Clinical Trials /

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

NCT02323113

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: C34002
  • SECONDARY ID: U1111-1163-2185
  • NCT ID: NCT02323113

Conditions

  • Acute Myelogenous Leukemia

Interventions

DrugSynonymsArms
TAK-659Phase 1b: TAK-659

Purpose

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

      The drug being tested in this study is called 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 (up to 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 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 and Canada. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1b: TAK-659ExperimentalTAK-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.
  • TAK-659
Phase 2: TAK-659ExperimentalTAK-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.
  • TAK-659

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female participants 18 years or older.

          2. 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).

          3. 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.

          4. Eastern Cooperative Oncology Group performance status of 0 to 1.

          5. 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 subject. (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 subject. (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).

          6. 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.

          7. 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.

          8. Suitable venous access for the study-required blood sampling, including
             pharmacokinteic (PK) and pharmacodynamic (PD) sampling and blood transfusion support.

          9. 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:

          1. Clinically active central nervous system leukemia.

          2. 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.

          3. 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.

          4. 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.)

          5. 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).

          6. 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).

          7. 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.

          8. Major surgery within 14 days before the first dose of study drug and have not
             recovered fully from any complications from surgery.

          9. Radiotherapy less than 2 weeks before the first dose of study treatment or have not
             recovered from acute toxic effects from radiotherapy.

         10. Known human immunodeficiency virus (HIV) positive (testing not required).

         11. Known hepatitis B surface antigen-positive, known or suspected active hepatitis C
             infection (testing not required).

         12. 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.

         13. 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.

         14. 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.

         15. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1b: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame:Up to 28 days after last dose of study drug
Safety Issue:
Description:An AE is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. AEs will be recorded from first dose of study drug through 28 days after the last dose of study drug or to the start of anticancer therapy, whichever occurs first. A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. SAEs will be reported from signing of informed consent form through 28 days after the last dose of study drug even if the participant starts nonprotocol therapy.

Secondary Outcome Measures

Measure:Duration of Response (DOR)
Time Frame:From first documented response until disease progression (Up to 13 months)
Safety Issue:
Description:Duration of response is defined as the time from the date of first documentation of a response to the date of first documentation of disease progression.
Measure:Time to Progression (TTP)
Time Frame:From the date randomization to the date of first documented progressive disease (Up to 13 months)
Safety Issue:
Description:TTP is defined as the time from baseline to the date of first documentation of progressive disease.
Measure:Mortality Rate
Time Frame:Months 3 and 6
Safety Issue:
Description:Rate of death at 3 and 6 months.
Measure:Overall Survival (OS)
Time Frame:Cycle 1 Day 1 through 12 months after discontinuation of study drug
Safety Issue:
Description:Overall survival is defined as the time from study entry to the time of death.
Measure: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, and 4, Cycle 5 and beyond as needed
Safety Issue:
Description:ORR is defined as the percentage of participants with CR, CRp, Cri, and PR.
Measure:Duration of Response (DOR) in FLT-3-ITD Mutant Versus Wild Type (WT) Populations
Time Frame:From first documented response until disease progression (Up to 13 months)
Safety Issue:
Description:Duration of response is defined as the time from the date of first documentation of a response to the date of first documentation of disease progression.
Measure:Time to Progression (TTP) in FLT-3-ITD Mutant Versus Wild Type (WT) Populations
Time Frame:From the date randomization to the date of first documented progressive disease (Up to 13 months)
Safety Issue:
Description:TTP is defined as the time from baseline to the date of the first documentation of progressive disease.
Measure:Mortality Rate in FLT-3-ITD Mutant Versus Wild Type (WT) Populations
Time Frame:Months 3 and 6
Safety Issue:
Description:Rate of death at 3 and 6 months.
Measure:Overall Survival (OS) in FLT-3-ITD Mutant Versus Wild Type (WT) Populations
Time Frame:Cycle 1 Day 1 through 12 months after discontinuation of study drug
Safety Issue:
Description:Overall survival is defined as the time from the date of first study entry to death.
Measure:Cmax: Maximum Observed Plasma Concentration for TAK-659
Time Frame:Cycle 1, Day 1 and Day 15
Safety Issue:
Description:Maximum observed plasma concentration (Cmax) is the observed peak plasma concentration of a drug after administration.
Measure:Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for TAK-659
Time Frame:Cycle 1, Day 1 and 15
Safety Issue:
Description:Time to reach the maximum observed plasma concentration (Cmax) of a drug after administration.
Measure:AUCtau: Area Under the Plasma Concentration-Time Curve During a Dosing Interval for TAK-659
Time Frame:Cycle 1, Day 1 and 15
Safety Issue:
Description:Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval.
Measure:Apparent Clearance (CL/F) for TAK--659
Time Frame:Cycle 1, Day 1 and 15
Safety Issue:
Description:Apparent clearance after extravascular administration, calculated as Dose/AUC∞ after a single dose and as Dose/AUCtau after multiple dosing (at steady state).
Measure:Accumulation Ratio (Rac) for TAK-659
Time Frame:Cycle 1 Day 15
Safety Issue:
Description:Accumulation ratio (based on AUC), calculated as AUCtau after multiple dosing (at steady state)/AUCtau after a single dose.
Measure:Peak Trough Ratio (PTR) for TAK-659
Time Frame:Cycle 1 Day 15
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Drug therapy

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