A Study of Clofarabine and Cytarabine for Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)(CLASSIC I)

NCT ID: NCT00317642

Last Updated: 2014-04-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 326 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-08-31
• Study Completion Date: 2012-01-31

Brief Summary

Clofarabine (injection) is approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients 1 to 21 years old with relapsed acute or refractory lymphoblastic leukemia (ALL) who have had at least 2 prior treatment regimens.

There is no recommended standard treatment for relapsed or refractory acute myelogenous leukemia in older patients. Cytarabine is the most commonly used drug to treat these patients. This study will determine if there is benefit by combining clofarabine with cytarabine. Patients will be randomized to receive up to 3 cycles of treatment with either placebo in combination with cytarabine or clofarabine in combination with cytarabine. Randomization was stratified by remission status following the first induction regimen (no remission [i.e., CR1 = refractory] or remission <6 months vs CR1 = remission ≥6 months). CR1 is defined as remission after first pre-study induction regimen. The safety and tolerability of clofarabine in combination with cytarabine and cytarabine alone will be monitored throughout the study.

Detailed Description

After screening and eligibility assessment, patients were randomized (in a 1:1 ratio) to receive either clofarabine or matching placebo, in addition to cytarabine. Randomization was stratified by remission status following the first induction regimen (CR1): no remission [i.e., CR1 = refractory] or remission <6 months vs remission ≥6 months. During randomization by interactive voice response system (IVRS), there were 10 participants misclassified to the CR1 <6 months stratum and 12 participants misclassified to CR1 ≥6 months stratum. The error did not affect the participants' treatment, only the stratification. Due to the misclassification, outcomes that used strata in their analysis were analyzed twice: once with the 'randomized stratification' which includes the misclassification and once with the 'calculated stratification' in which participants appear in the 'correct' strata.

Two clinical study reports were written for this study.

1. Clinical study report dated 7 April 2011 includes the entire treatment period of all participants plus much of the follow-up. At that time, 33 participants in the Clofarabine+cytarabine group and 29 participants in the placebo+cytarabine group were still being follow-up post treatment. Results were reported on clinicaltrials.gov in August 2011. Outcomes that used strata reported the 'calculated strata' on clinicaltrials.gov.

2. Clinical study report dated 9 July 2012 includes all patient treatment experience plus all long-term follow-up (a minimum of 2 years from the end of treatment or until the patient died). The study was completed at that time. Outcomes that used strata reported the 'randomized strata' on clinicaltrials.gov. AE records on clinicaltrials.gov reflect the final database.

Outcomes that changed between the two clinical study reports due to the additional long-term follow-up data are reported twice on clinicaltrials.gov (once from each clinical study report) and the appropriate report date is included in the outcome description. Outcomes from the 9 July 2012 report represent more complete data.

Conditions

Acute Myelogenous Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

clofarabine (IV formulation) and cytarabine

Participants received clofarabine (40 mg/m^2) administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m^2 administered as a 2-hour infusion. Participants could receive up to 3 cycles of treatment (induction, re-induction, and consolidation)

Complete induction cycle = 5 consecutive days of treatment

Re-induction cycle = 5 consecutive days of treatment at the original or modified dose

Consolidation cycle = 4 consecutive days of treatment at the original or modified dose

Group Type: EXPERIMENTAL

clofarabine (IV formulation)

Intervention Type: DRUG

clofarabine (IV formulation) infusion 40mg/m\^2 / day up to 3 cycles

cytarabine

Intervention Type: DRUG

cytarabine IV infusion 1g/m\^2/day for up to 3 cycles

placebo and cytarabine

Participants received placebo administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m\^2 administered as a 2-hour infusion. Patients could receive up to 3 cycles of treatment (induction, re-induction, and consolidation)

