Decitabine With GCLAM for Adults With Newly Diagnosed, Relapsed, or Refractory AML or High-Risk MDS
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| ClinicalTrials.gov Identifier: NCT02921061 |
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Recruitment Status :
Completed
First Posted : September 30, 2016
Results First Posted : March 17, 2020
Last Update Posted : March 17, 2020
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Mixed Phenotype Acute Leukemia Previously Treated Myelodysplastic Syndrome Recurrent Adult Acute Myeloid Leukemia Recurrent High Risk Myelodysplastic Syndrome Refractory Acute Myeloid Leukemia Refractory High Risk Myelodysplastic Syndrome Untreated Adult Acute Myeloid Leukemia | Drug: Cladribine Drug: Cytarabine Drug: Decitabine Biological: Filgrastim Other: Laboratory Biomarker Analysis Drug: Mitoxantrone Hydrochloride | Phase 1 Phase 2 |
PRIMARY OBJECTIVES:
I. Estimate the maximum tolerated dose (MTD) of decitabine when used concomitantly with filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride (G-CLAM) in patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).
II. Compare, within the limits of a phase 1/2 study, the rate of complete remission without measurable residual disease (minimal residual disease negative [MRDneg] complete remission [CR]) with decitabine + G-CLAM at the MTD compared to similar patients treated previously with G-CLAM alone.
SECONDARY OBJECTIVES:
I. Evaluate, within the limits of a phase 1/2 study, disease response (complete remission, overall response rate) relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in patients with newly-diagnosed AML / high-risk MDS.
II. Describe, within the limits of a phase 1/2 study, the toxicity profile of the study regimen.
OUTLINE: This is a dose de-escalation study of decitabine.
INDUCTION: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10. Patients also receive filgrastim subcutaneously (SC) on days 0-5, cladribine IV over 2 hours on days 1-5, cytarabine IV over 2-4 hours on days 1-5, and mitoxantrone hydrochloride IV over 60 minutes on days 1-3.
RE-INDUCTION: Patients who do not achieve MRDneg CR after first induction are eligible for re-induction. Patients receive the same treatment as during induction except that decitabine is omitted.
CONSOLIDATION THERAPY: Beginning 6 weeks after achieving MRDneg CR or CR/CR with incomplete count recovery (CRi) after induction and/or re-induction, patients are eligible to receive filgrastim, cladribine, and cytarabine as in Induction. Treatment may be repeated for up to 4 courses in the absence of disease progression or unacceptable toxicity. Subsequent consolidation cycles would be given after recovery from the previous cycle (roughly 4-6 weeks).
After completion of study treatment, patients are followed up at for 1 month and every 3 months for up to 5 years.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 28 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase 1/2 Study of Concurrent Decitabine in Combination With G-CSF, Cladribine, Cytarabine, and Mitoxantrone (G-CLAM) in Adults With Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndromes (MDS) |
| Actual Study Start Date : | November 17, 2016 |
| Actual Primary Completion Date : | October 24, 2018 |
| Actual Study Completion Date : | October 24, 2018 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (decitabine, G-CLAM)
INDUCTION: Patients receive decitabine IV over 1 hour on days 1-10. Patients also receive filgrastim SC on days 0-5, cladribine IV over 2 hours on days 1-5, cytarabine IV over 2-4 hours on days 1-5, and mitoxantrone hydrochloride IV over 60 minutes on days 1-3. RE-INDUCTION: Patients who do not achieve MRDneg CR after first induction are eligible for re-induction. Patients receive the same treatment as during induction except that decitabine is omitted. CONSOLIDATION THERAPY: Beginning 6 weeks after achieving MRDneg CR or CR/CR with CRi after induction and/or re-induction, patients are eligible to receive filgrastim, cladribine, and cytarabine as in Induction. Treatment may be repeated for up to 4 courses in the absence of disease progression or unacceptable toxicity. Subsequent consolidation cycles would be given after recovery from the previous cycle (roughly 4-6 weeks). |
Drug: Cladribine
Given IV
Other Names:
Drug: Cytarabine Given IV
Other Names:
Drug: Decitabine Given IV
Other Names:
Biological: Filgrastim Given SC
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Mitoxantrone Hydrochloride Given IV
Other Names:
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- Number of Participants Experiencing Dose Limiting Toxicities (DLTs) at the Maximum Tolerated Dose (MTD) for Decitabine When Given Together With G-CLAM Toxicities (DLTs) (Phase I) [ Time Frame: Up to 49 days ]
Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. MTD is defined as the highest dose studied in which the incidence of DLT is < 33%. Each participant was monitored for DLTs in the first 20 days of treatment. DLTs monitored included
- any grade 3 non-hematologic toxicity lasting more than 48 hours that resulted in more than a 7 day delay of the subsequent treatment cycle (except for febrile neutropenia or infection)
- any grade 4 or greater non-hematologic toxicity (except febrile neutropenia and infection unless a direct consequence of a treatment-related toxicity, and except constitutional symptoms if they recovered to grade 2 or less within 14 days)
- lack of recovery of the absolute neutrophil count to 500/microliter or greater and lack of self-sustained platelet count of at least 50,000/microliter by treatment day +49 with no evidence of residual leukemia
- Number of Participants With Minimal Residual Disease Negative (MRDneg) Complete Remission (Phase II) [ Time Frame: Up to 1 year ]Compared to historical controls of filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride (G-CLAM) alone. A Simon Minimax two-stage design will be used.
