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

Acute Myelogenous Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00317642
• Other study ID #: CLO34100405
• Secondary ID: 2008-001043-19
• Status: Completed
• Phase: Phase 3
• First received: April 24, 2006
• Last updated: March 17, 2014
• Start date: August 2006
• Est. completion date: January 2012

Study information

• Verified date: March 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationItaly: Ministry of HealthGermany: Federal Institute for Drugs and Medical DevicesFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Canada: Health Canada
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 326
• Est. completion date: January 2012
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 55 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myelogenous Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• clofarabine (IV formulation)
clofarabine (IV formulation) infusion 40mg/m^2 / day up to 3 cycles
• placebo
placebo (sodium Chloride) 1-hour IV infusion
• cytarabine
cytarabine IV infusion 1g/m^2/day for up to 3 cycles

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Italy, 

References & Publications (4)

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

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. Clof — View Citation

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+

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. Haematologi

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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.)	Yes