Safety, Tolerability, and Efficacy of TAK-659 in Adults With Relapsed or Refractory Acute Myelogenous Leukemia (AML)

Study Overview
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Brief Summary
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The purpose of the Phase 1b dose finding phase is to determine the safety, tolerability, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659 in participants with relapsed or refractory AML. The purpose of the Phase 2 expansion phase is to evaluate preliminary efficacy of TAK-659 in relapsed or refractory AML as measured by overall response rate (ORR).

Detailed Description
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The drug being tested in this study is TAK-659. TAK-659 is being tested to treat people who have relapsed or refractory acute myelogenous leukemia (AML). This study will be conducted in 2 phases. The first phase will determine a safe and well-tolerated dose of TAK-659 to be used in the second phase, and the second phase will look at response to treatment in people who take TAK-659. The study will enroll approximately 106 participants (approximately 40 in the first phase and 66 in the second phase). There will be two separate cohorts during Phase 2 portion of the study, one for participants with FLT-3 internal tandem duplication (ITD) mutations and the other for FLT-3 wild-type participants. Phase 1b: • TAK-659 60 milligram (mg) tablet starting dose escalated in 20 mg or higher increments to a maximum tolerated dose or RP2D Phase 2: • TAK-659 tablet at the maximum tolerated dose or RP2D determined in Phase 1b. All participants will be asked to take their prescribed tablets at the same time each day throughout the study. This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to 24 months (12 months of treatment and 12 months of follow up) unless the treating physician believes the participant would continue to derive benefit from the study drug.

Official Title
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An Open-Label, Phase 1b/2 Study Investigating Recommended Phase 2 Dose, Safety, Tolerability, and Preliminary Efficacy of TAK-659 in Adult Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)

Conditions
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Acute Myelogenous Leukemia

Intervention / Treatment
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* Drug: TAK-659


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants 18 years or older. Must have a histopathologically documented diagnosis of primary or secondary AML (excluding acute promyelocytic leukemia), as defined by World Health Organization (WHO) criteria (Jaffe et al, 2001), for whom no standard therapies are anticipated to result in a durable remission according to the clinical judgment of the principal investigator, or who refuses standard therapies (phase 1b and 2). Participants for the phase 2 portion of the study must, in addition, meet the following: o Must be refractory to or relapsed after no more than 2 prior chemotherapy regimens. Re-induction with the same regimen or stem cell transplant will not be considered a separate regimen. Eastern Cooperative Oncology Group performance status of 0 to 1. Female participants who: Are postmenopausal for at least 1 year before the screening visit, or Are surgically sterile, or If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 180 days after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together). Male participants, even if surgically sterilized (that is, status postvasectomy), who: Agree to practice effective barrier contraception during the entire study treatment period and through 180 days after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together). Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care. In the absence of rapid progressive disease, the interval from prior systemic anticancer treatment to time of TAK-659 administration should be at least 2 weeks for cytotoxic agents (other than hydroxyurea), or at least 5 half-lives for noncytotoxic agents, and participants have to have recovered from acute toxicities of these therapies. Participants who are on hydroxyurea may be included in the study and may continue on hydroxyurea for the first 28 days while participating in this study. Suitable venous access for the study-required blood sampling, including pharmacokinteic (PK) and pharmacodynamic (PD) sampling and blood transfusion support. Clinical laboratory values as specified in the following: Total bilirubin must be less than or equal to (<=) 1.5* the upper limit of normal (ULN). