Clinical trial NCT00317642: A Study of Clofarabine and Cytarabine for Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)(CLASSIC I)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myelogenous Leukemia
Keywords: acute myelogenous leukemia
acute myeloid leukemia
relapsed AML
refractory AML
clofarabine
cytarabine
CLO341
clolar
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2006-04-25
Enrollment: 326
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall Survival - Overall and by Calculated Strata (CSR 7-April-11)
timeFrame: Day 1 (randomization) up to approximately 4 years
measure: Overall Survival - Overall and by Randomized Strata (CSR 9-July-12)
timeFrame: Day 1 (randomization) up to approximately 4 years
Secondary outcomes:
measure: Best Response Per Independent Response Review Panel (IRRP) Assessment - Overall and by Calculated Strata (CSR 7-April-11)
timeFrame: Day 12 up to approximately 6 months
measure: Duration of Remission (DOR) Per IRRP Assessment-Overall and by Calculated Strata (CSR 7-April-11)
timeFrame: Day 12 to approximately 4 years
measure: Duration of Remission (DOR) Per IRRP Assessment-Overall and by Randomized Strata (CSR 9-July-12)
timeFrame: Day 12 to approximately 4 years
measure: Disease-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
timeFrame: Day 12 to approximately 4 years
measure: Disease-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
timeFrame: Day 12 to approximately 4 years
measure: Event-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
timeFrame: Day 1 (randomization) up to approximately 4 years
measure: Event-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
timeFrame: Day 1 (randomization) up to approximately 4 years
measure: Four-Month Event-free Survival Per IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
timeFrame: Day 1 (randomization) to Day 122
measure: Four-Month Event-free Survival Per IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
timeFrame: Day 1 (randomization) to Day 122
measure: Participants With Adverse Events (CSR 7-April-11)
timeFrame: 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.)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinical Hospital
state: Arizona
city: Tucson
country: United States
facility: Arizona Cancer Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences, Arkansas Cancer Research Center
state: Arkansas
city: La Jolla
country: United States
facility: Scripps Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA School of Medicine
state: California
city: Los Angeles
country: United States
facility: University of Southern California, Kenneth Norris Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Health Science Center
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: Southington
country: United States
facility: Cancer Center of Central Connecticut
state: Connecticut
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Evanston
country: United States
facility: Evanston Northwestern Healthcare
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky, Markey Cancer Center
state: Kentucky
city: Shreveport
country: United States
facility: Louisiana State University Health Science Center
state: Louisiana
city: Augusta
country: United States
facility: Harold Alfond Center for Cancer Care
state: Maine
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Josephine Ford Cancer Center
state: Michigan
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Hackensack
country: United States
facility: The Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Center
state: New York
city: New York
country: United States
facility: Mt. Sinai School of Medicine
state: New York
city: Valhalla
country: United States
facility: New York Medical Center
state: New York
city: Charlotte
country: United States
facility: Mecklenburg Medical Group
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University School of Medicine
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health Science University
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center, Simmons Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Sciences Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Huntsman Cancer Institute
state: Utah
city: Morgantown
country: United States
facility: West Virginia University Hospitals, Mary Babb Randolph Cancer Center
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Hamilton
country: Canada
facility: Juravinski Cancer Center
state: Ontario
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Angers Cedex 01
country: France
facility: Service Maladies du Sang, CHU Angers
city: Lille
country: France
facility: Hopital Claude Huriez CHRU de Lille
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Nantes
country: France
facility: Hopital Hotel Dieu
city: Toulouse
country: France
facility: Hopital Purpan
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Zentrum fur Innere Medizin, Abt. Haematologie / Onkologie
city: Munich
country: Germany
facility: Medizinische Klinik der Technischen, Universität München
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Bergamo
country: Italy
facility: Ospedali Riuniti Bergamo
city: Milano
country: Italy
facility: A.O Ospedale Niguarda Ca'Granda
city: Monza
country: Italy
facility: N.O. San Gerardo
city: Napoli
country: Italy
facility: Azienda Ospedaliera "Antonio Cardarelli"
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
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+Ara-C or Ara-C alone: a landmark analysis from the CLASSIC I trial. Biol Blood Marrow Transplant 2012;18(2Suppl):S211-S212.
citation: 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