Clinical trial NCT00112554: Cytarabine With or Without VNP40101M in Treating Patients With Relapsed Acute Myeloid Leukemia
Official title: A Phase III Randomized of Cloretazine™ (VNP40101M) and Cytosine Arabinoside (AraC) in Patients With Acute Myeloid Leukemia in First Relapse
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia
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 basophilic leukemia
adult acute eosinophilic leukemia
adult erythroleukemia (M6a)
adult pure erythroid leukemia (M6b)
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)
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2005-06-03
Enrollment: 420
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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®)

Primary outcomes:
measure: Overall response rate
Secondary outcomes:
measure: Time to tumor progression
measure: Duration of response
measure: Overall response
measure: Toxicity
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center at UCLA
state: California
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center at University of California Irvine Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Hartford
country: United States
facility: Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center
state: Connecticut
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center
state: Florida
city: Tampa
country: United States
facility: Veterans Affairs Medical Center - Tampa (Haley)
state: Florida
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center at Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Indianapolis
country: United States
facility: American Health Network - North Meridian
state: Indiana
city: Baltimore
country: United States
facility: Greenebaum Cancer Center at University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Las Vegas
country: United States
facility: Nevada Cancer Institute
state: Nevada
city: Albuquerque
country: United States
facility: New Mexico Cancer Care Alliance
state: New Mexico
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Greenville
country: United States
facility: Brody School of Medicine at East Carolina University
state: North Carolina
city: Columbus
country: United States
facility: Riverside Methodist Hospital Cancer Care
state: Ohio
city: Hershey
country: United States
facility: Penn State Cancer Institute at Milton S. Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Hollings Cancer Center at Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: M.D. Anderson Cancer Center at University of Texas
state: Texas
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Montigny-le-Tilleul
country: Belgium
facility: CHU Charleroi - Site Vesale
city: Vancouver
country: Canada
facility: Vancouver Hospital and Health Science Center
state: British Columbia
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: St. John's
country: Canada
facility: Memorial University of Newfoundland
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: Capital District Health Authority Center for Clinical Research
state: Nova Scotia
city: Ottawa
country: Canada
facility: Ottawa Hospital Regional Cancer Centre - General Campus
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Besancon
country: France
facility: Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Marseille
country: France
facility: Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
city: Nantes
country: France
facility: CHR Hotel Dieu
city: Pessac
country: France
facility: Hopital Haut Leveque
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin
city: Cologne
country: Germany
facility: Medizinische Universitaetsklinik I at the University of Cologne
city: Frankfurt
country: Germany
facility: Universitaetsfrauenklinik Frankfurt
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Muenster
country: Germany
facility: Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster
city: Munich
country: Germany
facility: Klinikum der Universitaet Muenchen - Grosshadern Campus
city: Wurzburg
country: Germany
facility: University Wurzburg
city: Athens
country: Greece
facility: Evaggelismos Hospital
city: Rio Patras
country: Greece
facility: University of Patras Medical School
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Gdansk
country: Poland
facility: Medical University of Gdansk
city: Lodz
country: Poland
facility: Medical University of Lodz
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiez
city: Warsaw
country: Poland
facility: Wojskowy Instytut Medyczny
city: Warsaw
country: Poland
facility: Institute of Haematology and Blood Transfusion
city: Belgrade
country: Serbia
facility: Clinical Centre of Serbia
city: Nis
country: Serbia
facility: Clinical Centre Nis
city: Novi Sad
country: Serbia
facility: Clinic Centre Novi Sad
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: London
country: United Kingdom
facility: King's College Hospital
state: England
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
state: England
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: Wales
Study officials:
affiliation: Vion Pharmaceuticals
name: Bonny L. Johnson, RN, MSN
References:
citation: 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.
citation: 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.