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be less than or equal to (<=) 2.5*the ULN. Lipase <=1.5*ULN and amylase <=1.5*ULN with no clinical symptoms suggestive of pancreatitis or cholecystitis. Creatinine clearance greater than or equal to (>=) 60 milliliter per minute (mL/min) either as estimated by the Cockcroft-Gault equation or based on urine collection (12 or 24 hours). Exclusion Criteria: Clinically active central nervous system leukemia. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug. Any serious medical or psychiatric illness, including drug or alcohol abuse that could, in the investigator's opinion, potentially jeopardize the safety of the participant or interfere with the objectives of the study. Systemic anti-cancer treatment (including investigational agents) <=21 days or <= 5*their half-lives before the first dose of study treatment. (For example, if the 5*the half-life is shorter than 21 days, 5*half-life should be used as the washout period. However, a minimum of 10 days should elapse from prior therapy to initiating protocol therapy). Persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or higher by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (v4.03). Receipt of hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of TAK-659; clinically significant graft-versus-host disease (GVHD) requiring ongoing immunosuppressive therapy post HSCT at the time of screening (use of topical steroids for ongoing skin GVHD is permitted). Active, systemic infection requiring intravenous (IV) antibiotic, antifungal, or antiviral therapy or other serious infection within 14 days before the first dose of study drug. Major surgery within 14 days before the first dose of study drug and have not recovered fully from any complications from surgery. Radiotherapy less than 2 weeks before the first dose of study treatment or have not recovered from acute toxic effects from radiotherapy. Known human immunodeficiency virus (HIV) positive (testing not required). Known hepatitis B surface antigen-positive, known or suspected active hepatitis C infection (testing not required). Evidence of currently uncontrolled cardiovascular conditions as listed in the protocol; acute myocardial infarction with 6 months before starting study drug; baseline QT interval (QTcF) greater than (>) 450 milliseconds (msec) (males) or > 475 msec (females); or abnormalities on baseline 12-lead electrocardiogram (ECG) that are considered clinically significant per investigator. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659 including difficulty swallowing tablets; diarrhea > Grade 1 despite supportive therapy. Use or consumption of any of the following substances: Medications or supplements that are known to be inhibitors of P-glycoprotein (P-gp) or strong inhibitors or inducers of Cytochrome (CY) P3A within 5 times the inhibitor half-life (if a reasonable half-life estimate is known) or within 7 days (if a reasonable half-life estimate is unknown) before the first dose of study drug. In general, the use of these agents is not permitted during the study except for AE management. Medications or supplements that are known to be strong CYP3A mechanism based inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) before the first dose of study drug. In general, the use of these agents is not permitted during the study except for AE management. Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are not permitted during the study. White blood cell count > 50,000 per micro liter (/µL); hydroxyurea may be used to control the level of circulating leukemic blast cell counts prior to study entry and, if needed, concomitantly while on TAK-659 treatment during the first 28 days of the study. Hydroxyurea can be used up to a maximum dose of 5 gram per (g/) day.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: TAK-659<br>TAK-659 tablets taken orally, once daily or twice daily on Days 1-28 in a 28 day cycle, for up to 12 cycles or until disease progression. Dosage of TAK-659 may increase in 20 mg increments using a 3 + 3 dose escalation design to determine a MTD and/or RP2D. | Drug: TAK-659<br>* TAK-659 tablets.<br>|
