Decitabine Followed by Mitoxantrone Hydrochloride, Etoposide, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

Phase 1

Completed

Conditions: Recurrent Adult Acute Myeloid Leukemia
Previously Treated Myelodysplastic Syndrome

Interventions: Drug: Cytarabine
Drug: Decitabine
Drug: Etoposide
Other: Laboratory Biomarker Analysis
Drug: Mitoxantrone Hydrochloride

Registration Number: NCT01729845

Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary: This phase I/II trial studies the side effects and best dose of decitabine followed by mitoxantrone hydrochloride, etoposide, and cytarabine and to see how well they work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that has returned after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as mitoxantrone hydrochloride, etoposide, cytarabine, and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (decitabine, MEC)	Mitoxantrone Hydrochloride	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.
Treatment (decitabine, MEC)	Laboratory Biomarker Analysis	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.
Treatment (decitabine, MEC)	Cytarabine	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.
Treatment (decitabine, MEC)	Decitabine	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.
Treatment (decitabine, MEC)	Etoposide	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.

Primary Outcome Measures

Name	Time	Method
Most Efficacious and Tolerated Dosage of Decitabine (Period 1)	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)

Secondary Outcome Measures

Name	Time	Method
Remission Rate Including CR and CRp	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)	Up to 5 years	Categorized according to criteria recommended by International Working Groups.
Overall Survival	Up to 5 years	Survival measured as of day of last contact. Categorized according to criteria recommended by International Working Groups.

Trial Locations

Locations (3): Kadlec Clinic Hematology and Oncology
🇺🇸
Kennewick, Washington, United States
EvergreenHealth Medical Center
🇺🇸
Kirkland, Washington, United States
Fred Hutch/University of Washington Cancer Consortium
🇺🇸
Seattle, Washington, United States
Kadlec Clinic Hematology and Oncology
🇺🇸Kennewick, Washington, United States