Clinical Trials /

Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia

NCT03983824

Description:

This phase I trial studies the best dose and side effects of M3814 when given in combination with mitoxantrone, etoposide, and cytarabine in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). M3814 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone, etoposide, 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 M3814 in combination with mitoxantrone, etoposide, and cytarabine may lower the chance of the acute myeloid leukemia growing or spreading.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: A Phase 1 Study of M3814 in Combination With MEC in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-03607
  • SECONDARY ID: NCI-2019-03607
  • SECONDARY ID: PHI-103
  • SECONDARY ID: 10273
  • SECONDARY ID: 10273
  • SECONDARY ID: UM1CA186717
  • NCT ID: NCT03983824

Conditions

  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

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 (M3814, mitoxantrone, etoposide, cytarabine)
Cytarabine HydrochlorideAra-C HCl, Arabinosylcytosine Hydrochloride, Aracytidine Hydrochloride, CHX-3311, Cytosar Hydrochloride, Cytosine Arabinosine Hydrochloride, U-19920ATreatment (M3814, mitoxantrone, etoposide, cytarabine)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Treatment (M3814, mitoxantrone, etoposide, cytarabine)
Etoposide PhosphateEtopophosTreatment (M3814, mitoxantrone, etoposide, cytarabine)
MitoxantroneDihydroxyanthracenedione, MitozantroneTreatment (M3814, mitoxantrone, etoposide, cytarabine)
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanTreatment (M3814, mitoxantrone, etoposide, cytarabine)
Nedisertib3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-, M 3814, M-3814, M3814, MSC 2490484A, MSC-2490484A, MSC2490484ATreatment (M3814, mitoxantrone, etoposide, cytarabine)

Purpose

This phase I trial studies the best dose and side effects of M3814 when given in combination with mitoxantrone, etoposide, and cytarabine in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). M3814 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone, etoposide, 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 M3814 in combination with mitoxantrone, etoposide, and cytarabine may lower the chance of the acute myeloid leukemia growing or spreading.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the safety and tolerability and determine the recommended phase two dose (RP2D)
      of M3814 in combination with mitoxantrone, etoposide, and cytarabine (MEC) in patients with
      relapsed or refractory (R/R) acute myeloid leukemia (AML).

      SECONDARY OBJECTIVES:

      I. To characterize the pharmacokinetic (PK) profile of MEC alone and of M3814 in combination
      with MEC.

      II. To evaluate the preliminary efficacy of M3814 in combination with MEC in patients with
      R/R AML as measured by the response rate (complete remission [CR] plus CR with incomplete
      count recovery), duration of CR/CRi (DOR), event-free survival (EFS) and overall survival
      (OS).

      EXPLORATORY OBJECTIVES:

      I. To evaluate correlative biomarkers of M3814 target engagement and response. II. To
      correlate cytogenetic and molecular abnormalities with response. III. To evaluate the rates
      of early mortality and allogeneic hematopoietic cell transplantation.

      IV. To perform molecular profiling assays on malignant and normal tissues, including, but not
      limited to, whole exome sequencing (WES) and messenger ribonucleic acid (RNA) sequencing
      (RNAseq), in order to:

      IVa. Identify potential predictive and prognostic biomarkers beyond any genomic alteration by
      which treatment may be assigned.

      IVb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based
      assessment platforms.

      V. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
      Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
      and future research; specimens will be annotated with key clinical data, including
      presentation, diagnosis, staging, summary treatment, and if possible, outcome.

      OUTLINE: This is a dose-escalation study of M3814.

      Patients receive M3814 orally (PO) twice daily (BID) on days 2-21, mitoxantrone intravenously
      (IV) over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days
      1-5 in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 3 months for
      1 year, then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (M3814, mitoxantrone, etoposide, cytarabine)ExperimentalPatients receive M3814 PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • Cytarabine Hydrochloride
  • Etoposide
  • Etoposide Phosphate
  • Mitoxantrone
  • Mitoxantrone Hydrochloride
  • Nedisertib

Eligibility Criteria

        Inclusion Criteria:

          -  An established and confirmed diagnosis of AML by World Health Organization criteria,
             excluding acute promyelocytic leukemia (APL) (with promyelocytic leukemia -retinoic
             acid receptor alpha [PML-RARA])

          -  Patients with R/R AML, defined as:

               -  Relapsed: >= 5% bone marrow blasts by morphology or reappearance of minimal
                  residual disease by flow cytometry, reappearance of peripheral blood blasts, or
                  development of extramedullary leukemia after one or two prior lines of therapy.
                  First or second relapse is eligible, and consolidation regimens, including
                  autologous and allogeneic hematopoietic cell transplant, do not count as a
                  separate prior line of therapy

               -  Refractory: no CR or CRi after two courses of induction

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (or Karnofsky >=
             60%)

          -  Serum bilirubin =< 1.5 institutional upper limit of normal (ULN) (unless resulting
             from hemolysis, Gilbert's syndrome or liver infiltration with leukemia)

          -  Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional ULN (unless resulting from liver infiltration with leukemia)

          -  Serum creatinine =< 1.5 x institutional ULN OR

          -  Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2

          -  Patients must be medically eligible to receive MEC, including acceptable pre-study
             cardiac function (left ventricular ejection fraction of >= 45%) and lifetime
             anthracycline exposure (=< 400 mg/m^2 doxorubicin equivalents)

          -  Patients may have had prior allogeneic hematopoietic cell transplant at least 3 months
             prior to enrollment but should not have evidence of active graft versus host disease
             or require systemic immune suppression