- Number of Participants Who Achieved Remission (Complete Remission [CR]/CR With Incomplete Peripheral Blood Count Recovery [CRi]) [ Time Frame: Up to 1 year ]
- Number of Participants With Overall Survival [ Time Frame: Up to 1 year ]
- Number of Participants With Relapse-free Survival [ Time Frame: Up to 1 year ]
- Number of Participants With Event-free Survival [ Time Frame: Up to 1 year ]
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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:
- For patients with newly diagnosed disease: diagnosis of "high-grade" MDS (>= 10% blasts by morphology) or AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2016 World Health Organization (WHO) classification; for patients with relapsed/refractory disease: prior diagnosis of "high-risk" MDS or non-APL AML, with relapsed/refractory disease according to 2003 recommendations of the International Working Group, requiring first or subsequent salvage therapy; patients with mixed phenotype acute leukemia (MPAL) are eligible
- Outside diagnostic material is acceptable as long as peripheral blood and/or bone marrow slides are reviewed at the study institution; flow cytometric analysis of peripheral blood and/or bone marrow should be performed according to institutional practice guidelines
- Patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT) are eligible if relapse occurs provided symptoms of graft-versus host disease are well controlled with stable use of immunosuppressive agents
- Treatment-related mortality (TRM) score =< 9.2 as calculated with simplified model
- Should be off any active therapy for AML with the exception of hydroxyurea for at least 14 days prior to study registration unless patient has rapidly progressive disease, and all grade 2-4 non-hematologic toxicities should have resolved
- May have previously received monotherapy with demethylating agents for MDS or AML or treatment with a mitoxantrone- or cladribine-based regimen for MDS or AML, including G-CLAM, but not demethylating agent as priming for or in combination with chemotherapy
- 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
- 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 registration)
- Serum creatinine =< 2.0 mg/dL (assessed within 14 days prior to registration)
- Left ventricular ejection fraction >= 45%, assessed within 3 months prior to registration, e.g. by multigated acquisition scan (MUGA) scan or echocardiography, or other appropriate diagnostic modality and no clinical evidence of congestive heart failure; if the patient had anthracycline-based therapy since the most recent cardiac assessment, cardiac evaluation should be repeated if there is clinical or radiographic suspicion of cardiac dysfunction, or if the previous cardiac assessment was abnormal
- Women of childbearing potential and men must agree to use adequate contraception
- Ability to understand and willingness to sign a written 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. chronic viral hepatitis, human immunodeficiency virus (HIV)]); patient needs to be clinically stable as defined as being afebrile and hemodynamically stable for 24-48 hours
- Known hypersensitivity to any study drug
- Pregnancy or lactation
- Patients may not be receiving any other investigational agents
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): NCT02921061
| United States, Washington | |
| Fred Hutch/University of Washington Cancer Consortium | |
| Seattle, Washington, United States, 98109 | |
| Principal Investigator: | Roland Walter | Fred Hutch/University of Washington Cancer Consortium |
Documents provided by Fred Hutchinson Cancer Research Center:
| Responsible Party: | Fred Hutchinson Cancer Research Center |
| ClinicalTrials.gov Identifier: | NCT02921061 |
| Other Study ID Numbers: |
9713 NCI-2016-01401 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 9713 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ) P30CA015704 ( U.S. NIH Grant/Contract ) RG9216023 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ) |
| First Posted: | September 30, 2016 Key Record Dates |
| Results First Posted: | March 17, 2020 |
| Last Update Posted: | March 17, 2020 |
| Last Verified: | January 2020 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Product Manufactured in and Exported from the U.S.: | Yes |
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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Myelodysplastic Syndromes Syndrome Disease Pathologic Processes Neoplasms by Histologic Type Neoplasms Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Cytarabine Decitabine |
2-chloro-3'-deoxyadenosine Mitoxantrone Cladribine 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 |