Gemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine and Mitoxantrone in Treating Participants With Previously Untreated Acute Myeloid Leukemia or High-Grade Myeloid Neoplasm
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| ClinicalTrials.gov Identifier: NCT03531918 |
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Recruitment Status :
Recruiting
First Posted : May 22, 2018
Last Update Posted : October 1, 2019
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Myeloid Leukemia High-Grade Myeloid Neoplasm Blasts 10 Percent or More of Bone Marrow Nucleated Cells Blasts 10 Percent or More of Peripheral Blood White Cells High Grade Myeloid Neoplasm | Drug: Cladribine Drug: Cytarabine Drug: Gemtuzumab Ozogamicin Biological: Granulocyte Colony-Stimulating Factor Other: Laboratory Biomarker Analysis Drug: Mitoxantrone Hydrochloride | Phase 1 Phase 2 |
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 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 course of induction are eligible for a second course, 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 course 1, and cytarabine IV every 12 hours on days 1-6 of courses 2-3. Treatment repeats every month for up to 3 courses 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 : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 72 participants |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 (GCLAM) for Previously Untreated Adult Acute Myeloid Leukemia or High-Grade Myeloid Neoplasm |
| Actual Study Start Date : | September 14, 2018 |
| Estimated Primary Completion Date : | July 1, 2021 |
| Estimated Study Completion Date : | July 1, 2025 |
| Arm | Intervention/treatment |
|---|---|
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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 course of induction are eligible for a second course, 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 course 1, and cytarabine IV every 12 hours on days 1-6 of courses 2-3. Treatment repeats every month for up to 3 courses in the absence of disease progression or unacceptable toxicity. |
Drug: Cladribine
Given IV
Other Names:
Drug: Cytarabine Given IV
Other Names:
Drug: Gemtuzumab Ozogamicin Given IV
Other Names:
Biological: Granulocyte Colony-Stimulating Factor Given SC
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Mitoxantrone Hydrochloride Given IV
Other Names:
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- 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.
- Event-free survival (EFS) rate (Phase 2) [ Time Frame: From the start of study treatment up to 6 months ]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 EFS accounting for censoring will be done, including estimating 6-month 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.
- Remission rates [ Time Frame: Up to 5 years ]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.
- Measurable residual disease (MRD) rates [ Time Frame: Up to 5 years ]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.
- Incidence of adverse events reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: Up to 5 years ]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.
- EFS [ Time Frame: Up to 5 years ]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.
- Relapse-free survival [ Time Frame: Up to 5 years ]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 [ Time Frame: Up to 5 years ]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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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): NCT03531918
| United States, Washington | |
| Fred Hutch/University of Washington Cancer Consortium | Recruiting |
| Seattle, Washington, United States, 98109 | |
| Contact: Roland Walter 206-667-3599 rwalter@fredhutch.org | |
| Principal Investigator: Roland Walter | |
| Principal Investigator: | Roland Walter | Fred Hutch/University of Washington Cancer Consortium |
| Responsible Party: | Fred Hutchinson Cancer Research Center |
| ClinicalTrials.gov Identifier: | NCT03531918 |
| Other Study ID Numbers: |
10000 NCI-2018-00776 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 10000 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ) P30CA015704 ( U.S. NIH Grant/Contract ) RG9218023 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ) |
| First Posted: | May 22, 2018 Key Record Dates |
| Last Update Posted: | October 1, 2019 |
| Last Verified: | September 2019 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms Neoplasms by Histologic Type Cytarabine Mitoxantrone Cladribine Gemtuzumab Lenograstim Sargramostim Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action |
Antineoplastic Agents Antiviral Agents Anti-Infective Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Adjuvants, Immunologic Analgesics Sensory System Agents Peripheral Nervous System Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Antineoplastic Agents, Immunological |