Back to resultsGemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine & Mitoxantrone for Untreated AML & High-Grade Myeloid Neoplasm
Primary Purpose
Acute Myeloid Leukemia
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cladribine
Cytarabine
Gemtuzumab Ozogamicin
Recombinant Granulocyte Colony-Stimulating Factor
Laboratory Biomarker Analysis
Mitoxantrone Hydrochloride
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia
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
Sites / Locations
- Fred Hutch/University of Washington Cancer Consortium
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (GO, GCLAM)
Arm Description
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.
Outcomes
Primary Outcome Measures
Maximum Tolerated Dose (MTD) of Gemtuzumab Ozogamicin (GO) When Added to GCLAM (Phase 1)
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.
Event-free Survival (EFS) Rate (Phase 2)
A two-stage design will be used to evaluate the EFS. Patients treated at the maximum tolerated dose (MTD) from the phase 1 portion of the trial will be used in the phase 2 analysis. If censoring occurs, secondary analyses analyzing 6-month or 1-year EFS accounting for censoring will be done, including estimating 6-month or 1-year EFS using the Kaplan-Meier method. The first stage of the two-stage phase 2 design will evaluate 30 patients. If 20 or more of the first 30 patients are alive without event at 6-months after study registration, an additional 30 patients will be enrolled. If 46 or more of the 60 patients treated at the MTD are alive and without event at 6-months after study registration, the study will consider the regimen of interest for further investigation. Patients last known to be alive in CR were censored at date of last contact.
Secondary Outcome Measures
30-day All-cause Mortality
As a summary of adverse events (captured on trial using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), 30-day all cause mortality is reported as a percent of patients treated at the MTD/RP2D.
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.
Relapse-free Survival of GO3 Cohort
RFS was calculated for participants who achieved a complete remission (with or without count recovery; CR or CRi) and measured from the date remission to the first of relapse from CR/CRi or death from any cause. Patients last known to be alive in CR /CRi were censored at date of last contact. 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.
Overall Survival
OS was calculated for all participants and measured from initial trial therapy to death from any cause. Patients last known ot be alive were censored at date of last contact. 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.
Measurable Residual Disease (MRD) Rates and Remission Rates: CR
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.
Complete response (CR) rate is defined as the frequency of patients achieving CR, which is defined by the European LeukemiaNet 2017 guidelines as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 x 109/L (1000/mL); platelet count ≥100 x 109/L. (100 000/mL). MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance tests were not performed.
Measurable Residual Disease (MRD) and Remission Rates: CRi (MRDneg)
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.
Complete response with incomplete hematologic recovery (CRi) rate is defined as the frequency of patients achieving CRi, which is defined by the European LeukemiaNet 2017 guidelines as all CR criteria except for residual neutropenia (ANC <1.0 x 109/L [1000/mL]) or thrombocytopenia (platelet count <100 x 109/L [100,000/mL]). MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance tests were not performed.
Measurable Residual Disease (MRD) and Remission Rates: CR/CRi
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.
Complete response (CR) + complete response with incomplete hematologic recovery (CRi) rate is defined as the frequency of patients achieving CR or CRi per the European LeukemiaNet 2017 criteria as defined above. MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance tests were not performed.
Measurable Residual Disease (MRD) and Remission Rates: MLFS (MRDneg)
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.
Morphologic leukemia free state (MLFS) rate is defined as the frequency of patients achieving MLFS, which is defined by the European LeukemiaNet guidelines as bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required. At least 200 cells should be enumerated or cellularity should be at least 10%. MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance
Measurable Residual Disease (MRD) and Remission Rates: Alapasia (MRDneg)
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.
o Aplasia rate is defined in this protocol as frequency of patients without blood count recovery after chemotherapy and bone marrow examination showing hypocellularity not meeting cellularity criteria for morphologic leukemia free state (MLFS). MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance tests were not performed.
Full Information
NCT ID
NCT03531918
First Posted
May 9, 2018
Last Updated
August 10, 2023
Sponsor
Fred Hutchinson Cancer Center
Collaborators
Pfizer
1. Study Identification
Unique Protocol Identification Number
NCT03531918
Brief Title
Gemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine & Mitoxantrone for Untreated AML & 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 for Previously Untreated Adult Acute Myeloid Leukemia or High-Grade Myeloid Neoplasm
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
September 14, 2018 (Actual)
Primary Completion Date
July 1, 2021 (Actual)
Study Completion Date
November 1, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
Pfizer
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
66 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment (GO, GCLAM)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cladribine
Other Intervention Name(s)
2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
.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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Gemtuzumab Ozogamicin
Other Intervention Name(s)
Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody, CDP-771, CMA-676, gemtuzumab, hP67.6-Calicheamicin, Mylotarg, WAY-CMA-676
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Recombinant Granulocyte Colony-Stimulating Factor
Other Intervention Name(s)
143011-72-7, Recombinant Colony-Stimulating Factor 3, rhG-CSF
Intervention Description
Given SC
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Mitoxantrone Hydrochloride
Other Intervention Name(s)
CL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, Pralifan
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) of Gemtuzumab Ozogamicin (GO) When Added to GCLAM (Phase 1)
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.
