Clinical Trials /

Gemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine and Mitoxantrone in Treating Participants With Previously Untreated Acute Myeloid Leukemia or High-Grade Myeloid Neoplasm

NCT03531918

Description:

This phase I/II trial studies the side effects and best dosing frequency of gemtuzumab ozogamicin when given in combination with granulocyte colony stimulating factor (G-CSF), cladribine, cytarabine and mitoxantrone (GCLAM) and to see how well they work in treating participants with acute myeloid leukemia or high-grade myeloid tumors (neoplasms) that have not been previously treated. Antibody-drug conjugates, such as gemtuzumab ozogamicin, act by directly delivering toxic chemotherapy to cancer cells. Granulocyte colony stimulating factor is a growth factor used to stimulate leukemia cells and render them more sensitive to chemotherapy drugs. Drugs used in chemotherapy, such as cladribine, cytarabine and mitoxantrone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving gemtuzumab ozogamicin in combination with G-CSF, cladribine, cytarabine and mitoxantrone hydrochloride may work better in treating participants with acute myeloid leukemia or high-grade myeloid neoplasm.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myeloid Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Gemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine and Mitoxantrone in Treating Participants With Previously Untreated Acute Myeloid Leukemia or High-Grade Myeloid Neoplasm
  • Official Title: A Single-Center Phase 1/2 Study of Single- or Fractioned-Dose Gemtuzumab Ozogamicin in Combination With G-CSF, Cladribine, Cytarabine and Mitoxantrone (GCLAM) for Previously Untreated Adult Acute Myeloid Leukemia or High-Grade Myeloid Neoplasm

Clinical Trial IDs

  • ORG STUDY ID: 10000
  • SECONDARY ID: NCI-2018-00776
  • SECONDARY ID: 10000
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG9218023
  • NCT ID: NCT03531918

Conditions

  • Acute Myeloid Leukemia
  • High-Grade Myeloid Neoplasm
  • Blasts 10 Percent or More of Bone Marrow Nucleated Cells
  • Blasts 10 Percent or More of Peripheral Blood White Cells
  • High Grade Myeloid Neoplasm

Interventions

DrugSynonymsArms
Cladribine2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251Treatment (GO, GCLAM)
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 (GO, GCLAM)
Gemtuzumab OzogamicinCalicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody, CDP-771, CMA-676, gemtuzumab, hP67.6-Calicheamicin, Mylotarg, WAY-CMA-676Treatment (GO, GCLAM)
Granulocyte Colony-Stimulating FactorColony Stimulating Factor 3, Colony-Stimulating Factor (Granulocyte), Colony-Stimulating Factor 3, CSF3, G CSF, G-CSF, Granulocyte Colony Stimulating Factor, PluripoietinTreatment (GO, GCLAM)
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanTreatment (GO, GCLAM)

Purpose

This phase I/II trial studies the side effects and best dosing frequency of gemtuzumab ozogamicin when given in combination with granulocyte colony stimulating factor (G-CSF), cladribine, cytarabine and mitoxantrone (GCLAM) and to see how well they work in treating participants with acute myeloid leukemia or high-grade myeloid tumors (neoplasms) that have not been previously treated. Antibody-drug conjugates, such as gemtuzumab ozogamicin, act by directly delivering toxic chemotherapy to cancer cells. Granulocyte colony stimulating factor is a growth factor used to stimulate leukemia cells and render them more sensitive to chemotherapy drugs. Drugs used in chemotherapy, such as cladribine, cytarabine and mitoxantrone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving gemtuzumab ozogamicin in combination with G-CSF, cladribine, cytarabine and mitoxantrone hydrochloride may work better in treating participants with acute myeloid leukemia or high-grade myeloid neoplasm.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum-tolerated dose (MTD) of gemtuzumab ozogamicin (GO) when added to
      GCLAM in patients with newly-diagnosed AML requiring induction chemotherapy. (Phase I) II. To
      evaluate the 6-month event-free survival (EFS) rate with GO + GCLAM treated at the MTD.
      (Phase II)

      SECONDARY OBJECTIVES:

      I. Describe, within the limits of a phase 1/2 study, the toxicity profile of the study
      regimen.

      II. Compare, within the limits of a phase 1/2 study, measurable residual disease (MRD) rates
      with GO + GCLAM at the MTD to patients treated previously with GCLAM alone.

