Clinical Trials /

Study Augmenting TAK-659 Action in Relapsed/Refractory AML by Addition Ofthe Proteasome Inhibitor Ixazomib

NCT04079738

Description:

This is a Phase I/II study augmenting TAK-659 action in relapsed/refractory AML by addition of the proteasome inhibitor Ixazomib. Phase I of the study will determine the safety, tolerability, and maximum tolerated dose (MTD) of the combination of TAK-659 and Ixazomib. During the phase I, dose escalation will be conducted according to a standard 3+3 dose escalation schema, and up to 18 response-evaluable patients will be enrolled. Phase II of the study will evaluate the efficacy of the combination by measuring the overall response rate (ORR).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study Augmenting TAK-659 Action in Relapsed/Refractory AML by Addition Ofthe Proteasome Inhibitor Ixazomib
  • Official Title: Phase I/II Study Augmenting TAK-659 Action in Relapsed/Refractory AML by Addition of the Proteasome Inhibitor Ixazomib: Big Ten Cancer Research Consortium BTCRC-HEM17-092

Clinical Trial IDs

  • ORG STUDY ID: BTCRC-HEM17-092
  • NCT ID: NCT04079738

Conditions

  • AML
  • AML, Adult

Interventions

DrugSynonymsArms
TAK-659Phase I:TAK-659 + Ixazomib
IxazomibPhase I:TAK-659 + Ixazomib

Purpose

This is a Phase I/II study augmenting TAK-659 action in relapsed/refractory AML by addition of the proteasome inhibitor Ixazomib. Phase I of the study will determine the safety, tolerability, and maximum tolerated dose (MTD) of the combination of TAK-659 and Ixazomib. During the phase I, dose escalation will be conducted according to a standard 3+3 dose escalation schema, and up to 18 response-evaluable patients will be enrolled. Phase II of the study will evaluate the efficacy of the combination by measuring the overall response rate (ORR).

Trial Arms

NameTypeDescriptionInterventions
Phase I:TAK-659 + IxazomibExperimentalPhase I: TAK-659 (Days 1-15) + Ixazomib dose escalation (Days 1, 8, 15)
  • TAK-659
  • Ixazomib
Phase II:TAK-659 + IxazomibExperimentalPhase II: TAK-659 at MTD (Days 1-15) + Ixazomib at MTD (Days 1, 8, 15)
  • TAK-659
  • Ixazomib

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization for release of personal health
             information. NOTE: HIPAA authorization may be included in the informed consent or
             obtained separately.

          -  Male or female patients 18 years or older at the time of consent.

          -  Patients must have a diagnosis of primary or secondary AML with relapsed or refractory
             disease (WHO update 2016, [34]) other than acute promyelocytic leukemia, or complex
             karyotype or monosomy 7 (or containing monosomy 7) for whom no standard therapies are
             anticipated to result in a durable remission according to the clinical judgment of the
             treating physician, or in a patient who refuses standard therapies.

          -  Must have submitted for Next Generation Sequencing (NGS) testing by: 1) (preferred)
             having submitted a tumor sample for commercial myeloid NGS from Foundation One, Mayo,
             Tempus, Quest, ARUP or an institutional CLIA-certified laboratory and/or 2) obtaining
             a bone marrow aspirate during screening for submission to Foundation One, Mayo,
             Tempus, Quest, ARUP or an institutional CLIA-certified laboratory and ordered as
             standard of care. If bone marrow aspiration has failed, a peripheral blood sample with
             circulating blasts may be substituted. Screening reports on tumor cytogenetics and/or
             mutation assays (eg, FLT-3, and NGS) performed as part of the standard of care will be
             recorded in the study database or obtained at the time of screening if not previously
             available.

          -  Patient's disease must be characterized for the presence/absence of Flt3ITD/TKD
             mutation from an FDA-approved vendor (ex. LabPMM).

          -  In addition, patients for the phase 2 portion of the study must meet the following:

               -  Patients, if relapsed/ refractory, must have exposure to no more than 2 prior
                  chemotherapy regimens. Re-induction with the same regimen or stem cell transplant
                  will not be considered a separate regimen.

               -  Patients must not have prior exposure to any investigational Flt3 inhibitors
                  (midostaurin or gilteritinib are allowed)

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Life expectancy of greater than 3 months as determined by the treating physician.

          -  Female patients 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 is in line with the preferred and usual
                  lifestyle of the subject. Periodic abstinence [eg, 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.)

               -  Agree not to donate eggs (ova) during the course of this study or 180 days after
                  receiving their last dose of study drug.

          -  Male patients, even if surgically sterilized (i.e., status post-vasectomy), 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 [eg, calendar, ovulation,
                  symptothermal, postovulation methods for the female partner] and withdrawal are
                  not acceptable methods of contraception. Female and male condoms should not be
                  used together.)

               -  Agree not to donate sperm during the course of this study or within 180 days
                  after receiving their last dose of study drug.

