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Testing the Combination of Standard Induction Therapy With Gemtuzumab Ozogamicin and Midostaurin as a Novel Approach to Treating Patients With Newly Diagnosed FLT-3 Mutated Acute Myeloid Leukemia

NCT03900949

Description:

This phase I study hopes to explore how safe and tolerable is the combination of gemtuzumab ozogamicin (GO) and midostaurin, with the standard induction therapy (cytarabine and daunorubicin) in patients with newly diagnosed FLT-3 mutated Acute Myeloid Leukemia (AML). GO is FDA approved for the treatment of adults with newly diagnosed CD33 positive AML and used in combination with chemotherapy, cytarabine and daunorubicin. Midostaurin is FDA approved for use with cytarabine and daunorubicin in patients with FLT3-mutated AML. By combining standard induction therapy with GO and midostaurin, our aim is to investigate a novel approach to treating patients with newly diagnosed FLT3-mutated AML.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Suspended

Phase:

Phase 1

URL:

https://clinicaltrials.gov/show/NCT03900949

Trial Eligibility

Document

Title

  • Brief Title: Testing the Combination of Standard Induction Therapy With Gemtuzumab Ozogamicin and Midostaurin as a Novel Approach to Treating Patients With Newly Diagnosed FLT-3 Mutated Acute Myeloid Leukemia
  • Official Title: A Phase I Study to Evaluate the Safety and Tolerability of Gemtuzumab Ozogamicin and Midostaurin When Used in Combination With Standard Cytarabine and Daunorubicin Induction for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: STUDY00018684
  • SECONDARY ID: NCI-2019-01726
  • SECONDARY ID: STUDY00018684
  • NCT ID: NCT03900949

Conditions

  • 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 (gemtuzumab ozogamicin, cytarabine, daunorubicin)
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 (gemtuzumab ozogamicin, cytarabine, daunorubicin)
Gemtuzumab OzogamicinCalicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody, CDP-771, CMA-676, gemtuzumab, hP67.6-Calicheamicin, Mylotarg, WAY-CMA-676Treatment (gemtuzumab ozogamicin, cytarabine, daunorubicin)
MidostaurinCGP 41251, CGP41251, N-Benzoyl-Staurosporine, N-Benzoylstaurosporine, PKC-412, PKC412, RydaptTreatment (gemtuzumab ozogamicin, cytarabine, daunorubicin)

Purpose

This phase I study hopes to explore how safe and tolerable is the combination of gemtuzumab ozogamicin (GO) and midostaurin, with the standard induction therapy (cytarabine and daunorubicin) in patients with newly diagnosed FLT-3 mutated Acute Myeloid Leukemia (AML). GO is FDA approved for the treatment of adults with newly diagnosed CD33 positive AML and used in combination with chemotherapy, cytarabine and daunorubicin. Midostaurin is FDA approved for use with cytarabine and daunorubicin in patients with FLT3-mutated AML. By combining standard induction therapy with GO and midostaurin, our aim is to investigate a novel approach to treating patients with newly diagnosed FLT3-mutated AML.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the maximum tolerated dose (MTD) of combining gemtuzumab ozogamicin (GO) to the
      induction regimen of cytarabine and daunorubicin (DA) and midostaurin.

      SECONDARY OBJECTIVES:

      I. To assess the frequency of early death associated with study treatment. II. To evaluate
      the preliminary efficacy of the study treatment. III. To assess the safety profile of the
      study treatment.

      EXPLORATORY OBJECTIVES:

      I. Quantify CD33 expression on acute myeloid leukemia (AML) blasts. II. Determine the CD33
      single-nucleotide polymorphism (SNP) status previously reported to correlate with response
      and correlate clinical outcomes of patients with the CD33 genotype.

      OUTLINE: This is a dose finding study to identify the maximum tolerated dose (MTD) schedule
      of GO, and its safety and tolerability in combination with midostaurin in FLT3-mutated newly
      diagnosed AML patients.

