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

A Phase III Randomized, Double-blind, Controlled Study Comparing Clofarabine and Cytarabine Versus Cytarabine Alone in Adult Patients 55 Years and Older With Acute Myelogenous Leukemia (AML) Who Have Relapsed or Are Refractory After Receiving up to Two Prior Induction Regimens

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.

Study Overview

• Status: Completed
• Conditions: Acute Myelogenous Leukemia
• Intervention / Treatment: Drug: clofarabine (IV formulation); Drug: cytarabine; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 326
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • New Brunswick
    • Saint John, New Brunswick, Canada
      • Saint John Regional Hospital
  • Ontario
    • Hamilton, Ontario, Canada
      • Juravinski Cancer Center
  • Quebec
    • Montreal, Quebec, Canada
      • Hôpital Maisonneuve-Rosemont
• France
  • Angers Cedex 01, France
    • Service Maladies du Sang, CHU Angers
  • Lille, France
    • Hopital Claude Huriez CHRU de Lille
  • Lyon, France
    • Hôpital Edouard Herriot
  • Marseille, France
    • Institut Paoli Calmettes
  • Nantes, France
    • Hôpital Hotel Dieu
  • Toulouse, France
    • Hopital Purpan
• Germany
  • Hannover, Germany
    • Medizinische Hochschule Hannover, Zentrum fur Innere Medizin, Abt. Haematologie / Onkologie
  • Munich, Germany
    • Medizinische Klinik der Technischen, Universität München
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
• Italy
  • Bergamo, Italy
    • Ospedali Riuniti Bergamo
  • Milano, Italy
    • A.O Ospedale Niguarda Ca'Granda
  • Monza, Italy
    • N.O. San Gerardo
  • Napoli, Italy
    • Azienda Ospedaliera "Antonio Cardarelli"
• United States
  • Arizona
    • Scottsdale, Arizona, United States
      • Mayo Clinical Hospital
    • Tucson, Arizona, United States
      • Arizona Cancer Center
  • Arkansas
    • Little Rock, Arkansas, United States
      • University of Arkansas for Medical Sciences, Arkansas Cancer Research Center
  • California
    • La Jolla, California, United States
      • Scripps Cancer Center
    • Los Angeles, California, United States
      • UCLA School of Medicine
    • Los Angeles, California, United States
      • University of Southern California, Kenneth Norris Cancer Center
    • Stanford, California, United States
      • Stanford Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States
      • University of Colorado Health Science Center
    • Denver, Colorado, United States
      • Rocky Mountain Cancer Center
  • Connecticut
    • Southington, Connecticut, United States
      • Cancer Center of Central Connecticut
  • Illinois
    • Chicago, Illinois, United States
      • Northwestern University
    • Chicago, Illinois, United States
      • Rush University Medical Center
    • Evanston, Illinois, United States
      • Evanston Northwestern Healthcare
  • Kansas
    • Kansas City, Kansas, United States
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States
      • University of Kentucky, Markey Cancer Center
  • Louisiana
    • Shreveport, Louisiana, United States
      • Louisiana State University Health Science Center
  • Maine
    • Augusta, Maine, United States
      • Harold Alfond Center for Cancer Care
  • Massachusetts
    • Boston, Massachusetts, United States
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Detroit, Michigan, United States
      • Josephine Ford Cancer Center
  • New Hampshire
    • Lebanon, New Hampshire, United States
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States
      • The Cancer Center at Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States
      • Roswell Park Cancer Center
    • New York, New York, United States
      • Mt. Sinai School of Medicine
    • Valhalla, New York, United States
      • New York Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States
      • Mecklenburg Medical Group
    • Durham, North Carolina, United States
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States
      • Wake Forest University School of Medicine
  • Ohio
    • Canton, Ohio, United States
      • Gabrail Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States
      • Oregon Health Science University
  • South Carolina
    • Charleston, South Carolina, United States
      • Medical University of South Carolina
  • Tennessee
    • Knoxville, Tennessee, United States
      • University of Tennessee Medical Center
    • Nashville, Tennessee, United States
      • Sarah Cannon Research Institute
    • Nashville, Tennessee, United States
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States
      • UT Southwestern Medical Center, Simmons Comprehensive Cancer Center
    • Houston, Texas, United States
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States
      • Cancer Care Centers of South Texas
    • San Antonio, Texas, United States
      • University of Texas Health Sciences Center
  • Utah
    • Salt Lake City, Utah, United States
      • University of Utah - Huntsman Cancer Institute
  • West Virginia
    • Morgantown, West Virginia, United States
      • West Virginia University Hospitals, Mary Babb Randolph Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States
      • Medical College Of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: clofarabine (IV formulation); clofarabine (IV formulation) infusion 40mg/m^2 / day up to 3 cycles; Other Names: Clolar®; Evoltra®; Drug: cytarabine; cytarabine IV infusion 1g/m^2/day for up to 3 cycles
Experimental: 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)	Drug: cytarabine; cytarabine IV infusion 1g/m^2/day for up to 3 cycles; Drug: placebo; placebo (sodium Chloride) 1-hour IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival - Overall and by Calculated Strata (CSR 7-April-11)	Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 calculated strata. OS was defined as the number of months from date of randomization until date of death due to any cause.	Day 1 (randomization) up to approximately 4 years
