Decitabine Followed by Mitoxantrone Hydrochloride, Etoposide, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes
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| ClinicalTrials.gov Identifier: NCT01729845 |
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Recruitment Status :
Completed
First Posted : November 20, 2012
Results First Posted : January 12, 2018
Last Update Posted : February 7, 2019
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Previously Treated Myelodysplastic Syndrome Recurrent Adult Acute Myeloid Leukemia | Drug: Cytarabine Drug: Decitabine Drug: Etoposide Other: Laboratory Biomarker Analysis Drug: Mitoxantrone Hydrochloride | Phase 1 Phase 2 |
PRIMARY OBJECTIVES:
I. Estimate the maximum tolerated dose (MTD) of decitabine priming followed by sequential mitoxantrone hydrochloride/etoposide/cytarabine (MEC) chemotherapy in adults with relapsed/refractory acute myeloid leukemia (AML).
SECONDARY OBJECTIVES:
I. Determine, within the limits of a Phase 1/2 study, disease response and duration of remission.
II. Identify biomarkers (e.g., deoxyribonucleic acid [DNA] methylation and/or gene expression changes) associated with treatment responses.
OUTLINE: This is a phase I, dose-escalation study of decitabine followed by a phase II study.
Patients receive decitabine intravenously (IV) on days -9 to -5 (dose level 1), days -11 to -5 (dose level 2), or days -14 to -5 (dose level 3).
INDUCTION THERAPY: Patients receive mitoxantrone hydrochloride IV on days 1-5, etoposide IV on days 1-5, and cytarabine IV on days 1-5. Patients achieving complete response (CR) or CR with incomplete platelet count recovery (CRp) may receive up to 2 courses of induction therapy and up to 2 courses of consolidation therapy.
After completion of study treatment, patients are followed up every 3 months for up to 5 years.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 52 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Mitoxantrone, Etoposide, and Cytarabine (MEC) Following Epigenetic Priming With Decitabine in Adults With Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndromes (MDS): A Phase 1/2 Study |
| Actual Study Start Date : | December 20, 2012 |
| Actual Primary Completion Date : | August 25, 2016 |
| Actual Study Completion Date : | April 3, 2017 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (decitabine, MEC)
Patients receive decitabine IV on days -9 to -5 (dose level 1), days -11 to -5 (dose level 2), or days -14 to -5 (dose level 3). INDUCTION THERAPY: Patients receive mitoxantrone hydrochloride IV on days 1-5, etoposide IV on days 1-5, and cytarabine IV on days 1-5. Patients achieving CR or CR with CRp may receive up to 2 courses of induction therapy and up to 2 courses of consolidation therapy. |
Drug: Cytarabine
Given IV
Other Names:
Drug: Decitabine Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Mitoxantrone Hydrochloride Given IV
Other Names:
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- Most Efficacious and Tolerated Dosage of Decitabine (Period 1) [ Time Frame: through day 45 ]MTD (most tolerated dose) of decitabine, measured in number of dose limiting toxicities. MTD defined as the highest dose in which the incidence of dose limiting toxicity is < 33%, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I)
- Remission Rate Including CR and CRp [ Time Frame: Up to 5 years ]
Complete remission (CR) and Complete remission with incomplete platelet recovery (CRp) categorized according to criteria recommended by International Working Groups:
Complete resolution of disease-related symptoms and signs including palpable hepatosplenomegaly; hemoglobin level at least 110 g/L, platelet count at least 100x10^9/L, and absolute neutrophil count at least 1.0 x10^9/L. In addition, all 3 blood counts should be no higher than the upper normal limit; Normal leukocyte differential; Bone marrow histologic remission defined as the presence of age-adjusted normocellularity, no more than 5% myeloblasts, and an osteomyelofibrosis grade no higher than 1.
- Duration of Relapse-free Survival (for Patients Achieving CR or CRp) [ Time Frame: Up to 5 years ]Categorized according to criteria recommended by International Working Groups.
- Overall Survival [ Time Frame: Up to 5 years ]Survival measured as of day of last contact. Categorized according to criteria recommended by International Working Groups.
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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:
- Prior diagnosis of "high-risk" myelodysplastic syndrome (MDS) (>= 10% blasts) or AML other than acute promyelocytic leukemia (APL) with t(15;17) (q22;q12) or variants according to the 2008 World Health Organization (WHO) classification; patients with biphenotypic AML are eligible
- Relapsed/persistent disease according to standard criteria requiring salvage therapy; 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
- May have previously received chemotherapy with MEC for MDS or AML
- 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 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 7 days prior to study day 1)
- Serum creatinine =< 1.5 x IULN (assessed within 7 days prior to study day 1)
- Left ventricular ejection fraction >= 40%, assessed within 3 months prior to study day 1, e.g. by multi gated acquisition (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 radiographical suspicion of cardiac dysfunction, or if the previous cardiac assessment was abnormal
- Women of childbearing potential and men must agree to use adequate contraception
- Provide written informed consent
Exclusion Criteria:
- Refractory/relapsing 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 hours; patients with fever thought to be likely secondary to leukemia are eligible
- 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): NCT01729845
| United States, Washington | |
| Kadlec Clinic Hematology and Oncology | |
| Kennewick, Washington, United States, 99336 | |
| EvergreenHealth Medical Center | |
| Kirkland, Washington, United States, 98033 | |
| Fred Hutch/University of Washington Cancer Consortium | |
| Seattle, Washington, United States, 98109 | |
| Principal Investigator: | Anna Halpern | Fred Hutch/University of Washington Cancer Consortium |
| Responsible Party: | Anna Halpern, Principal Investigator, Fred Hutchinson Cancer Research Center |
| ClinicalTrials.gov Identifier: | NCT01729845 |
| Other Study ID Numbers: |
2652.00 NCI-2012-02224 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 2652 FH#2652 2652.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ) P30CA015704 ( U.S. NIH Grant/Contract ) |
| First Posted: | November 20, 2012 Key Record Dates |
| Results First Posted: | January 12, 2018 |
| Last Update Posted: | February 7, 2019 |
| Last Verified: | February 2019 |
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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 Etoposide |
Podophyllotoxin Mitoxantrone Etoposide phosphate Decitabine Antineoplastic Agents, Phytogenic Antineoplastic Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antimetabolites, Antineoplastic Antimetabolites Antiviral Agents Anti-Infective Agents Immunosuppressive Agents |