      INDUCTION THERAPY: Patients receive cytarabine intravenously (IV) on days 1-7, daunorubicin
      IV on days 1-3 and midostaurin 50mg orally (PO) twice daily (BID) on days 8-21. Patients also
      receive gemtuzumab ozogamicin IV either on day or days 1 and 4 or days 1, 4 and 7 depending
      on dose level in the absence of disease progression or unacceptable toxicity.

      RE-INDUCTION THERAPY: Between days 14 and 21 of Induction Therapy, patients who achieve at
      least 5% bone marrow blasts after an optional bone marrow biopsy may receive a single 28-day
      cycle of cytarabine and daunorubicin with or without midostaurin per the treating physician.
      Patients who achieve a complete remission (CR) or complete remission with incomplete blood
      count recovery (CRi) may undergo allogeneic stem cell transplantation (SCT) or receive
      consolidation therapy.

      CONSOLIDATION THERAPY:

      PATIENTS < 60 YEARS: Patients receive high dose cytarabine (HiDAC) IV on days 1, 3, and 5 and
      gemtuzumab ozogamicin IV on day 1 of cycle 1 and midostaurin 50mg PO BID on days 8-21.
      Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or
      unacceptable toxicity.

      PATIENTS >= 60 YEARS: Patients receive cytarabine (MiDAC) IV on days 1, 3, and 5 and
      gemtuzumab ozogamicin IV on day 1 of cycle 1 and midostaurin 50mg PO BID on days 8-21.
      Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 24 months.

Trial Arms

NameTypeDescriptionInterventions
Treatment (gemtuzumab ozogamicin, cytarabine, daunorubicin)ExperimentalINDUCTION THERAPY: Cytarabine intravenously (IV) on days 1-7, daunorubicin IV on days 1-3 and midostaurin 50 mg orally (PO) twice daily (BID) on days 8-21. Gemtuzumab ozogamicin IV may be given either on days 1, or days 1 and 4 or days 1, 4 and 7. RE-INDUCTION THERAPY: Between days 14 and 21 of Induction Therapy, patients may receive a single 28-day cycle of cytarabine and daunorubicin with or without midostaurin per the treating physician. Patients may also undergo allogeneic stem cell transplantation (SCT) or receive consolidation therapy. CONSOLIDATION THERAPY: PATIENTS < 60 YEARS: high dose cytarabine (HiDAC) IV on days 1, 3, and 5 and gemtuzumab ozogamicin IV on day 1 of cycle 1 and midostaurin 50 mg PO BID on days 8-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. PATIENTS >= 60 YEARS: Same as above except cytarabine (MiDAC) IV on days 1, 3, and 5.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Gemtuzumab Ozogamicin
  • Midostaurin

Eligibility Criteria

        Inclusion Criteria:

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

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Newly diagnosed AML as confirmed by bone marrow and/or peripheral blood examination as
             indicated, with:

               -  Confirmed CD33 positivity, per institutional standards

               -  Presence of FLT3 internal tandem duplication (ITD) or tyrosine kinase domain
                  (TKD) mutation as confirmed by next-generation sequencing (NGS) or other
                  molecular method

          -  Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN; local laboratory)

          -  Alanine aminotransferase (ALT) < 2.5 x ULN

          -  Total bilirubin < 2 x ULN (except for patients with known Gilbert's syndrome)

          -  Calculated creatinine clearance (according to the Cockcroft-Gault equation) > 40
             mL/min OR serum creatinine < 1.5 x the ULN

          -  Female patients of childbearing potential must agree to use adequate contraception (2
             forms of contraception or abstinence) from the screening visit until 6 months
             following 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

          -  Male patients of childbearing potential having intercourse with females of
             childbearing potential must agree to abstain from heterosexual intercourse or have
             their partner use 2 forms of contraception from the screening visit until 3 months
             following the last dose of study treatment. They must also refrain from sperm donation
             from the screening visit until 90 days following the last dose of study treatment

        Exclusion Criteria:

          -  Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement to
             enter study)

          -  Acute promyelocytic leukemia (per World Health Organization classification)

          -  Active central nervous system (CNS) involvement by AML, as assessed at discretion of
             principal investigator (PI) or treating physician and confirmed by lumbar puncture

