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

NCT02323113 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: C34002U1111-1163-2185
• Study Type: interventional
• Target: 43
• Locations: 2 countries
• Sites: 17

Brief Summary

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).

Conditions

Acute Myelogenous Leukemia

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (17)

• Phase 2: Duration of Response (DOR)

  Up to 13 months

• Phase 2: Time to Progression (TTP)

  Up to 13 months

• Phase 2: Mortality Rate at Months 3 and 6

  Months 3 and 6

• Phase 2: Overall Survival (OS)

  Up to 13 months

• Phase 2: Overall Response Rate (ORR) in FLT-3-internal Tandem Duplication (ITD) Mutant Versus Wild Type (WT) Populations

  Days 22 to 28 of Cycles 1, 2, 4 and 5 (each cycle was of 28-days)

Study Arms (2)

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.

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.

Drug: TAK-659

Interventions

TAK-659 DRUG

TAK-659 tablets.

Phase 1b: TAK-659; Phase 2: TAK-659

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Calithera Biosciences, Inc: lead

Study Sites (17)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Chicago, Illinois, 60611, United States

Location

Oncology Specialists, S.C.

Niles, Illinois, 60714, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Karmanos Cancer Center

Detroit, Michigan, 48201, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

North Shore Long Island Jewish Medical Center

New York, New York, 10024, United States

Location

University of North Carolina Hospital

Chapel Hill, North Carolina, 27514, United States

Location

UC Health Clinical Trials Office

Cincinnati, Ohio, 45206, United States

Location

Baylor University Medical Center

Dallas, Texas, 75204, United States

Location

Medical College of Wisconsin, Inc.

Milwaukee, Wisconsin, 53266, United States

Location

Queen Elizabeth II Health Sciences Centre

Halifax, Nova Scotia, B3H 3A7, Canada

Location

Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

Wake Forest University Baptist Medical Center

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (1)

• 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.

  PMID: 36226495 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

TAK-659

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Study Director
• Organization: Takeda

TrialDisclosures@takeda.com

+1-877-825-3327

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 18, 2014
• First Posted: December 23, 2014
• Study Start: March 9, 2015
• Primary Completion: June 8, 2018
• Study Completion: August 15, 2018
• Last Updated: February 8, 2023
• Results First Posted: May 11, 2021

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Locations

US (14); CA (3)