      III. Estimate, within the limits of a phase 1/2 study, the relationship between MRD status
      after induction therapy and relapse risk/time to relapse as well as relapse-free and overall
      survival.

      IV. Compare, within the limits of a phase 1/2 study, complete remission rates with GO + GCLAM
      at the MTD to patients treated previously with GCLAM alone.

      V. Compare, within the limits of a phase 1/2 study, overall survival rates with GO + GCLAM at
      the MTD to patients treated previously with GCLAM alone VI. Evaluate, within the limits of a
      phase 1/2 study, the impact of GO dosing regimens on the duration of cytopenias.

      VII. Collect biological specimens for use for the future laboratory investigation of
      biomarkers for response to GO.

      OUTLINE: This is a phase I dose escalation study of gemtuzumab ozogamicin followed by a phase
      II study.

      INDUCTION THERAPY: Participants receive gemtuzumab ozogamicin intravenously (IV) either as a
      single dose on day 1, or as three doses on days 1, 4, and 7. Participants also receive G-CSF
      subcutaneously (SC) on days 0-5, cladribine IV over 2 hours on days 1-5, cytarabine IV over 2
      hours on days 1-5, and mitoxantrone hydrochloride IV on days 1-3. Patients who do not achieve
      a CR or CRi following the first course of induction are eligible for a second course, which
      is given without gemtuzumab ozogamicin. Participants with a complete remission (CR) or
      complete remission with incomplete count recovery (CRi) may then proceed to Post-Remission
      Therapy.

      POST-REMISSION THERAPY: Participants receive G-CSF, cladribine, and cytarabine as in
      Induction Therapy during course 1, and cytarabine IV every 12 hours on days 1-6 of courses
      2-3. Treatment repeats every month for up to 3 courses in the absence of disease progression
      or unacceptable toxicity.

      After completion of study treatment, participants are followed up every 3 months for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (GO, GCLAM)ExperimentalINDUCTION THERAPY: Participants receive gemtuzumab ozogamicin IV either as a single dose on day 1, or as three doses on days 1, 4, and 7. Participants also receive G-CSF SC on days 0-5, cladribine IV over 2 hours on days 1-5, cytarabine IV over 2 hours on days 1-5, and mitoxantrone hydrochloride IV on days 1-3. Patients who do not achieve a CR or CRi following the first course of induction are eligible for a second course, which is given without gemtuzumab ozogamicin. Participants with a CR or CRi may then proceed to Post-Remission Therapy. POST-REMISSION THERAPY: Participants receive G-CSF, cladribine, and cytarabine as in Induction Therapy during course 1, and cytarabine IV every 12 hours on days 1-6 of courses 2-3. Treatment repeats every month for up to 3 courses in the absence of disease progression or unacceptable toxicity.
  • Cladribine
  • Cytarabine
  • Gemtuzumab Ozogamicin
  • Granulocyte Colony-Stimulating Factor
  • Mitoxantrone Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of untreated "high-grade" myeloid neoplasm (≥ 10% blasts in blood or bone
             marrow) or acute myeloid leukemia (AML) other than acute promyelocytic leukemia (APL)
             with t(15;17)(q22;q12) or variants according to the 2016 World Health Organization
             (WHO) classification; outside diagnostic material is acceptable to establish
             diagnosis; submission of peripheral blood specimen for flow cytometry performed at the
             study institution should be considered; diagnostic material must have been submitted
             for cytogenetic and/or molecular testing as clinically appropriate