| Experimental: Phase 2: TAK-659<br>TAK-659, tablets taken orally, once daily or twice daily on Days 1-28 in a 28 day cycle, for up to 12 cycles or until disease progression. Dosage for this phase will be determined from results of Phase 1b MTD/RP2D. | Drug: TAK-659<br>* TAK-659 tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | AE meant any untoward medical occurrence in a participant or participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose may result in death, life-threatening, required in participant hospitalization or prolongation of an existing hospitalization or can be a medically important event. TEAEs were defined as any AE that occurs after administration of the first dose of study treatment and up through 28 days after the last dose of study medication, or until the start of subsequent antineoplastic therapy, whichever occurs first. | From the first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months) | 
| Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) | Toxicity was evaluated according to the NCI CTCAE, v4.03. DLT was defined as any of the following considered related to any of the treatment, by investigator: Prolonged myelosuppression with persistence of Grade ≥4 neutropenia or thrombocytopenia in absence of leukemia (blast count <5% in bone marrow) ≥42 days after initiation of Cycle 1 therapy; Any Grade ≥3 nonhematologic toxicity with exceptions- Grade 3 nausea or emesis resolved to Grade ≤1 or baseline in a week after use of optimal antiemetic regimen. Grade 3 diarrhea that resolved to Grade ≤1 or baseline in a week after receiving maximal supportive therapy, Brief (<1 week) Grade 3 fatigue, Asymptomatic Grade 3 laboratory abnormalities that were not clinically significant; Failure to administer ≥75% of planned doses of study drug due to TAK-659 -related or possibly related hematological or nonhematologic toxicities; related Grade ≥2 nonhematologic toxicities that required dose reduction or discontinuation of therapy. | Up to Cycle 1 (28 days) | 
| Phase 1b: Number of Participants With Clinically Significant Laboratory Findings Reported as TEAEs | Clinical laboratory evaluations were performed locally for Hematology, Serum Chemistry, Urinalysis. Any abnormal laboratory values were reported as a TEAE if that value led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from Baseline. | From first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months) | 
| Phase 1b: Number of Participants With Clinically Significant Vital Sign Findings Reported as TEAEs | Vital signs measurement (blood pressure, heart rate, and temperature) were performed before dosing on visit days and as clinically indicated. Any vital sign finding were reported as a TEAE if that value led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from Baseline. | From first dose of study drug through 28 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurred first (Up to 13 months) | 
| Phase 2: Overall Response Rate (ORR) | ORR was defined as percentage of participants who achieved complete response (CR), complete response with incomplete platelet recovery (CRp), incomplete hematologic recovery (CRi), partial hematologic recovery (CRh), composite complete remission (CRc), and partial response (PR) in response-evaluable population. CR: morphologic leukemia-free state and have absolute neutrophil count (ANC) of more than 1000/μL and platelets of ≥100,000/μL. CRp: satisfied all CR criteria except platelets <100,000/μL. CRi: fulfill all of the criteria for CR after chemotherapy except for residual neutropenia (<1000/μL) or thrombocytopenia (<100,000/μL). CRh: no evidence of peripheral blasts and partial recovery of peripheral blast counts including ANC above 500/μL and platelets above 50,000/μL. CRc: sum of participant achieving CR, CRh, CRi, or CRp. PR required all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in bone marrow aspirate. | Up to 13 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Duration of Response (DOR) | DOR was defined as the time from the date of first documentation of a response to the date of first documented progressive disease (PD). PD was defined as >50% increase in bone marrow blasts from baseline value. | Up to 13 months | 
| Phase 2: Time to Progression (TTP) | TTP was defined as the time from the date of first study drug administration to the date of first documentation of PD by the investigator. PD was defined as >50% increase in bone marrow blasts from baseline value. | Up to 13 months | 
| Phase 2: Mortality Rate at Months 3 and 6 | Percentage of participants who died at Months 3 and 6. | Months 3 and 6 | 
| Phase 2: Overall Survival (OS) | OS was defined as the time from the date of study entry to the date of death. | Up to 13 months | 
