Clinical Trials /

Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and MLL Gene Rearrangement

NCT03724084

Description:

This phase Ib/II trial studies the side effects and best dose of pinometostat and how well it works with standard chemotherapy in treating patients with newly diagnosed acute myeloid leukemia and a type of genetic mutation called MLL gene rearrangement. Pinometostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in standard chemotherapy, such as daunorubicin hydrochloride and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pinometostat with standard chemotherapy may work better at treating acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and MLL Gene Rearrangement
  • Official Title: A Phase 1b/2 Study of Pinometostat in Combination With Standard Induction Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia With MLL Rearrangement

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-02349
  • SECONDARY ID: NCI-2018-02349
  • SECONDARY ID: 10212
  • SECONDARY ID: 10212
  • SECONDARY ID: UM1CA186712
  • NCT ID: NCT03724084

Conditions

  • Acute Myeloid Leukemia
  • KMT2A Gene Rearrangement

Interventions

DrugSynonymsArms
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (DOT1L inhibitor EPZ-5676)
Daunorubicin HydrochlorideCerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin Hydrochloride, RubilemTreatment (DOT1L inhibitor EPZ-5676)
DOT1L Inhibitor EPZ-5676EPZ-5676Treatment (DOT1L inhibitor EPZ-5676)

Purpose

This phase Ib/II trial studies the side effects and best dose of pinometostat and how well it works with standard chemotherapy in treating patients with newly diagnosed acute myeloid leukemia and a type of genetic mutation called MLL gene rearrangement. Pinometostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in standard chemotherapy, such as daunorubicin hydrochloride and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pinometostat with standard chemotherapy may work better at treating acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine a safe and tolerable schedule of DOT1L inhibitor EPZ-5676 (pinometostat)
      continuous intravenous infusion in combination with daunorubicin hydrochloride (daunorubicin)
      and cytarabine in patients with untreated, newly diagnosed acute myeloid leukemia harboring
      MLL rearrangement.

      II. Determine the rate of complete remission (complete remission [CR], CR with incomplete
      hematologic recovery [CRi]) in patients with newly diagnosed acute myeloid leukemia harboring
      MLL rearrangement after treatment with pinometostat in combination with daunorubicin and
      cytarabine.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. II. Estimate biologic activity of 7 day window
      treatment of pinometostat monotherapy.

      III. Estimate the toxicity profile of pinometostat alone (week 1) and in combination with
      daunorubicin and cytarabine.

      IV. Estimate event free and overall survival of patients with MLL rearranged acute myeloid
      leukemia after combination treatment with pinometostat, daunorubicin, and cytarabine.

      V. Estimate the early death rate (death =< 30 days) of pinometostat, daunorubicin, and
      cytarabine.

      VI. Determine the rate of minimal residual disease (MRD) negativity by clinical flow
      cytometry on post-treatment recovery bone marrow.

      OUTLINE: This is a phase I, dose-escalation study of DOT1L inhibitor EPZ-5676 followed by a
      phase II study.

      Patients receive DOT1L inhibitor EPZ-5676 intravenously (IV) continuously on days 1-35,
      daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously
      on days 8-14 in the absence of disease progression or unacceptable toxicity.

      Patients who do not achieve CR/CRi after treatment receive DOT1L inhibitor EPZ-5676 IV
      continuously on days 1-28, daunorubicin hydrochloride IV over 10-30 minutes on days 1 and 2
      and cytarabine IV continuously on days 1-5 in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up monthly for 1 year, then every
      3 months for up to 4 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (DOT1L inhibitor EPZ-5676)ExperimentalPatients receive DOT1L inhibitor EPZ-5676 IV continuously on days 1-35, daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously on days 8-14 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve CR/CRi after treatment receive DOT1L inhibitor EPZ-5676 IV continuously on days 1-28, daunorubicin hydrochloride IV over 10-30 minutes on days 1 and 2 and cytarabine IV continuously on days 1-5 in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • DOT1L Inhibitor EPZ-5676

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed acute myeloid leukemia by World Health
             Organization (WHO) criteria

          -  Presence of a cytogenetic rearrangement of KMT2A (MLL) by interphase fluorescent
             in-situ hybridization (FISH)

          -  Patients must have previously untreated (with exception of hydroxyurea for count
             control or all-trans retinoic acid [ATRA] for acute promyelocytic leukemia [APML] that
             was initially suspected but later ruled out) AML by World Health Organization (WHO)
             criteria

          -  Age >=14 years at time of screening, although individual sites may further restrict
             age eligibility in accordance with local Institutional Review Board (IRB) and hospital
             policy.

