immunodeficiency virus infection.
8. Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis C virus (HCV) infection. Note: Participants who have isolated positive hepatitis B core antibody (HBcAb) and/or hepatitis B surface antibody (HBsAb) (that is, in the setting of negative HBsAg) may be enrolled but must have an undetectable hepatitis B virus (HBV) viral load. Participants who have positive hepatitis C virus antibody (HCVAb) may be enrolled but must have an undetectable HCV viral load.
9. Significant active cardiovascular or pulmonary disease before the first dose of study drug, including:

   * Uncontrolled hypertension (that is, systolic blood pressure \>180 millimeter of mercury \[mmHg\]; diastolic blood pressure \>95 mmHg).
   * Pulmonary hypertension.
   * Uncontrolled asthma or oxygen saturation less than (\<) 90% by pulse oximetry on room air.
   * Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention; or history of valve replacement.
   * Medically significant (symptomatic) bradycardia.
   * History of arrhythmia requiring an implantable cardiac defibrillator.
   * Baseline prolongation of the rate corrected QT interval (QTc) (example, repeated demonstration of QTc interval \>480 millisecond \[ms\], or history of congenital long QT syndrome, or torsades de pointes).
10. Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
measure: Number of Participants With Grade 3 or Higher TEAEs
timeFrame: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
measure: Number of Participants With Serious TEAEs
timeFrame: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
measure: Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) During Cycle 1
timeFrame: Baseline up to Day 28 in Cycle 1 (Cycle length= 28 days)
measure: Number of Participants With TEAEs Leading to Study Drug Discontinuation
timeFrame: Baseline up to 30 days after the last dose of study drug (up to Cycle 12 Day 58) (Cycle length= 28 days)
measure: Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
measure: Cmax: Maximum Observed Plasma Concentration for TAK-228 on Cycle 1 Day 15
timeFrame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-228 on Cycle 1 Day 15
timeFrame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
measure: Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
measure: Daily Dosing Arms, AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours for TAK-228 on Cycle 1 Day 15
timeFrame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
measure: Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
measure: Weekly Dosing Arms, AUC168: Area Under the Concentration-time Curve From 0 to 168 Hours for TAK-228 on Cycle 1 Day 15
timeFrame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
measure: AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
measure: AUClast: Area Under the Plasma Concentration-time Curve From 0 to Time of Last Measurable Concentration for TAK-228 on Cycle 1 Day 15
timeFrame: Cycle 1 Day 15 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
measure: AUC∞: Area Under the Plasma Concentration-time Curve From 0 to Infinity for TAK-228 on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
Secondary outcomes:
measure: Clinical Benefit Rate (CBR)
timeFrame: Baseline Up to 1 Year 7 Months
Other outcomes:
Locations:
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
state: Chiba-Ken
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo-To
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Taipei
country: Taiwan
facility: National Taiwan-University Hospital
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.