| Phase 2: Overall Response Rate (ORR) in FLT-3-internal Tandem Duplication (ITD) Mutant Versus Wild Type (WT) Populations | ORR was defined as percentage of participants who achieved complete response (CR), complete response with incomplete platelet recovery (CRp), incomplete hematologic recovery (CRi), partial hematologic recovery (CRh), composite complete remission (CRc), and partial response (PR) in response-evaluable population. CR: morphologic leukemia-free state and have absolute neutrophil count (ANC) of more than 1000/μL and platelets of ≥100,000/μL. CRp: satisfied all CR criteria except platelets <100,000/μL. CRi: fulfill all of the criteria for CR after chemotherapy except for residual neutropenia (<1000/μL) or thrombocytopenia (<100,000/μL). CRh: no evidence of peripheral blasts and partial recovery of peripheral blast counts including ANC above 500/μL and platelets above 50,000/μL. CRc: sum of participant achieving CR, CRh, CRi, or CRp. PR required all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in bone marrow aspirate. | Days 22 to 28 of Cycles 1, 2, 4 and 5 (each cycle was of 28-days) | 
| Phase 2: Duration of Response (DOR) in FLT-3-ITD Mutant Versus WT Populations | DOR was defined as the time from the date of first documentation of a response to the date of first documented PD. PD was defined as >50% increase in bone marrow blasts from baseline value. | Up to 13 months | 
| Phase 2: Time to Progression (TTP) in FLT-3-ITD Mutant Versus WT Populations | TTP was defined as the time from the date of first study drug administration to the date of first documentation of PD by the investigator. PD was defined as >50% increase in bone marrow blasts from baseline value. | Up to 13 months | 
| Phase 2: Mortality Rate in FLT-3-ITD Mutant Versus WT Populations | Number of participants who died at Months 3 and 6. | Months 3 and 6 | 
| Phase 2: Overall Survival (OS) in FLT-3-ITD Mutant Versus WT Populations | OS was defined as the time from the date of study entry to the date of death. | Cycle 1 (28-day Cycle), Day 1 to 12 months | 
| Phase 1: Cmax: Maximum Observed Plasma Concentration After Single Dose (Day 1) and Multiple Dose (Day 15) for TAK-659 |  | Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 24 hours for QD arms and Up to 8 hours for BID arms) post-dose | 
| Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration After Single Dose (Day 1) and Multiple Dose (Day 15) for TAK-659 |  | Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 24 hours for QD arms and Up to 8 hours for BID arms) post-dose | 
| Phase 1: AUC0-24: Area Under the Plasma Concentration-Time Curve During a Dosing Interval After Single Dose (Day 1) and Once-Daily (QD) Multiple Dose (Day 15) for TAK-659 | AUC0-24 was analyzed in the QD arms/cohorts as their sampling was done up to 24 hours. | Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 24 hours for QD arms) post-dose | 
| Phase 1: AUC0-8: Area Under the Plasma Concentration-Time Curve During a Dosing Interval After Single Dose (Day 1) and Twice-Daily (BID) Multiple Dose (Day 15) for TAK-659 | AUC0-8 was analyzed in the BID arms/cohorts as their sampling was done up to 8 hours. | Cycle 1 (28-day cycle), Days 1 and 15 pre-dose and at multiple time points (Up to 8 hours for BID arms) post-dose | 
| Phase 1: CL/Fss: Apparent Clearance After Extravascular Administration at Steady State After Once-Daily (QD) Multiple Dose (Day 15) for TAK-659 |  | Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (Up to 24 hours for QD arms) post-dose | 
| Phase 1: Rac(AUC0-24): Accumulation Ratio Based on AUC0-24 After Once-Daily (QD) Multiple Dose (Day 15) for TAK-659 | Accumulation ratio (based on AUC0-24), calculated as AUC0-24 after multiple dosing (at steady state)/AUC0-24 after a single dose. | Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (up to 24 hours for QD arms) post-dose | 
| Phase 1: Rac(AUC0-8): Accumulation Ratio Based on AUC0-8 After Twice-Daily (BID) Multiple Dose (Day 15) for TAK-659 | Accumulation ratio (based on AUC0-8), calculated as AUC0-8 after multiple dosing (at steady state)/AUC0-8 after a single dose. | Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (up to 8 hours for BID arms) post-dose | 
| Phase 1: PTR: Peak Trough Ratio After Multiple Dose (Day 15) for TAK-659 | The ratio of the maximum observed plasma concentration to the observed trough plasma concentration, where trough concentration is the concentration at the end of the dosing interval at steady-state before the next dose is administered. | Cycle 1 (28-day cycle), Day 15 pre-dose and at multiple time points (Up to 24 hours for QD arms and Up to 8 hours for BID arms) post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy