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

Information source: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Acute Biphenotypic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia

Intervention: Cytarabine (Drug); Decitabine (Drug); Etoposide (Drug); Laboratory Biomarker Analysis (Other); Mitoxantrone Hydrochloride (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center

Official(s) and/or principal investigator(s):
Anna Halpern, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

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 that has returned after a period of improvement or does not respond to treatment or high-risk myelodysplastic syndromes. 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 or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Clinical Details

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

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

MTD of decitabine 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 (Phase II)

Secondary outcome:

Disease-free survival (for patients achieving CR or CRp)

Event-free survival

Overall survival

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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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 registration)

- Serum creatinine =< 1. 5 x IULN (assessed within 7 days prior to registration)

- Left ventricular ejection fraction >= 40%, assessed within 3 months prior to

registration, 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 24-48 hours

- Known hypersensitivity to any study drug

- Pregnancy or lactation

- Patients may not be receiving any other investigational agents

Locations and Contacts

Kadlec Clinic Hematology and Oncology, Kennewick, Washington 99336, United States; Completed

EvergreenHealth Medical Center, Kirkland, Washington 98033, United States; Completed

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, Washington 98109, United States; Recruiting
Anna Halpern, Phone: 206-667-6233, Email: halpern2@uw.edu
Anna Halpern, Principal Investigator

Additional Information

Starting date: December 2012
Last updated: July 8, 2015

Page last updated: August 23, 2015

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