Cytarabine With or Without VNP40101M in Treating Patients With Relapsed Acute Myeloid Leukemia

A Phase III Randomized of Cloretazine™ (VNP40101M) and Cytosine Arabinoside (AraC) in Patients With Acute Myeloid Leukemia in First Relapse

RATIONALE: Drugs used in chemotherapy, such as cytarabine and VNP40101M, 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 III trial is studying cytarabine and VNP40101M to see how well they work compared to cytarabine alone in treating patients with relapsed acute myeloid leukemia.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: cytarabine; Other: placebo; Drug: laromustine

Detailed Description

OBJECTIVES:

Primary

• Compare the complete response (CR) and CR (with platelet count < 100,000/mm^3 but ≥ 20,000/mm^3 [transfusion independent for ≥ 7 consecutive days]) (CRp) rates in patients with acute myeloid leukemia in first relapse treated with cytarabine with vs without VNP40101M.

Secondary

• Compare time to progression in patients treated with these regimens.
• Compare duration of response in patients treated with these regimens.
• Compare the survival of patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, parallel group, multicenter study. Patients are stratified according to age (< 60 years vs ≥ 60 years) and duration of first complete response (CR) or CR (with platelet count < 100,000/mm³ but ≥ 20,000/mm³ [transfusion independent for ≥ 7 consecutive days]) (CRp) (< 12 months vs ≥ 12 months).

• Induction therapy: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive cytarabine IV continuously on days 1-3 and VNP40101M IV over 30-60 minutes on day 2 (at least 12 hours after the start of cytarabine).
  • Arm II: Patients receive cytarabine as in arm I and placebo IV over 30-60 minutes on day 2 (at least 12 hours after the start of cytarabine).

In both arms, patients demonstrating at least 20% reduction of blasts in bone marrow (based on total cellularity and percent blasts) after course 1 may receive 1 additional course of induction therapy between days 35-60 in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp after 1 or 2 courses of induction therapy proceed to consolidation therapy.

• Consolidation therapy: Beginning 6 weeks after initial documentation of CR or CRp, patients receive 1 course of consolidation therapy, as per induction therapy, according to their randomized treatment arm. These patients may then proceed to other consolidation, maintenance, and/or intensification therapy (including stem cell transplantation) off study at the discretion of the physician.

After completion of study treatment, patients are followed monthly for 6 months, every 2 months for 6 months, and then every 3 months for 2 years.

PROJECTED ACCRUAL: A total of 420 patients (280 in arm I and 140 in arm II) will be accrued for this study within 24-30 months.

• Study Type: Interventional
• Enrollment (Anticipated): 420
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Leuven, Belgium, B-3000
    • U.Z. Gasthuisberg
  • Montigny-le-Tilleul, Belgium, 6110
    • CHU Charleroi - Site Vesale
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E3
      • Vancouver Hospital and Health Science Center
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Saint John Regional Hospital
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Memorial University of Newfoundland
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Capital District Health Authority Center for Clinical Research
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital Regional Cancer Centre - General Campus
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
• France
  • Besancon, France, 25030
    • Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
  • Lyon, France, 69437
    • Hôpital Edouard Herriot
  • Marseille, France, 13273
    • Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
  • Nantes, France, 44093
    • CHR Hotel Dieu
  • Pessac, France, 33604
    • Hôpital Haut Levêque
• Germany
  • Berlin, Germany, D-12200
    • Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin
  • Cologne, Germany, D-50924
    • Medizinische Universitaetsklinik I at the University of Cologne
  • Frankfurt, Germany, D-60596
    • Universitaetsfrauenklinik Frankfurt
  • Heidelberg, Germany, D-69115
    • Universitätsklinikum Heidelberg
  • Muenster, Germany, D-48149
    • Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster
  • Munich, Germany, D-81377
    • Klinikum der Universitaet Muenchen - Grosshadern Campus
  • Wurzburg, Germany, D-97070
    • University Würzburg
• Greece
  • Athens, Greece, 10676
    • Evaggelismos Hospital
  • Rio Patras, Greece, GR-26500
    • University of Patras Medical School
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen
• Poland
  • Gdansk, Poland, 80-211
    • Medical University of Gdansk
  • Lodz, Poland, 90-419
    • Medical University of Lodz
  • Lublin, Poland, 20-954
    • Centrum Onkologii Ziemi Lubelskiez
  • Warsaw, Poland, 00-957
    • Institute of Haematology and Blood Transfusion
  • Warsaw, Poland, 00-909
    • Wojskowy Instytut Medyczny
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Centre of Serbia
  • Nis, Serbia, 18000
    • Clinical Centre Nis
  • Novi Sad, Serbia, 21000
    • Clinic Centre Novi Sad
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B9 5SS
      • Birmingham Heartlands Hospital
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust
    • Leicester, England, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary
    • London, England, United Kingdom, SE5 9RS
      • King's College Hospital
    • Manchester, England, United Kingdom, M13 9WL
      • Manchester Royal Infirmary
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • University Hospital of Wales
• United States
  • California
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center at UCLA
    • Los Angeles, California, United States, 90089-9181
      • USC/Norris Comprehensive Cancer Center and Hospital
    • Orange, California, United States, 92868
      • Chao Family Comprehensive Cancer Center at University of California Irvine Medical Center
    • San Francisco, California, United States, 94115
      • UCSF Comprehensive Cancer Center
  • Connecticut
    • Hartford, Connecticut, United States, 06105
      • Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
    • Tampa, Florida, United States, 33612
      • Veterans Affairs Medical Center - Tampa (Haley)
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • American Health Network - North Meridian
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Nevada
    • Las Vegas, Nevada, United States, 89135
      • Nevada Cancer Institute
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • New Mexico Cancer Care Alliance
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Greenville, North Carolina, United States, 27858
      • Brody school of Medicine at East Carolina University
  • Ohio
    • Columbus, Ohio, United States, 43214-3998
      • Riverside Methodist Hospital Cancer Care
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15224
      • Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Houston, Texas, United States, 77030-4009
      • M.D. Anderson Cancer Center at University of Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed acute myeloid leukemia (AML)

