Clofarabine, Cytarabine, and Idarubicin in Treating Patients With Intermediate-Risk or High-Risk Acute Myeloid Leukemia or High-Risk Myelodysplasia (AML-14A)

European Organisation for Research and Treatment of Cancer (EORTC)

Status and phase: Unknown; Phase 2; Phase 1

Conditions: Leukemia; Myelodysplastic Syndromes

Treatments: Drug: clofarabine; Drug: idarubicin; Drug: cytarabine

Study type: Interventional

Funder types: Other; NETWORK

Identifiers

NCT00838240

2006-004912-28 (EudraCT Number)

GIMEMA-AML-14A

EU-20905

EORTC-06061

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as clofarabine, cytarabine, and idarubicin, 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.

PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of clofarabine and to see how well it works when given together with cytarabine and idarubicin in treating patients with intermediate-risk or high-risk acute myeloid leukemia or high-risk myelodysplasia.

Full description

OBJECTIVES:

Primary

• To determine the optimum dose of clofarabine in combination with cytarabine and idarubicin in patients with previously untreated intermediate- and high-risk acute myeloid leukemia or high-risk myelodysplasia. (Phase I)
• To determine the safety and tolerance of this regimen in order to determine the recommended phase II dose. (Phase I)
• To explore the antitumor activity of this regimen in these patients. (Phase II)
• To determine the activity expressed as complete remission (CR)/CR with incomplete hematopoietic recovery (CRi) rate following induction therapy. (Phase II)

Secondary

• To determine the activity expressed as CR/CRi rate following induction (1 or 2 courses) and consolidation therapy. (Phase I)
• To determine hematopoietic recovery (platelets and neutrophils) after induction and consolidation therapy.
• To determine safety and tolerability of this regimen. (Phase II)
• To determine activity expressed as CR/CRi rate after consolidation therapy. (Phase II)
• To determine feasibility of blood CD34 harvesting after consolidation therapy. (Phase II)
• To determine disease-free and overall survival from CR/CRi. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of clofarabine followed by an randomized phase II study. Patients are stratified according to center, and presence of poor prognostic features (WBC at diagnosis ≥ 100,000/μL vs presence of very high risk cytogenetic features -5/5q-, -7/7q-, presence of complex abnormalities [> 3 abnormalities], 3q, t[6;9], or t[9;22]). Patients are randomized to 1 of 2 treatment arms.

• Induction therapy:

  • Arm I: Patients receive idarubicin IV over 5 minutes on days 1, 3, and 5, cytarabine IV continuously on days 1-10, and clofarabine IV over 1 hour on days 2, 4, 6, 8, and 10.
  • Arm II: Patients receive idarubicin IV and cytarabine IV as in arm I. Patients also receive clofarabine IV by push injection over 10 minutes on days 2, 4, 6, 8, and 10.

• Consolidation therapy: Patients receive cytarabine IV over 2 hours every 12 hours on days 1-6 and idarubicin IV over 5 minutes once daily on days 4-6.

After completion of study therapy, patients are followed periodically for 12 months.

Enrollment: 114 estimated patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following by WHO criteria:

  • Acute myeloid leukemia (AML) (≥ 20% bone marrow blasts by bone marrow aspiration or biopsy)

    • No acute promyelocytic leukemia (M3)

    • All cytogenetic groups allowed, except for the following:

      • t(15;17)
      • t(8;21) or inv(16) AND a WBC count at diagnosis of < 100,000/μL

    • Primary or secondary AML allowed, including AML after myelodysplasia (MDS)

  • High-risk MDS (≥ 10% bone marrow blasts by bone marrow aspiration or biopsy)

• No chronic myelogenous leukemia in blast crisis or AML supervening a myeloproliferative disorder

• Previously untreated disease, except for ≤ 14 days of hydroxyurea

• No CNS leukemia

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Serum creatinine ≤ 1.0 mg/dL or glomerular filtration rate > 60 mL/min
• AST/ALT ≤ 2.5 times upper limit of normal (ULN)
• ALP ≤ 2.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for ≥ 3 months after completion of study treatment
• No active uncontrolled infection
• No HIV positivity
• No psychological, familial, sociological, or geographical conditions precluding compliance with study treatment or follow up
• No concurrent severe uncontrolled cardiovascular disease (i.e., symptomatic congestive heart failure or symptomatic ischemic heart disease [NYHA class III-IV])
• No concurrent malignant disease

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No concurrent cytotoxic drugs or experimental therapies (e.g., antiangiogenic drugs, tyrosine kinase inhibitors)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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114 participants in 2 patient groups

Arm I

Experimental group

Description:

Patients receive idarubicin IV over 5 minutes on days 1, 3, and 5, cytarabine IV continuously on days 1-10, and clofarabine IV over 1 hour on days 2, 4, 6, 8, and 10.

Treatment:

Drug: clofarabine

Drug: cytarabine

Drug: idarubicin

Arm II

Experimental group

Description:

Patients receive idarubicin IV and cytarabine IV as in arm I. Patients also receive clofarabine IV by push injection over 10 minutes on days 2, 4, 6, 8, and 10.

Treatment:

Drug: clofarabine

Drug: cytarabine

Drug: idarubicin