Acute Myelogenous LeukemiaPhase 1/2NCT02323113

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

A Phase 1/2 study testing TAK-659 in people with Acute Myelogenous Leukemia, run by Calithera Biosciences, Inc at 17 sites in 2 countries.

Terminated

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

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Acute Myelogenous Leukemia
What is being tested?: TAK-659
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 43 participants
Where: 17 sitesin 2 countries
Study dates: 9 Mar 2015to 15 Aug 2018
Phase: Phase 1/2
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

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:

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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).

Who cannot join

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).

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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.

Trial locations and contacts

17 sites in 2 countries.

Country

City, postcode or hospital

17 sites in 2 countries

United States14 sites

University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
Johns Hopkins Hospital
Baltimore, Maryland, 21287
University of Alabama at Birmingham
Birmingham, Alabama, 35233
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
University of North Carolina Hospital
Chapel Hill, North Carolina, 27514
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, Illinois, 60611
UC Health Clinical Trials Office
Cincinnati, Ohio, 45206
Baylor University Medical Center
Dallas, Texas, 75204
Karmanos Cancer Center
Detroit, Michigan, 48201
Henry Ford Health System
Detroit, Michigan, 48202
Medical College of Wisconsin, Inc.
Milwaukee, Wisconsin, 53266
North Shore Long Island Jewish Medical Center
New York, New York, 10024
Oncology Specialists, S.C.
Niles, Illinois, 60714
Mayo Clinic
Rochester, Minnesota, 55905

Other trials in United States

Canada3 sites

Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, B3H 3A7
Princess Margaret Hospital
Toronto, Ontario, M5G 2M9
Wake Forest University Baptist Medical Center
Toronto, Ontario, M5G 2M9

Other trials in Canada

About this study

Official title: 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)

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).

Read the detailed description

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.

Conditions: Acute Myelogenous Leukemia
Being tested: TAK-659
Keywords: Drug therapy
Medical subject headings: Leukemia, Myeloid, Acute

What participants receive

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

TAK-659Drug
TAK-659 tablets.

Study groups in NCT02323113
Study group	Role	What they receive
Phase 1b: TAK-659	Experimental	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. Receives: Drug: TAK-659
Phase 2: TAK-659	Experimental	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. Receives: Drug: TAK-659

What is being measured

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

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Up to 13 months

Secondary outcomes (17)

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.
Measured: 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.
Measured: Up to 13 months
Phase 2: Mortality Rate at Months 3 and 6
Percentage of participants who died at Months 3 and 6.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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

Timeline

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

9 Mar 201515 Aug 2018

First posted23 Dec 2014 (estimated)
Study start9 Mar 2015
Primary completion8 Jun 2018
Study completion15 Aug 2018

Why it stopped: Business Decision; No Safety or Efficacy Concerns.

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 Acute Myelogenous LeukemiaStudies 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 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 43 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02323113
Sponsor's protocol ID: C34002
Other IDs: U1111-1163-2185
Status last verified: Feb 2023
First submitted: 18 Dec 2014
Last updated: 8 Feb 2023
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
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

Pratz KW, Kaplan J, Levy M, Bixby D, Burke PW, Erba H, Wise-Draper TM, Roboz GJ, Papadantonakis N, Rajkhowa T, Hernandez D, Dobler I, Gregory RC, Li C, Wang S, Stumpo K, Kannan K, Miao H, Levis M. A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia. Haematologica. 2023 Mar 1;108(3):705-716. doi: 10.3324/haematol.2022.281216.
PubMed 36226495

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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All Acute Myelogenous Leukemia trials

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: 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)
ClinicalTrials.gov ID: NCT02323113
Acronym / sponsor ID: C34002
Conditions: Acute Myelogenous Leukemia
Keywords: Drug therapy
Phase: Phase 1/2
Study type: Interventional
Recruitment status: TerminatedReason stopped: Business Decision; No Safety or Efficacy Concerns.
Enrolment: 43 participants (actual)
Lead sponsor: Calithera Biosciences, IncIndustry (pharma, biotech, devices)
Study start: 9 Mar 2015 (actual)
Primary completion: 8 Jun 2018 (actual)
Study completion: 15 Aug 2018 (actual)
First posted: 23 Dec 2014 (estimated)
Results: Posted 11 May 2021

Clinical summary

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

Detailed description

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.

Study design

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

Arm	Type	Receives
Phase 1b: TAK-659	Experimental	Drug: TAK-659TAK-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.
Phase 2: TAK-659	Experimental	Drug: TAK-659TAK-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.

Who may qualify

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

Key inclusion criteria (21 listed)

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.

Key exclusion criteria (18 listed)

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).

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-659TAK-659 tablets.	Drug	Phase 1b: TAK-659, Phase 2: TAK-659

Primary outcome

Phase 1b: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
Time frame: 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)
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.
Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs)
Time frame: Up to Cycle 1 (28 days)
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.
Phase 1b: Number of Participants With Clinically Significant Laboratory Findings Reported as TEAEs
Time frame: 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)
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.
Phase 1b: Number of Participants With Clinically Significant Vital Sign Findings Reported as TEAEs
Time frame: 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)
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.
Phase 2: Overall Response Rate (ORR)
Time frame: Up to 13 months
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.