Overall Survival - Overall and by Randomized Strata (CSR 9-July-12)	Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 randomized strata. OS was defined as the number of months from date of randomization until date of death due to any cause.	Day 1 (randomization) up to approximately 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Response Per Independent Response Review Panel (IRRP) Assessment - Overall and by Calculated Strata (CSR 7-April-11)	Percentage of participants whose best response was assessed by the IRRP as complete remission (CR) or complete remission with incomplete peripheral blood count recovery (CRi) using the revised International Working Group for Response Criteria (Cheson 2003). CR is defined on morphologic criteria at a single response assessment: a bone marrow aspirate or biopsy of <5% blasts, with evidence of normal hematopoiesis;; absence of Auer rods in the blasts that are present;; absence of extramedullary disease;; absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping;; only rare evidence of circulating blasts. If present, evidence of a regenerating bone marrow;; recovery of peripheral counts (platelets ≥100*10^9/L and absolute neutrophil count (ANC) ≥1.0*10^9/L). CRi met all criteria for CR except for either residual neutropenia (ANC <1.0*10^9/L) or thrombocytopenia (platelet count <100*10^9/L).	Day 12 up to approximately 6 months
Duration of Remission (DOR) Per IRRP Assessment-Overall and by Calculated Strata (CSR 7-April-11)	DOR was defined as the time from first CR or CRi to the date of first objective documentation of disease recurrence, initiation of alternative antileukemic therapy [including hematopoietic stem cell transplant] while in remission, or death due to any cause, whichever occurred first. CR is defined on morphologic criteria at a single response assessment: a bone marrow aspirate or biopsy of <5% blasts, with evidence of normal hematopoiesis;; absence of Auer rods in the blasts that are present;; absence of extramedullary disease;; absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping;; only rare evidence of circulating blasts. If present, evidence of a regenerating bone marrow;; recovery of peripheral counts (platelets ≥100*10^9/L and absolute neutrophil count (ANC) ≥1.0*10^9/L). CRi met all criteria for CR except for either residual neutropenia (ANC <1.0*10^9/L) or thrombocytopenia (platelet count <100*10^9/L).	Day 12 to approximately 4 years
Duration of Remission (DOR) Per IRRP Assessment-Overall and by Randomized Strata (CSR 9-July-12)	DOR was defined as the time from first CR or CRi to the date of first objective documentation of disease recurrence, initiation of alternative antileukemic therapy [including hematopoietic stem cell transplant] while in remission, or death due to any cause, whichever occurred first. CR is defined on morphologic criteria at a single response assessment: a bone marrow aspirate or biopsy of <5% blasts, with evidence of normal hematopoiesis;; absence of Auer rods in the blasts that are present;; absence of extramedullary disease;; absence of a unique phenotype determined at the pretreatment specimen, as assessed by immunophenotyping;; only rare evidence of circulating blasts. If present, evidence of a regenerating bone marrow;; recovery of peripheral counts (platelets ≥100*10^9/L and absolute neutrophil count (ANC) ≥1.0*10^9/L). CRi met all criteria for CR except for either residual neutropenia (ANC <1.0*10^9/L) or thrombocytopenia (platelet count <100*10^9/L).	Day 12 to approximately 4 years
Disease-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)	Disease-free survival was defined as the time from first complete remission (CR) or complete remission with incomplete peripheral blood count recovery (CRi) until the date of first objective documentation of disease recurrence or death due to any cause, whichever occurred first. See Outcome #3 for definition of CR and CRi. Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.	Day 12 to approximately 4 years
Disease-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)	Disease-free survival was defined as the time from first complete remission (CR) or complete remission with incomplete peripheral blood count recovery (CRi) until the date of first objective documentation of disease recurrence or death due to any cause, whichever occurred first. See Outcome #3 for definition of CR and CRi. Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.	Day 12 to approximately 4 years
Event-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)	Event-free survival (EFS) was defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.	Day 1 (randomization) up to approximately 4 years
Event-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)	Event-free survival (EFS) was defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.	Day 1 (randomization) up to approximately 4 years
Four-Month Event-free Survival Per IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)	Four-month event-free survival (EFS) was defined as achieving an EFS of at least 122 days, where EFS is defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.	Day 1 (randomization) to Day 122
Four-Month Event-free Survival Per IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)	Four-month event-free survival (EFS) was defined as achieving an EFS of at least 122 days, where EFS is defined as the time from randomization to the date of treatment failure, first disease recurrence (for participants who achieved remission), or death due to any cause, whichever occurred first. Treatment Failure - ≥5% leukemic blasts by bone marrow exam, with no evidence of hematologic response (ie, <30% decrease in % leukemic blasts). Disease recurrence - reappearance of leukemic blasts in the peripheral blood, confirmed by ≥5% blasts in the bone marrow, and reappearance or development of pathologically proven extramedullary disease.	Day 1 (randomization) to Day 122
Participants With Adverse Events (CSR 7-April-11)	Number of participants with treatment emergent adverse events (TEAEs) or death due to related AE. Related AEs for the combination arm can be related to either clofarabine or cytarabine. Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, Grade 4 = Life Threatening AE, Grade 5 = Death	Day 1 up to a maximum of 4 years (includes up to a maximum of 3 cycles of therapy plus 45 days follow up. Related AEs are followed to resolution.)

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): January 1, 2012
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: April 24, 2006
• First Submitted That Met QC Criteria: April 24, 2006
• First Posted (Estimate): April 25, 2006

Study Record Updates

• Last Update Posted (Estimate): April 14, 2014
• Last Update Submitted That Met QC Criteria: March 17, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: acute myeloid leukemia; cytarabine; relapsed AML; refractory AML; acute myelogenous leukemia; clofarabine; clolar; CLO341
• 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; Clofarabine; Cytarabine
• Other Study ID Numbers: CLO34100405; 2008-001043-19 (EudraCT Number)