          -  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 patient 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/Ixazomib administration should be at least 2
             weeks for cytotoxic agents (other than hydroxyurea), or at least 5 half-lives for
             noncytotoxic agents, and patients have to have recovered from acute toxicities of
             these therapies. Patients who are on hydroxyurea may be included in the study and may
             continue on hydroxyurea for the first 21 days while participating in this study. NOTE:
             For patients with a white blood cell count >50,000/uL, 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 21 days of the
             study.

          -  Suitable venous access for the study-required blood sampling, and transfusion support.

          -  Demonstrate adequate organ function as defined in the protocol; all screening labs to
             be obtained within 28 days prior to registration.

        Exclusion Criteria:

          -  Clinically active central nervous system leukemia.

          -  Female patients who are lactating and breastfeeding (NOTE: breast milk cannot be
             stored for future use while the mother is being treated on study)

          -  Female patients who 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 patient
             or interfere with the objectives of the study.

          -  Prior treatment with investigational agents ≤ 21 days or ≤ 5 half-lives (whichever is
             shorter) before the first dose of study treatment. A minimum of 10 days should elapse
             from prior investigational therapy to initiating protocol therapy.

          -  Persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or
             higher by the NCI CTCAE (v5).

          -  Receipt of HSCT within 60 days of the first dose of TAK-659/Ixazomib; 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 10 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.

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

          -  Any of the following cardiovascular conditions:

               -  Acute myocardial infarction within 6 months before starting study drug.

               -  Current or history of New York Heart Association Class III or IV heart failure
                  (see Study Procedures Manual [SPM]).

               -  Evidence of current, uncontrolled cardiovascular conditions including cardiac
                  arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence of
                  acute ischemia or active conduction system abnormalities.

               -  Fridericia corrected QT interval (QTcF) >450 milliseconds (msec) (men) or >475
                  msec (women) on a 12-lead ECG during the Screening period.

               -  Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and
                  intervals that, in the opinion of the treating physician, are considered to be
                  clinically significant.

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance to study drugs, including difficulty swallowing tablets,
             diarrhea > Grade I despite supportive therapy.

          -  Use or consumption of any of the following medications, supplements, or
             foods/beverages that are inhibitors or inducers of P-gp or strong reversible
             inhibitors or inducers of CYP3A within the indicated timeframes below. Note that use
             or consumption of these substances is not permitted during the study.

               -  Inhibitors of P-gp and/or strong reversible inhibitors of CYP3A 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 in cases where an AE must be managed. See SPM for a nonexhaustive list of
                  strong CYP3A reversible inhibitors and/ or Pgp inhibitors based on the FDA Draft
                  DDI Guidance.

               -  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. However, if a patient
                  has a strong indication for fungal prophylaxis, then the moderate CYP3A
                  inhibitors fluconazole or isovuconazole (mold-active) is recommended for
                  prophylaxis, and the TAK-659 dose should be reduced to 60mg, along with increased
                  scrutiny for toxicity. Similarly, if the patient develops a fungal infection
                  during a productive intervention with TAK-659/Ixazomib combination, isovuconazole
                  (mold-active) should be used, along with increased scrutiny for toxicity. In
                  general, the use of these agents is not recommended during the study except in
                  cases where such an AE must be managed, and the intermittent schedule of
                  TAK-659/Ixazomib combination will not prevent profound neutropenia. See SPM for a
                  non-exhaustive list of strong CYP3A mechanism-based inhibitors or strong CYP3A
                  inducers and/or P-gp inducers based on the FDA Draft DDI Guidance.

               -  Grapefruit-containing food or beverages within 5 days before the first dose of
                  study drug.

          -  Lack of suitable venous access for the study-required blood sampling.

          -  Diagnosed or treated for another malignancy within 2 years before study enrollment or
             previously diagnosed with another malignancy and have any evidence of residual
             disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are
             not excluded if they have undergone complete resection.

          -  Patient has Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical
             examination during the screening period.

          -  Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) and recommended phase 2 dose(s) (RP2D)
Time Frame:At the end of Cycle 2(each cycle is 28 days)
Safety Issue:
Description:To determine the maximum tolerated dose (MTD) and recommended phase 2 dose(s) (RP2D) of the combination of TAK-659 and Ixazomib in patients with relapsed or refractory AML.

Secondary Outcome Measures

Measure:Duration of Response (DOR)
Time Frame:6 Months
Safety Issue:
Description:DOR defined as the time from the date of first documentation of a response to the date of first documented progressive disease
Measure:Time to Progression (TTP)
Time Frame:6 Months
Safety Issue:
Description:TTP defined as the time from first dose of study drug until tumor progression as defined by the Revised Recommendations of the International Working Group (IWG) for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia
Measure:Overall Survival (OS)
Time Frame:6 Months
Safety Issue:
Description:OS defined as the time from the date of study entry to death
Measure:Frequency of Grade 3 and higher adverse events
Time Frame:6 Months
Safety Issue:
Description:Summarize Grade 3 and higher adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:H Scott Boswell

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