Time Frame
At time of count recovery, second cycle of treatment, response assessment or removal from protocol (at approximately 1 month).
Title
Event-free Survival (EFS) Rate (Phase 2)
Description
A two-stage design will be used to evaluate the EFS. Patients treated at the maximum tolerated dose (MTD) from the phase 1 portion of the trial will be used in the phase 2 analysis. If censoring occurs, secondary analyses analyzing 6-month or 1-year EFS accounting for censoring will be done, including estimating 6-month or 1-year EFS using the Kaplan-Meier method. The first stage of the two-stage phase 2 design will evaluate 30 patients. If 20 or more of the first 30 patients are alive without event at 6-months after study registration, an additional 30 patients will be enrolled. If 46 or more of the 60 patients treated at the MTD are alive and without event at 6-months after study registration, the study will consider the regimen of interest for further investigation. Patients last known to be alive in CR were censored at date of last contact.
Time Frame
From the start of study treatment, assessed at 6 months and 1 year
Secondary Outcome Measure Information:
Title
30-day All-cause Mortality
Description
As a summary of adverse events (captured on trial using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), 30-day all cause mortality is reported as a percent of patients treated at the MTD/RP2D.
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.
Time Frame
Up to 5 years. 30-day all-cause mortality is reported
Title
Relapse-free Survival of GO3 Cohort
Description
RFS was calculated for participants who achieved a complete remission (with or without count recovery; CR or CRi) and measured from the date remission to the first of relapse from CR/CRi or death from any cause. Patients last known to be alive in CR /CRi were censored at date of last contact. 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.
Time Frame
Up to 5 years. 2-year RFS reported.
Title
Overall Survival
Description
OS was calculated for all participants and measured from initial trial therapy to death from any cause. Patients last known ot be alive were censored at date of last contact. 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.
Time Frame
3 years and 1 month
Title
Measurable Residual Disease (MRD) Rates and Remission Rates: CR
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.
Complete response (CR) rate is defined as the frequency of patients achieving CR, which is defined by the European LeukemiaNet 2017 guidelines as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 x 109/L (1000/mL); platelet count ≥100 x 109/L. (100 000/mL). MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance tests were not performed.
Time Frame
90 days
Title
Measurable Residual Disease (MRD) and Remission Rates: CRi (MRDneg)
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.
Complete response with incomplete hematologic recovery (CRi) rate is defined as the frequency of patients achieving CRi, which is defined by the European LeukemiaNet 2017 guidelines as all CR criteria except for residual neutropenia (ANC <1.0 x 109/L [1000/mL]) or thrombocytopenia (platelet count <100 x 109/L [100,000/mL]). MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance tests were not performed.
Time Frame
90 days
Title
Measurable Residual Disease (MRD) and Remission Rates: CR/CRi
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.
Complete response (CR) + complete response with incomplete hematologic recovery (CRi) rate is defined as the frequency of patients achieving CR or CRi per the European LeukemiaNet 2017 criteria as defined above. MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance tests were not performed.
Time Frame
90 days
Title
Measurable Residual Disease (MRD) and Remission Rates: MLFS (MRDneg)
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.
Morphologic leukemia free state (MLFS) rate is defined as the frequency of patients achieving MLFS, which is defined by the European LeukemiaNet guidelines as bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required. At least 200 cells should be enumerated or cellularity should be at least 10%. MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance
Time Frame
90 days
Title
Measurable Residual Disease (MRD) and Remission Rates: Alapasia (MRDneg)
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.
o Aplasia rate is defined in this protocol as frequency of patients without blood count recovery after chemotherapy and bone marrow examination showing hypocellularity not meeting cellularity criteria for morphologic leukemia free state (MLFS). MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry.
Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS.
Statistical significance tests were not performed.
Time Frame
90 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roland Walter
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Gemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine & Mitoxantrone for Untreated AML & High-Grade Myeloid Neoplasm
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