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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


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic Leukemia, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia

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Trial Information

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


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) over 60 minutes 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 over 30 minutes on days
1-5, etoposide IV over 1 hour on days 1-5, and cytarabine IV over 1 hour 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.


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 > 180 days post-transplant 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 glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum pyruvate glutamate transaminase (SPGT) (alanine aminotransferase [ALT]) =< 2 x
IULN unless elevation is thought to be due to hepatic infiltration by AML (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 28 days 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,
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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

MTD of decitabine defined as the highest dose in which the incidence of dose limiting toxicity (DLT) is < 33%, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)

Outcome Time Frame:

Day 45

Safety Issue:

Yes

Principal Investigator

Roland Walter

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Federal Government

Study ID:

2652.00

NCT ID:

NCT01729845

Start Date:

December 2012

Completion Date:

Related Keywords:

  • Adult Acute Basophilic Leukemia
  • Adult Acute Eosinophilic Leukemia
  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Basophilic, Acute
  • Leukemia, Eosinophilic, Acute
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Chronic
  • Hypereosinophilic Syndrome

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109