          -  Patients must be willing to submit the blood sampling and bone marrow sampling for the
             PK and pharmacodynamics analyses and exploratory biomarkers

          -  Female patients with child bearing potential must have a negative serum pregnancy test
             within 72 hours prior to the first study drug administration and all patients must be
             willing to use effective methods of contraception during the treatment period and 3
             months after study completion

          -  Human immunodeficiency virus (HIV)-infected patients will be eligible for this trial
             if they are on effective antiretroviral regimens utilizing non-CYP-interacting agents,
             they have an undetectable viral load, they have a CD4 count > 350 cells/mm^3, and they
             have no history of acquired immune deficiency syndrome (AIDS)-defining opportunistic
             infections. If there is evidence of chronic hepatitis B virus (HBV) infection, HBV
             viral load must be undetectable on suppressive therapy, if indicated. If there is
             history of hepatitis C virus (HCV) infection, the patient must have been treated and
             have undetectable HCV viral load

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

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

        Exclusion Criteria:

          -  Patients must not have had prior treatment with MEC

          -  Patients must not have documented active central nervous system (CNS) involvement by
             leukemia. Patients with known brain metastases should be excluded from this clinical
             trial because of their poor prognosis and because they often develop progressive
             neurologic dysfunction that would confound the evaluation of neurologic and other
             adverse events (AEs)

          -  Patients must not have received any other investigational or commercial agents or
             therapies administered with the intention to treat their leukemia within 14 days or 5
             half-lives (whichever is shorter) of first receipt of study drug, with the exception
             of hydroxyurea used to control white blood cell counts

          -  All non-hematologic AEs of prior chemotherapy, surgery, or radiotherapy, except
             alopecia, must have resolved to National Cancer Institute (NCI) Common Terminology
             Criteria for Adverse Events (CTCAE) grade =< 2 prior to starting therapy

          -  Patients who cannot discontinue concomitant medications or herbal supplements that are
             strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5 and
             CYP2C19. Concomitant use of CYP3A4/5 substrates with a narrow therapeutic index are
             also excluded. Patients may confer with the study doctor to determine if alternative
             medications can be used. The following categories of medications and herbal
             supplements must be discontinued for at least the specified period of time before the
             patient can be treated:

               -  Strong inducers of CYP3A4/5 and CYP2C19: >= 3 weeks prior to study treatment

               -  Strong inhibitors of CYP3A4/5 and CYP2C19: >= 1 week prior to study treatment

               -  Substrates of CYP3A4/5 with a narrow therapeutic index: >= 1 day prior to study
                  treatment

          -  Patients who cannot discontinue concomitant H2 blockers or proton-pump inhibitors
             (PPIs). Patients may confer with the study doctor to determine if such medications can
             be discontinued. These must be discontinued >= 5 days prior to study treatment.
             Patients do not need to discontinue calcium carbonate

          -  Patients receiving sorivudine or any chemically related analogues (such as brivudine)
             are excluded

          -  Patients who require oral or parenteral anticoagulants or thrombolytic agents for
             therapeutic purposes (including coumadin and warfarin), or who received such agents
             within 5 days of the first dose of M3814. Low and high-molecular weight heparins are
             permitted provided the platelets are maintained at greater than 30,000/mm^3

          -  Patients who have received a live attenuated vaccine within 30 days of dosing with
             M3814

          -  Patients must not have known significant cardiopulmonary disease defined as:

               -  Unstable angina;

               -  Congestive heart failure (New York Heart Association [NYHA] class III or IV;

               -  Myocardial infarction (MI) within 6 months prior to first dose. Patients who had
                  ischemic heart disease such as acute coronary syndrome (ACS), MI, and/or
                  revascularization more than 6 months before screening and who are without cardiac
                  symptoms or those with a prior non-ST elevation MI (NSTEM) due to demand-supply
                  mismatch (NSTEM Type II) may enroll

          -  Patients should not have severe and/or uncontrolled medical conditions or other
             conditions that, in the opinion of the investigator, could affect their participation
             in the study

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Patients should not be pregnant or breastfeeding
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Coded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Secondary Outcome Measures

Measure:Pharmacokinetic (PK) profile of M3814 in combination with mitoxantrone, etoposide, and cytarabine (MEC)
Time Frame:Days 1 and 5
Safety Issue:
Description:Individual PK parameters will be estimated for maximum concentration (Cmax), area under the concentration-time curve (AUC), half-life (t1/2), apparent clearance (Cl/F), and apparent volume of distribution (V/F) using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters will be reported descriptively for exploratory comparison with historical data.
Measure:Overall response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Defined as the proportion of subjects with complete remission (CR) plus CR with incomplete count recovery (CRi) using European Leukemia Net response criteria. The percent of CR will be calculated and associated exact 95% confidence intervals will be constructed.
Measure:Duration of CR/CRi (DOR)
Time Frame:From first documented CR/CRi response to relapse, assessed up to 2 years
Safety Issue:
Description:Summarized using Kaplan-Meier plots.
Measure:Event-free survival (EFS)
Time Frame:From study entry to treatment failure (lack of response, i.e., no CR or CRi), relapse from CR or CRi, or death from any cause, assessed up to 2 years
Safety Issue:
Description:Summarized using Kaplan-Meier plots.
Measure:Overall survival (OS)
Time Frame:From study entry to death from any cause, assessed up to 2 years
Safety Issue:
Description:Summarized using Kaplan-Meier plots.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

December 9, 2019