  • Any WHO classification, excluding acute promyelocytic leukemia
  • At least 10% blasts by bone marrow aspirate and/or biopsy

• In first relapse after achieving a first complete response (CR) OR CR (with platelet count < 100,000/mm³ but ≥ 20,000/mm³ [transfusion independent for ≥ 7 consecutive days]) (CRp) that lasted ≥ 3 months but ≤ 24 months after completion of the initial induction regimen

  • Relapse confirmed by recurrence of blasts in peripheral blood, bone marrow histopathology, and/or histologically confirmed CNS or extramedullary disease

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST ≤ 3 times ULN
• Chronic hepatitis allowed

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• No myocardial infarction within the past 3 months
• No uncontrolled arrhythmias
• No uncontrolled congestive heart failure

Pulmonary

• No severe chronic obstructive pulmonary disease
• No requirement for supplemental oxygen at rest

Immunologic

• No uncontrolled active infection

  • Infections that are controlled and under active treatment with antibiotics allowed
• No evidence of invasive fungal infection by blood or tissue cultures

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• No clinical evidence of another active malignancy by tumor marker, pathology, or radiologic studies
• No other severe medical condition that would preclude study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• At least 12 hours since prior hydroxyurea

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No prior treatment while in first relapse except hydroxyurea
• No other concurrent standard or investigational treatment for AML
• No concurrent disulfiram (Antabuse®)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Induction therapy arm I; Patients receive cytarabine IV continuously on days 1-3 and VNP40101M IV over 30-60 minutes on day 2 (at least 12 hours after the start of cytarabine).	Drug: cytarabine; Given IV; Drug: laromustine; Given IV
Active Comparator: Induction therapy arm II; Patients receive cytarabine as in arm I and placebo IV over 30-60 minutes on day 2 (at least 12 hours after the start of cytarabine).	Drug: cytarabine; Given IV; Other: placebo; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Overall response rate

Secondary Outcome Measures

Outcome Measure
Toxicity
Duration of response
Overall response
Time to tumor progression

Collaborators and Investigators

• Sponsor: Vion Pharmaceuticals
• Investigators: Bonny L. Johnson, RN, MSN, Vion Pharmaceuticals

Publications and helpful links

General Publications

• Giles F, Vey N, DeAngelo D, Seiter K, Stock W, Stuart R, Boskovic D, Pigneux A, Tallman M, Brandwein J, Kell J, Robak T, Staib P, Thomas X, Cahill A, Albitar M, O'Brien S. Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse. Blood. 2009 Nov 5;114(19):4027-33. doi: 10.1182/blood-2009-06-229351. Epub 2009 Aug 26.
• Giles FJ, Stock W, Vey N, et al.: A double blind placebo-controlled randomized phase III study of high dose continuous infusion cytosine arabinoside (araC) with or without cloretazine in patients with first relapse of acute myeloid leukemia (AML). [Abstract] Blood 108 (11): A-1970, 2006.

Study record dates

Study Major Dates

• Study Start: March 1, 2005
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: June 2, 2005
• First Submitted That Met QC Criteria: June 2, 2005
• First Posted (Estimate): June 3, 2005

Study Record Updates

• Last Update Posted (Estimate): November 6, 2013
• Last Update Submitted That Met QC Criteria: November 5, 2013
• Last Verified: February 1, 2009

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); recurrent 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 acute basophilic leukemia; adult acute eosinophilic leukemia; adult erythroleukemia (M6a); adult pure erythroid leukemia (M6b)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cytarabine
• Other Study ID Numbers: CDR0000430677; VION-CLI-037