Gemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine & Mitoxantrone for Untreated AML & High-Grade Myeloid Neoplasm

NCT ID: NCT03531918

Last Updated: 2023-08-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-14
• Study Completion Date: 2021-11-01

Brief Summary

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 and 1-year 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 cycle of induction are eligible for a second cycle, 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 cycle 1, and cytarabine IV every 12 hours on days 1-6 of cycles 2-3. Treatment repeats every month for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

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

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (GO, GCLAM)

INDUCTION 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 cycle of induction are eligible for a second cycle, 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 cycle 1, and cytarabine IV every 12 hours on days 1-6 of cycles 2-3. Treatment repeats every month for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Cladribine

Intervention Type: DRUG

Given IV

Cytarabine

Intervention Type: DRUG

Given IV

Gemtuzumab Ozogamicin

Intervention Type: DRUG

Given IV

Recombinant Granulocyte Colony-Stimulating Factor

Intervention Type: BIOLOGICAL

Given SC

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Mitoxantrone Hydrochloride

Intervention Type: DRUG

Given IV

Interventions

Cladribine

Given IV

Intervention Type: DRUG

Cytarabine

Given IV

Intervention Type: DRUG

Gemtuzumab Ozogamicin

Given IV

Intervention Type: DRUG

Recombinant Granulocyte Colony-Stimulating Factor

Given SC

Intervention Type: BIOLOGICAL

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Mitoxantrone Hydrochloride

Given IV

Intervention Type: DRUG

Other Intervention Names

2-CdA; 2CDA; CdA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251; .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-28453; Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody; CDP-771; CMA-676; gemtuzumab; hP67.6-Calicheamicin; Mylotarg; WAY-CMA-676; 143011-72-7; Recombinant Colony-Stimulating Factor 3; rhG-CSF; CL 232315; DHAD; DHAQ; Dihydroxyanthracenedione Dihydrochloride; Mitoxantrone Dihydrochloride; Mitoxantroni Hydrochloridum; Mitozantrone Hydrochloride; Mitroxone; Neotalem; Novantrone; Onkotrone; Pralifan

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Roland B Walter

Professor, Clinical Research Division

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Roland Walter

Role: PRINCIPAL_INVESTIGATOR

Fred Hutch/University of Washington Cancer Consortium

Locations

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

NCI-2018-00776

Identifier Type: REGISTRY

Identifier Source: secondary_id

10000

Identifier Type: OTHER

Identifier Source: secondary_id

RG9218023

Identifier Type: OTHER

Identifier Source: secondary_id

10000

Identifier Type: -

Identifier Source: org_study_id