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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

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ClinicalTrials.gov Identifier: NCT03900949
Recruitment Status : Recruiting
First Posted : April 3, 2019
Last Update Posted : April 4, 2019
Sponsor:
Collaborators:
Oregon Health and Science University
Fred Hutchinson Cancer Research Center
Pfizer
Information provided by (Responsible Party):
Uma Borate, OHSU Knight Cancer Institute

Brief Summary:
This study is being done to evaluate the safety and tolerability of using the combination of gemtuzumab ozogamicin and midostaurin together with standard induction chemotherapy (cytarabine and daunorubicin) in the treatment of patients with newly diagnosed FLT-3 mutated acute myeloid leukemia (AML). The study will evaluate the benefit of adding gemtuzumab ozogamicin and midostaurin to standard induction chemotherapy efficacy, compared to standard induction for treating AML.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Daunorubicin Drug: Cytarabine Biological: Gemtuzumab Ozogamicin Drug: Midostaurin Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study to Evaluate the Safety and Preliminary Efficacy of Gemtuzumab Ozogamicin and Midostaurin When Used in Combination With Standard Cytarabine and Daunorubicin Induction for Newly Diagnosed FLT3-mutated AML.
Actual Study Start Date : March 21, 2019
Estimated Primary Completion Date : January 1, 2023
Estimated Study Completion Date : January 1, 2025


Arm Intervention/treatment
Experimental: Experimental

Participants receive one or two induction chemotherapy cycles, followed by one or two consolidation therapy cycles.

Induction includes daunorubicin (IV) days 1, 2, 3 at either 60 mg/m2 (Dose Levels 1, 2, 3) or 90 mg/m2 (Dose Level 4); cytarabine (IV) given days 1 through 7 (100 mg/m2) for 1-3 hours; ozogamuzumab ozogamicin (IV) (days 1, 4, 7), followed by midostaurin (oral) taken twice daily on Days 8 through 21. Induction may be repeated once.

Consolidation 1 consists of a 28 day cycle with high dose cytarabine (IV) (3 g/m2) given every 12 hours on Days 1, 3, and 5, with gemtuzumab ozogamicin (IV) given on Day 1, followed by midostaurin (50 mg, oral) taken twice daily on Days 8 through 21.

Consolidation 2 consists of a 28 day cycle with high dose cytarabine (IV) (3 g/m2) given every 12 hours on Days 1, 3, and 5, followed by midostaurin (50 mg, oral) taken twice daily on Days 8 through 21.

Drug: Daunorubicin
Anthrocycline component of the standard induction 7+3 chemotherapy regimen for treatment of AML.

Drug: Cytarabine
Component of standard 7+3 chemotherapy regimen for treatment of AML.
Other Name: ara-C

Biological: Gemtuzumab Ozogamicin
Anti-CD33 monoclonal antibody given during induction at different dose levels.
Other Name: Mylotarg

Drug: Midostaurin
An oral multi-kinase inhibitor with effects against FLT3, given through induction and consolidation.
Other Name: Rydapt




Primary Outcome Measures :
  1. Dose limiting toxicity during first treatment cycle [ Time Frame: 42 days after start of therapy ]
    A dose limiting toxicity (DLT) during the first treatment cycle, which is defined as: 1) any Grade 3+ non-hematological toxicity based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. and additional protocol-defined criteria; 2) a hematologic toxicity defined as: failure to recover ANC > 500/μL or platelet count > 50,000/μL (by 6 weeks after first induction or re-induction) in participants with < 5% blasts in the bone marrow, absence of myelodysplastic changes, and/or absence of evidence of disease (i.e., flow cytometry of bone marrow).


Secondary Outcome Measures :
  1. Incidents of serious adverse events [ Time Frame: 90 days after last day of study treatment or until participant receives alternative AML treatment ]
    Incidence and type of serious adverse events (SAEs) based on the NCI CTCAE v5.0

  2. Incidence of 30-day mortality [ Time Frame: 30 days after start of initial induction ]
    30 day mortality

  3. Rate of complete composite remission (CCR) [ Time Frame: End of consolidation treatment (up to 120 days) ]
    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).

  4. Objective response rate (ORR) [ Time Frame: End of consolidation treatment (up to 120 days) ]
    ORR is defined as the sum of CR, CRi, Morphologic leukemia-free state (MLFS), and Partial remission (PR)

  5. Event free survival (EFS) [ Time Frame: Date of primary refractory disease, relapse, or death from any cause (up to 24 months following end of treatment) ]
    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)

  6. Duration of response (DoR) [ Time Frame: Date of documented relapse (up to 24 months following end of treatment) ]
    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).

  7. Relapse free survival (RFS) [ Time Frame: Date of relapse or death from any cause (up to 24 months following end of treatment) ]
    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).

  8. Overall survival (OS) [ Time Frame: Date of death (up to 24 months following end of treatment) ]
    Survival



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Ability to understand and the willingness to sign a written informed consent document.
  2. Aged ≥ 18 years at time of informed consent. Both men and women and members of all races and ethnic groups will be included.
  3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  4. Newly diagnosed AML as confirmed by bone marrow and/or peripheral blood examination as indicated, with:

    1. Confirmed CD33 positivity, per institutional standards
    2. Presence of FLT3 ITD or TKD mutation as confirmed by NGS or other molecular method
  5. Participants must have the following clinical laboratory values:

    1. Aspartate aminotransferase (AST) <2.5 × upper limit of normal (ULN; local laboratory),
    2. Alanine aminotransferase (ALT) < 2.5 × ULN, and
    3. Total bilirubin < 2 × ULN (except for patients with known Gilbert's syndrome).
    4. Adequate renal function as defined by calculated creatinine clearance (according to the Cockcroft-Gault equation) > 40 mL/min OR serum creatinine < 1.5 × the ULN.
  6. 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.
  7. 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:

  1. Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement to enter study)
  2. Acute promyelocytic leukemia (per World Health Organization classification50)
  3. Active central nervous system (CNS) involvement by AML, as assessed at discretion of PI or treating physician and confirmed by lumbar puncture.
  4. Except for hydroxyurea, no other prior systemic anti-AML therapies may have been received prior to starting study therapy.
  5. Known history of veno-occlusive disease
  6. Known active human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C infection
  7. 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
  8. Patients with uncontrolled infection will not be enrolled until infection is treated
  9. Any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.
  10. Inability to take oral medication
  11. Hypersensitivity to any study agent, or its excipients, when administered alone
  12. Pregnancy or breastfeeding at the time of enrollment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03900949


Contacts
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Contact: Uma Borate, MD 503-494-5058 borate@ohsu.edu
Contact: Basak Gokcora 503-494-2929 gokcora@ohsu.edu

Locations
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United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Uma Borate, MD    503-494-5058    borate@ohsu.edu   
Sponsors and Collaborators
OHSU Knight Cancer Institute
Oregon Health and Science University
Fred Hutchinson Cancer Research Center
Pfizer

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Responsible Party: Uma Borate, Principal Investigator, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT03900949     History of Changes
Other Study ID Numbers: STUDY00018684
NCI-2019-01726 ( Other Identifier: NCI )
HEM-18147-L ( Other Identifier: OHSU Knight Cancer Institute )
First Posted: April 3, 2019    Key Record Dates
Last Update Posted: April 4, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Uma Borate, OHSU Knight Cancer Institute:
Acute Myeloid Leukemia
FLT3
FLT-3
Additional relevant MeSH terms:
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Cytarabine
Daunorubicin
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Gemtuzumab
Midostaurin
Staurosporine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Immunological
Protein Kinase Inhibitors