17 secondary outcomes

Phase 2: Duration of Response (DOR)
Time frame: Up to 13 months
Phase 2: Time to Progression (TTP)
Time frame: Up to 13 months
Phase 2: Mortality Rate at Months 3 and 6
Time frame: Months 3 and 6
Phase 2: Overall Survival (OS)
Time frame: Up to 13 months
Phase 2: Overall Response Rate (ORR) in FLT-3-internal Tandem Duplication (ITD) Mutant Versus Wild Type (WT) Populations
Time frame: 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
Time frame: Up to 13 months
Phase 2: Time to Progression (TTP) in FLT-3-ITD Mutant Versus WT Populations
Time frame: Up to 13 months
Phase 2: Mortality Rate in FLT-3-ITD Mutant Versus WT Populations
Time frame: Months 3 and 6
Phase 2: Overall Survival (OS) in FLT-3-ITD Mutant Versus WT Populations
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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

Results and safety

Results posted to the registry on 11 May 2021, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
TAK-659 60 mg QD	4	0
TAK-659 100 mg QD	7	0
TAK-659 120 mg QD	4	0
TAK-659 140 mg QD	5	0
TAK-659 160 mg QD	9	0
TAK-659 60 mg BID	8	0
TAK-659 80 mg BID	6	0
Phase 2 (Dose Expansion Phase)	0	0

Primary outcome: Phase 1b: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)

Time frame: 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). Count of participants. Unit: Participants

Measure	TAK-659 60 mg QD n = 4	TAK-659 100 mg QD n = 7	TAK-659 120 mg QD n = 4	TAK-659 140 mg QD n = 5	TAK-659 160 mg QD n = 9	TAK-659 60 mg BID n = 8	TAK-659 80 mg BID n = 6
TEAEs	4	7	4	5	9	8	6
SAEs	4	6	4	5	9	7	6

Population analysed: Safety population included all enrolled participants who received at least 1 dose of study drug.

Primary outcome: Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs)

Time frame: Up to Cycle 1 (28 days). Count of participants. Unit: Participants

Measure	TAK-659 60 mg QD n = 3	TAK-659 100 mg QD n = 6	TAK-659 120 mg QD n = 3	TAK-659 140 mg QD n = 3	TAK-659 160 mg QD n = 6	TAK-659 60 mg BID n = 7	TAK-659 80 mg BID n = 6
Value	0	0	0	0	1	0	3

Population analysed: DLT-evaluable population include all participants in the phase 1b portion of the study at each dose cohort who either experienced a DLT during Cycle 1 or completed at least 75% of planned doses of TAK-659 and had sufficient follow-up data to allow both the sponsor and investigators to determine whether a DLT occurred.

Primary outcome: Phase 1b: Number of Participants With Clinically Significant Laboratory Findings Reported as TEAEs

Time frame: 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). Count of participants. Unit: Participants

Measure	TAK-659 60 mg QD n = 4	TAK-659 100 mg QD n = 7	TAK-659 120 mg QD n = 4	TAK-659 140 mg QD n = 5	TAK-659 160 mg QD n = 9	TAK-659 60 mg BID n = 8	TAK-659 80 mg BID n = 6
Febrile neutropenia	0	3	3	4	5	5	6
Anaemia	0	1	1	1	4	2	3
Thrombocytopenia	1	3	1	0	0	0	0
Pancytopenia	0	1	0	0	2	0	0
Leukocytosis	1	1	0	0	0	0	0
Leukopenia	0	0	0	0	1	0	0
Neutropenia	0	0	0	1	0	0	0
Thrombocytosis	0	0	0	0	0	0	1

Population analysed: Safety population included all enrolled participants who received at least 1 dose of study drug.

Primary outcome: Phase 1b: Number of Participants With Clinically Significant Vital Sign Findings Reported as TEAEs

Measure	TAK-659 60 mg QD n = 4	TAK-659 100 mg QD n = 7	TAK-659 120 mg QD n = 4	TAK-659 140 mg QD n = 5	TAK-659 160 mg QD n = 9	TAK-659 60 mg BID n = 8	TAK-659 80 mg BID n = 6
Weight Increased	0	1	0	0	0	0	0
Tachycardia	0	1	1	0	1	0	1
Hypertension	1	0	2	0	1	0	0
Hypotension	0	0	0	0	2	1	0
Pyrexia	1	2	1	1	4	0	2

Population analysed: Safety population included all enrolled participants who received at least 1 dose of study drug.

17 secondary outcomes are reported in the full results.

Adverse events

Group	Serious adverse events	Other adverse events	Deaths
TAK-659 60 mg QD	4 of 4 (100%)	4 of 4 (100%)	1 of 4
TAK-659 100 mg QD	6 of 7 (85.7%)	7 of 7 (100%)	3 of 7
TAK-659 120 mg QD	4 of 4 (100%)	4 of 4 (100%)	3 of 4
TAK-659 140 mg QD	5 of 5 (100%)	5 of 5 (100%)	4 of 5
TAK-659 160 mg QD	9 of 9 (100%)	9 of 9 (100%)	7 of 9
TAK-659 60 mg BID	7 of 8 (87.5%)	8 of 8 (100%)	4 of 8
TAK-659 80 mg BID	6 of 6 (100%)	6 of 6 (100%)	4 of 6

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 36226495Pratz KW, Kaplan J, Levy M, Bixby D, Burke PW, Erba H, Wise-Draper TM, Roboz GJ, Papadantonakis N, Rajkhowa T, Hernandez D, Dobler I, Gregory RC, Li C, Wang S, Stumpo K, Kannan K, Miao H, Levis M. A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia. Haematologica. 2023 Mar 1;108(3):705-716. doi: 10.3324/haematol.2022.281216.
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.

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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.

Study Director study director

Takeda

17 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing TAK-659 in people with Acute Myelogenous Leukemia, run by Calithera Biosciences, Inc at 17 sites in 2 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 21 inclusion and 18 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 17 sites in United States, Canada. 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 combined 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.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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 11 May 2021). 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?

Phase 1b: Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) (time frame: 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)). The study lists 5 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 NCT02323113, 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.