          -  Medically fit, as defined by treatment-related mortality (TRM) score ≤13.1 calculated
             with simplified model

          -  The use of hydroxyurea prior to study registration is allowed; patients with
             symptoms/signs of hyperleukocytosis or white blood cells (WBC) > 100,000/uL can be
             treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500
             mg/m^2/dose) prior to enrollment

          -  Patients may have received low-intensity treatment (e.g. azacitidine/decitabine,
             lenalidomide, growth factors) for antecedent low-grade myeloid neoplasm (i.e. < 10%
             blasts in blood and bone marrow)

          -  Bilirubin ≤ 2.5 x institutional upper limit of normal (IULN) unless elevation is
             thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
             (assessed within 14 days prior to study day 0)

          -  Serum creatinine ≤ 2.0 mg/dL (assessed within 14 days prior to study day 0)

          -  Left ventricular ejection fraction ≥ 45%, assessed within 12 months prior to study day
             0, e.g. by multigated acquisition (MUGA) scan or echocardiography, or other
             appropriate diagnostic modality and no clinical evidence of congestive heart failure

          -  Women of childbearing potential and men must agree to use adequate contraception

          -  Provide written informed consent

        Exclusion Criteria:

          -  Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not
             considered candidate for tyrosine kinase inhibitor treatment

          -  Concomitant illness associated with a likely survival of < 1 year

          -  Active systemic fungal, bacterial, viral, or other infection, unless disease is under
             treatment with anti-microbials, and/or controlled or stable (e.g. if specific,
             effective therapy is not available/feasible or desired [e.g. known chronic viral
             hepatitis, human immunodeficiency virus (HIV)]); patient needs to be clinically stable
             as defined as being afebrile and hemodynamically stable for 24 hours; patients with
             fever thought to be likely secondary to leukemia are eligible

          -  Known hypersensitivity to any study drug

          -  Confirmed or suspected pregnancy or active breast feeding

          -  Treatment with any other investigational anti-leukemia agent; in phase 2, treatment
             with a tyrosine kinase inhibitor for patients with FLT3-mutated AML is permissible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of gemtuzumab ozogamicin (GO) when added to GCLAM (Phase 1)
Time Frame:At time of count recovery, second cycle of treatment, response assessment or removal from protocol (at approximately 1 month).
Safety Issue:
Description:Defined as the highest dose studied in which the incidence of Dose Limiting Toxicity (DLT) is ≤33% (≤4 of 12 patients experiencing DLT), defined as any Grade 3 non-hematologic toxicity lasting >48 hours that results in >7-day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection or toxicities secondary to febrile neutropenia or infection, or any Grade ≥4 non-hematologic toxicity except febrile neutropenia/infection (or toxicities secondary to febrile neutropenia or infection) unless felt to be a direct consequence of treatment-related toxicity (e.g. intestinal infection following mucosal barrier breakdown), and with the exception of constitutional symptoms if recovery to Grade ≤2 within 14 days. The National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 will be used.

Secondary Outcome Measures

Measure:Remission rates
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated and 95% confidence intervals will be calculated. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints [Cox models for the hazard of the subdistribution for events with competing risks]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors.
Measure:Measurable residual disease (MRD) rates
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated and 95% confidence intervals will be calculated. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints [Cox models for the hazard of the subdistribution for events with competing risks]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors.
Measure:Incidence of adverse events reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated and 95% confidence intervals will be calculated. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints [Cox models for the hazard of the subdistribution for events with competing risks]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors.
Measure:EFS
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints [Cox models for the hazard of the subdistribution for events with competing risks]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors.
Measure:Relapse-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method. Time to relapse will be estimated using non-parametric estimates of the cumulative incidence curve with death analyzed as a competing event. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints [Cox models for the hazard of the subdistribution for events with competing risks]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints [Cox models for the hazard of the subdistribution for events with competing risks]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated

September 27, 2019