Group Type: EXPERIMENTAL

placebo

Intervention Type: DRUG

placebo (sodium Chloride) 1-hour IV infusion

cytarabine

Intervention Type: DRUG

cytarabine IV infusion 1g/m\^2/day for up to 3 cycles

Interventions

clofarabine (IV formulation)

clofarabine (IV formulation) infusion 40mg/m\^2 / day up to 3 cycles

Intervention Type: DRUG

placebo

placebo (sodium Chloride) 1-hour IV infusion

Intervention Type: DRUG

cytarabine

cytarabine IV infusion 1g/m\^2/day for up to 3 cycles

Intervention Type: DRUG

Other Intervention Names

Clolar®; Evoltra®

Eligibility Criteria

Inclusion Criteria

• Have a diagnosis of Acute Myelogenous Leukemia (AML) according to World Health Organization (WHO) classification
• Relapsed after receiving up to 2 prior induction regimens (i.e. first or second relapse)or are refractory to not more than one prior combination chemotherapy induction regimen
• Be ≥ 55 years of age
• Have an Eastern Cooperative Oncology Group (ECOG) score of 0-2
• Be able to comply with study procedures and follow-up examinations
• Be nonfertile or agree to use birth control during the study through the end of treatment visit and for at least 90 days after the last dose of study drug
• Have adequate liver and renal function as indicated by certain laboratory values

Exclusion Criteria

• Received previous treatment with clofarabine
• Received bolus, intermediate or high-dose cytarabine as induction therapy unless certain remission criteria are met
• Have received a hematopoietic stem cell transplant (HSCT) within the previous 3 months
• Have moderate or severe graft versus host disease (GVHD), whether acute or chronic
• Are receiving any other chemotherapy or investigational therapy. Patients must have been off prior AML therapy for at least 2-6 weeks prior to entering study.
• Have a psychiatric disorder that would interfere with consent, study participation, or follow-up
• Have an active, uncontrolled infection
• Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system
• Have been diagnosed with another malignancy, unless disease-free for at least 5 years; patients with treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed; patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed.
• Have clinical evidence suggestive of central nervous system (CNS) involvement with leukemia unless lumbar puncture confirms absence of leukemic blasts in the cerebrospinal fluid(CSF)
• Known HIV positivity
• Are pregnant or lactating

• Minimum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Genzyme, a Sanofi Company

Locations

Mayo Clinical Hospital

Scottsdale, Arizona, United States

Arizona Cancer Center

Tucson, Arizona, United States

University of Arkansas for Medical Sciences, Arkansas Cancer Research Center

Little Rock, Arkansas, United States

Scripps Cancer Center

La Jolla, California, United States

UCLA School of Medicine

Los Angeles, California, United States

University of Southern California, Kenneth Norris Cancer Center

Los Angeles, California, United States

Stanford Comprehensive Cancer Center

Stanford, California, United States

University of Colorado Health Science Center

Aurora, Colorado, United States

Rocky Mountain Cancer Center

Denver, Colorado, United States

Cancer Center of Central Connecticut

Southington, Connecticut, United States

Northwestern University

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

Evanston Northwestern Healthcare

Evanston, Illinois, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Kentucky, Markey Cancer Center

Lexington, Kentucky, United States

Louisiana State University Health Science Center

Shreveport, Louisiana, United States

Harold Alfond Center for Cancer Care

Augusta, Maine, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Josephine Ford Cancer Center

Detroit, Michigan, United States

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, United States

The Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, United States

Roswell Park Cancer Center

Buffalo, New York, United States

Mt. Sinai School of Medicine

New York, New York, United States

New York Medical Center

Valhalla, New York, United States

Mecklenburg Medical Group

Charlotte, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Wake Forest University School of Medicine

Winston-Salem, North Carolina, United States

Gabrail Cancer Center

Canton, Ohio, United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Oregon Health Science University

Portland, Oregon, United States

Medical University of South Carolina

Charleston, South Carolina, United States

University of Tennessee Medical Center

Knoxville, Tennessee, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

UT Southwestern Medical Center, Simmons Comprehensive Cancer Center

Dallas, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

Cancer Care Centers of South Texas

San Antonio, Texas, United States

University of Texas Health Sciences Center

San Antonio, Texas, United States

University of Utah - Huntsman Cancer Institute

Salt Lake City, Utah, United States

West Virginia University Hospitals, Mary Babb Randolph Cancer Center

Morgantown, West Virginia, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Saint John Regional Hospital

