- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03531918
Gemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine & Mitoxantrone for Untreated AML & High-Grade Myeloid Neoplasm
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 Overview
Status
Conditions
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Washington
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Seattle, Washington, United States, 98109
- Fred Hutch/University of Washington Cancer Consortium
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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. |
Correlative studies
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given SC
Other Names:
Given IV
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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).
|
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.
|
At time of count recovery, second cycle of treatment, response assessment or removal from protocol (at approximately 1 month).
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Event-free Survival (EFS) Rate (Phase 2)
Time Frame: From the start of study treatment, assessed at 6 months and 1 year
|
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.
|
From the start of study treatment, assessed at 6 months and 1 year
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
30-day All-cause Mortality
Time Frame: Up to 5 years. 30-day all-cause mortality is reported
|
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. |
Up to 5 years. 30-day all-cause mortality is reported
|
Relapse-free Survival of GO3 Cohort
Time Frame: Up to 5 years. 2-year RFS reported.
|
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.
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Up to 5 years. 2-year RFS reported.
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Overall Survival
Time Frame: 3 years and 1 month
|
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.
|
3 years and 1 month
|
Measurable Residual Disease (MRD) Rates and Remission Rates: CR
Time Frame: 90 days
|
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. |
90 days
|
Measurable Residual Disease (MRD) and Remission Rates: CRi (MRDneg)
Time Frame: 90 days
|
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. |
90 days
|
Measurable Residual Disease (MRD) and Remission Rates: CR/CRi
Time Frame: 90 days
|
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. |
90 days
|
Measurable Residual Disease (MRD) and Remission Rates: MLFS (MRDneg)
Time Frame: 90 days
|
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 |
90 days
|
Measurable Residual Disease (MRD) and Remission Rates: Alapasia (MRDneg)
Time Frame: 90 days
|
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. |
90 days
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Roland Walter, Fred Hutch/University of Washington Cancer Consortium
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Peripheral Nervous System Agents
- Antiviral Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Antineoplastic Agents, Immunological
- Adjuvants, Immunologic
- Antibiotics, Antineoplastic
- Immunoconjugates
- Immunotoxins
- Lenograstim
- Cytarabine
- Mitoxantrone
- Cladribine
- Gemtuzumab
- Calicheamicins
- 2-chloro-3'-deoxyadenosine
Other Study ID Numbers
- 10000 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)
- NCI-2018-00776 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- RG9218023 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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