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), unless elevated
             due to Gilbert syndrome, hemolysis, or leukemia (at the time of eligibility screening)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN, unless due to leukemia in which case < 5 x ULN (at the
             time of eligibility screening)

          -  Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (at the
             time of eligibility screening)

          -  Prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN
             (both) (at the time of eligibility screening)

          -  Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral
             therapy with undetectable viral load within 6 months are eligible for this trial (at
             the time of eligibility screening)

          -  If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
             undetectable on suppressive therapy if indicated (at the time of eligibility
             screening)

          -  If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV
             viral load (at the time of eligibility screening)

          -  Be medically fit, in the opinion of the investigator, for intensive (7+3) induction
             chemotherapy

          -  Left ventricular ejection fraction (LVEF) >= 45% confirmed by echocardiogram or
             multi-gated acquisition scan (MUGA), AND no symptoms of congestive heart failure
             exceeding New York Heart Association (NYHA) class II

          -  Willingness to comply with all study procedures, including scheduled visits,
             investigational and standard of care drug administration plans, imaging studies,
             laboratory tests (including all biomarkers), procedures, and study- and
             disease-related restrictions

          -  The effects of pinometostat on the developing human fetus are unknown. For this reason
             and because other small molecule inhibitors as well as other therapeutic agents used
             in this trial are known to be teratogenic, women of child-bearing potential must agree
             to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry for the duration of study participation, and for 4
             weeks after the last dose of study treatment. Should a woman become pregnant or
             suspect she is pregnant while she or her partner is participating in this study, she
             should inform her treating physician immediately. Men treated or enrolled on this
             protocol must also agree to use adequate barrier contraception prior to the study, for
             the duration of study participation, and for 90 days after completion of pinometostat
             administration

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  Acute promyelocytic leukemia with t(15;17)(q22;q12) and/or PML-RARA molecular
             rearrangement, or other atypical RARA translocation partner

          -  Patients who have received prior chemotherapy for AML, excluding hydroxyurea for count
             control, or ATRA for APML that was initially suspected but later ruled out

          -  Patients who have received any prior investigational agent for acute myeloid leukemia

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1) with the exception of alopecia, or
             peripheral neuropathy (up to grade 2 is permitted)

          -  Patients who are receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to pinometostat or other agents used in study

          -  Patients receiving any medications or substances that are strong inhibitors or
             inducers of CYP3A4 are ineligible unless the offending medication can be safely
             stopped prior to enrollment. Because the lists of these agents are constantly
             changing, it is important to regularly consult a frequently-updated medical reference.
             As part of the enrollment/informed consent procedures, the patient will be counseled
             on the risk of interactions with other agents, and what to do if new medications need
             to be prescribed or if the patient is considering a new over-the-counter medicine or
             herbal product

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection requiring antibiotics (with exception), symptomatic congestive heart
             failure, unstable angina pectoris, unstable cardiac arrhythmia not controllable with
             medications, electrocardiographic evidence of ischemia, or psychiatric illness/social
             situations that would limit compliance with study requirements. Patients receiving an
             anti-microbial agent may be eligible if the patient remains afebrile and
             hemodynamically stable for 72 hours

          -  Patients with an active bleeding diathesis

          -  Pregnant women are excluded from this study because pinometostat is a small molecule
             inhibitor with the potential for teratogenic or abortifacient effects. Because there
             is an unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with pinometostat, breastfeeding should be discontinued if the
             mother is treated with pinometostat. These potential risks may also apply to other
             agents used in this study

          -  Subjects with known symptomatic leukemia of the central nervous system including
             leptomeningeal leukemic involvement

          -  History of active other malignancy that limits survival to less than 1 year

          -  Ongoing viral or drug induced liver injury, including active chronic hepatitis C virus
             (HCV), chronic active hepatitis B, clinically known alcoholic liver disease,
             non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, primary biliary
             cirrhosis, other cirrhosis of the liver, history of hepatic encephalopathy, or portal
             hypertension

          -  Any other prior condition that could, in the opinion of the investigator, compromise
             patient safety or evaluation of the primary outcome
      
Maximum Eligible Age:N/A
Minimum Eligible Age:14 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (Phase Ib)
Time Frame:Up to 35 days
Safety Issue:
Description:Safety and tolerability evaluation and dose escalation for phase 1b will be in the usual 3+3 fashion.

Secondary Outcome Measures

Measure:Incidence of adverse events according to Common Terminology Criteria for Adverse Events version 5
Time Frame:For up to 5 years
Safety Issue:
Description:The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Measure:Time to hematologic count recovery
Time Frame:Up to 5 years
Safety Issue:
Description:Will be analyzed using lab evaluation of complete blood counts and differential.
Measure:Differential blast counts
Time Frame:Baseline up to day 8
Safety Issue:
Description:Will be analyzed using lab evaluation of complete blood counts and differential.
Measure:Rate of minimal residual disease (MRD) positivity
Time Frame:Up to 5 years
Safety Issue:
Description:Will be evaluated by multiparameter flow cytometry, next-generation sequencing (or both) after induction therapy among those patients who attain morphologic and cytogenetic CR. Will be calculated with the exact binomial 95% confidence intervals.
Measure:Progression free survival
Time Frame:From the start of study treatment until progression or death, whichever occurs earliest, assessed up to 5 years
Safety Issue:
Description:Estimated using the Kaplan-Meier method.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:Estimated using the Kaplan-Meier method.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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