          -  Except for hydroxyurea, no other prior systemic anti-AML therapies may have been
             received prior to starting study therapy

          -  Known history of veno-occlusive disease

          -  Known active human immunodeficiency virus (HIV), active hepatitis B or active
             hepatitis C infection

          -  Patients with the following will be excluded: uncontrolled intercurrent illness
             including, but not limited to, symptomatic congestive heart failure, unstable angina
             pectoris, serious cardiac arrhythmia, myocardial infarction within 6 months prior to
             enrollment, New York Heart Association (NYHA) class III or IV heart failure, severe
             uncontrolled ventricular arrhythmias

          -  Patients with uncontrolled infection will not be enrolled until infection is treated

          -  Any concurrent condition that, in the investigator's opinion, would jeopardize the
             safety of the patient or compliance with the protocol

          -  Inability to take oral medication

          -  Hypersensitivity to any study agent, or its excipients, when administered alone

          -  Pregnancy or breastfeeding at the time of enrollment
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 combining gemtuzumab ozogamicin with cytarabine, daunorubicin, and midostaurin
Time Frame:42 days after start of last induction (i.e. induction or re-induction)
Safety Issue:
Description:The MTD will be estimated using isotonic regression. An incidence of dose limiting toxicity at each dose level will be summarized.

Secondary Outcome Measures

Measure:Incidence of 30-day treatment-related mortality
Time Frame:Up to 30 days after receiving initial induction therapy
Safety Issue:
Description:Will be estimated with exact confidence intervals.
Measure:Rate of complete composite remission (CCR)
Time Frame:At end of consolidation treatment (up to 120 days)
Safety Issue:
Description:Complete composite remission is defined as meeting criteria for complete remission (CR), complete remission with incomplete blood count recovery (CRi), or complete remission with incomplete platelet recovery (CRp). Will be measured and reported with 95% exact confidence intervals.
Measure:Objective response rate (ORR)
Time Frame:At end of consolidation treatment (up to 120 days)
Safety Issue:
Description:ORR is defined as the sum of CR, CRi, Morphologic leukemia-free state (MLFS), and Partial remission (PR). Will be measured and reported with 95% exact confidence intervals.
Measure:Event free survival
Time Frame:From date of primary refractory disease, or relapse from complete response (CR) or complete remission with incomplete blood count recovery (CRi) , or death from any cause, assessed up to 24 months
Safety Issue:
Description:EFS will be measured from start of on-study therapy (i.e., Day 1) to the date of primary refractory disease, relapse from CR or CRi, or death from any cause. Participants not known to have failed induction therapy, relapsed, or died at time of last follow-up will be censored on the date they were last examined (i.e., 2 years following completion of on-study therapy). The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available.
Measure:Duration of response
Time Frame:From date of first documented response (CR, CRi) to date of documented relapse, assessed up to 24 months
Safety Issue:
Description:For only participants that achieve CR or CRi, the DoR is measured from the date of first documented response (CR, CRi) until the date of relapse. Participants not known to have relapsed at time of last follow-up will be censored on the date they were last examined (i.e., 2 years following completion of on-study therapy). The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available.
Measure:Relapse-free survival
Time Frame:From date of first documented response (CR, CRi) to date of relapse or death from any cause, assessed up to 24 months
Safety Issue:
Description:For only participants that achieve CR or CRi, RFS will be measured from the date of first documented response (CR, CRi) to the date of relapse or death from any cause. Participants not known to have relapsed or died at time of last follow-up will be censored on the date they were last examined (i.e., 2 years following completion of on-study therapy). The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available.
Measure:Overall survival
Time Frame:From start of treatment until death, assessed up to 24 months
Safety Issue:
Description:The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available.
Measure:Incidence of adverse events and serious adverse events
Time Frame:Up to 90 days after last dose of treatment
Safety Issue:
Description:Will be tabulated and summarized by severity and major organ site according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Suspended
Lead Sponsor:OHSU Knight Cancer Institute

Trial Keywords

  • FLT
  • FLT-3
  • Acute Myeloid Leukemia

Last Updated

August 12, 2021