Saint John, New Brunswick, Canada

Juravinski Cancer Center

Hamilton, Ontario, Canada

Hopital Maisonneuve-Rosemont

Montreal, Quebec, Canada

Service Maladies du Sang, CHU Angers

Angers, , France

Hopital Claude Huriez CHRU de Lille

Lille, , France

Hopital Edouard Herriot

Lyon, , France

Institut Paoli Calmettes

Marseille, , France

Hopital Hotel Dieu

Nantes, , France

Hopital Purpan

Toulouse, , France

Medizinische Hochschule Hannover, Zentrum fur Innere Medizin, Abt. Haematologie / Onkologie

Hanover, , Germany

Medizinische Klinik der Technischen, Universität München

Munich, , Germany

Universitatsklinikum Ulm

Ulm, , Germany

Ospedali Riuniti Bergamo

Bergamo, , Italy

A.O Ospedale Niguarda Ca'Granda

Milan, , Italy

N.O. San Gerardo

Monza, , Italy

Azienda Ospedaliera "Antonio Cardarelli"

Napoli, , Italy

Countries

United States; Canada; France; Germany; Italy

References

Clofarabine + Ara-c improves response rates and event-free survival, not overall survival, in older patients with relapsed/refractory AML compared to Ara-c alone: Updated CLASSIC I study results. H.M. Kantarjian, M. Wetzler, D. Rizzieri, G. J. Schiller, M. H. Jagasia, R. K. Stuart, S. Ganguly, D. Avigan, M. Craig, R. Collins, M. B. Maris, T. Kovacsovics, S. Goldberg, K. Seiter, P. Hari, J. Greiner, N. Vey, C. Recher, F. Ravandi, E.S. Wang, S. Eckert, D. Huebner and S. Faderl. Haematologica - 16th Congress of EHA Abstracts. 2011; 96(S2): 196.

Reference Type: RESULT

Clofarabine plus cytarabine compared to cytarabine alone in older patients with relapsed or refractory (R/R) acute myelogenous leukemia (AML): Results from the phase III CLASSIC 1 trial. S. Faderl, M. Wetzler, D. Rizzieri, G. J. Schiller, M. H. Jagasia, R. K. Stuart, S. Ganguly, D. Avigan, M. Craig, R. Collins, M. B. Maris, T. Kovacsovics, S. Goldberg, K. Seiter, P. Hari, F. Ravandi, E. S. Wang, S. Eckert, D. Huebner, and H. Kantarjian JCO - ASCO Meeting Abstracts. 2011; 29:6503.

Reference Type: RESULT

Faderl S, Wetzler M, Rizzieri D, Schiller G, Jagasia M, Stuart R, Ganguly S, Avigan D, Craig M, Collins R, Maris M, Kovacsovics T, Goldberg S, Seiter K, Hari P, Greiner J, Vey N, Recher C, Ravandi F, Wang ES, Vasconcelles M, Huebner D, Kantarjian HM. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012 Jul 10;30(20):2492-9. doi: 10.1200/JCO.2011.37.9743. Epub 2012 May 14.

Reference Type: RESULT

PMID: 22585697 (View on PubMed)

Ganguly S, Kantarjian HM, Wetzler M, Rizzieri D, Schiller G, Jagasia M, et al. Subsequent hematopoietic stem cell transplantation (HSCT) associated with longer survival in patients with relapsed/refractory (R/R) acute myelogenous leukemia (AML) after Clo+Ara-C or Ara-C alone: a landmark analysis from the CLASSIC I trial. Biol Blood Marrow Transplant 2012;18(2Suppl):S211-S212.

Reference Type: RESULT

Ganguly S, Kantarjian HM, Wetzler M, Rizzieri D, Schiller G, Jagasia M, et al. Subsequent HSCT in the CLASSIC I Study Associated with Longer Survival in Patients With Relapsed/Refractory AML After Clo+Ara-C Or Ara-C Alone: A Landmark Analysis. Haematologica - 17th Congress of EHA Abstracts. 2012; 97(s1):32

Reference Type: RESULT

Other Identifiers

2008-001043-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLO34100405

Identifier Type: -

Identifier Source: org_study_id