Clofarabine and Daunorubicin in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

A Phase II Study Evaluating Mechanisms of Resistance Following Treatment With Clofarabine and Daunorubicin in Newly Diagnosed Adult Acute Myeloid Leukemia Patients > or = to 60 Years Old

RATIONALE: Drugs used in chemotherapy, such as clofarabine and daunorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving clofarabine together with daunorubicin may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving clofarabine together with daunorubicin works in treating older patients with newly diagnosed acute myeloid leukemia.

Study Overview

• Status: Terminated
• Conditions: Leukemia
• Intervention / Treatment: Genetic: protein expression analysis; Other: pharmacological study; Drug: clofarabine; Drug: daunorubicin hydrochloride; Genetic: cytogenetic analysis; Other: immunologic technique

Detailed Description

OBJECTIVES:

Primary

• Study complete response (CR) and CR without platelet recovery (CRp) following treatment with clofarabine and daunorubicin hydrochloride in older patients with newly diagnosed acute myeloid leukemia.

Secondary

• Study disease-free and overall survival of these patients following treatment with this regimen.
• Compare disease-free and overall survival of patients whose cells do or do not demonstrate apoptosis following treatment with this regimen.

OUTLINE:

• Induction therapy: Patients receive clofarabine IV over 1 hour on days 1-5 and daunorubicin hydrochloride IV over 5 minutes on days 1, 3, and 5. Patients are assessed after induction course 1. Patients with ≥ 5% blasts in bone marrow may receive another course of induction therapy beginning between 28-84 days after initiation of course 1. Patients who achieve complete remission (CR) or CR without platelet recovery (CRp) (after 1 or 2 courses of induction therapy) proceed to consolidation therapy.
• Consolidation therapy: Beginning between 28 -84 days after initiation of last course of induction therapy, patients receive clofarabine IV over 1 hour on days 1-3 and daunorubicin hydrochloride IV over 5 minutes on days 1 and 3. Patients may receive a second course of consolidation therapy beginning between 28-84 days of consolidation course 1.

Blood and bone marrow samples are collected periodically to assess response and for pharmacokinetic, cytogenetic, immunophenotyping, and molecular analyses.

After completion of study treatment, patients are followed for at least 2 years.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Newly diagnosed acute myeloid leukemia

  • At least 10% blasts in the peripheral blood
• De novo or secondary disease
• No acute promyelocytic leukemia with t[15;17] or any other variant
• No clinical evidence of CNS disease

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN
• LVEF ≥ 45%
• Estimated glomerular filtration rate ≥ 50 mL/min
• Not pregnant or nursing
• Fertile patients must use effective barrier contraception during and for at least 6 months following study treatment
• No known HIV positivity
• Able to comply with study procedures and follow-up examinations
• No psychiatric disorders that would interfere with consent, study participation, or follow-up
• No uncontrolled systemic fungal, bacterial, viral, or other infection (i.e., exhibiting ongoing signs/symptoms related to the infection and without improvement despite appropriate antibiotics or other treatment)
• No history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo induction therapy with both agents

• No other malignancy, unless disease-free for at least 3 years following curative intent therapy

  • Nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are allowed if definitive treatment for the condition has been completed
  • Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed
• No other severe concurrent disease

PRIOR CONCURRENT THERAPY:

• No other concurrent systemic antileukemic therapy (standard or investigational)
• No concurrent cytotoxic therapy or investigational therapy
• No concurrent alternative medications (e.g., herbal or botanical for anticancer purposes)

• No prior chemotherapy

  • Prior hydroxyurea allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clorafarbine with daunorubicin; Patients receive clofarabine IV over 1 hour on days 1-5 and daunorubicin hydrochloride IV over 5 minutes on days 1, 3, and 5.	Genetic: protein expression analysis; Correlative Study; Other: pharmacological study; Correlative Study; Drug: clofarabine; IV; Drug: daunorubicin hydrochloride; IV; Genetic: cytogenetic analysis; Correlative study; Other: immunologic technique; Correlative Study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission (CR)	Complete Response/Remission (CR) was defined on morphologic criteria at a single response assessment as follows: A bone marrow aspirate or biopsy of < 5% blasts, with evidence of normal hematopoiesis; Absence of Auer rods in the blast that are present; Absence of extramedullary disease [imaging required only if obtained pretreatment for known site(s) of disease]; If applicable and available, absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping; Recovery of peripheral counts (platelets ≥100x109/L, and ANC ≥1.0x109/L). Peripheral count recovery must be documented no earlier than 7 days prior to, and no later than 14 days following, the bone marrow assessment that provides evidence of the CR. Complete Response/Remission without platelet recovery (CRp) was defined as all criteria for CR except for thrombocytopenia (platelet count ≥75x109/L).	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free Survival	Disease-free survival was defined as time from first objective documentation of CR or CRp until the date of first objective documentation of disease relapse or death due to any cause, whichever occurs first.	5 years
Overall Survival	Overall survival was defined as time from date of treatment initiation until date of death due to any cause.	4 years
Differences in Disease-free and Overall Survival Between Patients Whose Cells do or do Not Demonstrate Apoptosis Following Clofarabine and Daunorubicin Hydrochloride Therapy		4 years
Difference in Disease-free and Overall Survival According to p53R2 Protein Sizes		4 years
Difference in Disease-free and Overall Survival According to Multi-drug Resistance Protein Expression		4 years
Difference in Disease-free and Overall Survival Based on Clofarabine Triphosphate Levels		4 years
A Preliminary Relationship Between Treatment Outcome and Biologic Parameters		4 years

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Collaborators: Genzyme, a Sanofi Company
• Investigators: Principal Investigator: Meir Wetzler, MD, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: December 23, 2008
• First Submitted That Met QC Criteria: December 23, 2008
• First Posted (Estimate): December 24, 2008

Study Record Updates

• Last Update Posted (Estimate): August 17, 2016
• Last Update Submitted That Met QC Criteria: July 7, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities; 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); secondary acute myeloid leukemia; untreated adult acute myeloid 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 myelomonocytic leukemia (M4); adult erythroleukemia (M6a); adult pure erythroid leukemia (M6b)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Clofarabine; Daunorubicin
• Other Study ID Numbers: CDR0000630678; RPCI-I-132208 (Other Identifier: Roswell Park Cancer Institute)