Acute Myelogenous LeukemiaPhase 3NCT00317642
A Study of Clofarabine and Cytarabine for Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)(CLASSIC I)
A Phase 3 study testing clofarabine (IV formulation) and cytarabine in people with Acute Myelogenous Leukemia, run by Genzyme, a Sanofi Company at 57 sites in 5 countries.
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. Read more about this study
- Who is it for?
- Ages 55 years and older
- Conditions the study is for
- Acute Myelogenous Leukemia
- What is being tested?
- clofarabine (IV formulation) and cytarabine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 326 participants
- Where
- 57 sitesin 5 countries
- Study dates
- Aug 2006to Jan 2012
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
57 sites in 5 countries.
57 sites in 5 countries
United States41 sites
Harold Alfond Center for Cancer Care
Augusta, Maine
University of Colorado Health Science Center
Aurora, Colorado
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Roswell Park Cancer Center
Buffalo, New York
Gabrail Cancer Center
Canton, Ohio
Medical University of South Carolina
Charleston, South Carolina
Mecklenburg Medical Group
Charlotte, North Carolina
Northwestern University
Chicago, Illinois
Rush University Medical Center
Chicago, Illinois
UT Southwestern Medical Center, Simmons Comprehensive Cancer Center
Dallas, Texas
Rocky Mountain Cancer Center
Denver, Colorado
Josephine Ford Cancer Center
Detroit, Michigan
Duke University Medical Center
Durham, North Carolina
Evanston Northwestern Healthcare
Evanston, Illinois
The Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey
MD Anderson Cancer Center
Houston, Texas
University of Kansas Medical Center
Kansas City, Kansas
University of Tennessee Medical Center
Knoxville, Tennessee
Scripps Cancer Center
La Jolla, California
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire
University of Kentucky, Markey Cancer Center
Lexington, Kentucky
University of Arkansas for Medical Sciences, Arkansas Cancer Research Center
Little Rock, Arkansas
UCLA School of Medicine
Los Angeles, California
University of Southern California, Kenneth Norris Cancer Center
Los Angeles, California
Medical College of Wisconsin
Milwaukee, Wisconsin
West Virginia University Hospitals, Mary Babb Randolph Cancer Center
Morgantown, West Virginia
Sarah Cannon Research Institute
Nashville, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee
Mt. Sinai School of Medicine
New York, New York
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma
Oregon Health Science University
Portland, Oregon
University of Utah - Huntsman Cancer Institute
Salt Lake City, Utah
Cancer Care Centers of South Texas
San Antonio, Texas
University of Texas Health Sciences Center
San Antonio, Texas
Mayo Clinical Hospital
Scottsdale, Arizona
Louisiana State University Health Science Center
Shreveport, Louisiana
Cancer Center of Central Connecticut
Southington, Connecticut
Stanford Comprehensive Cancer Center
Stanford, California
Arizona Cancer Center
Tucson, Arizona
New York Medical Center
Valhalla, New York
Wake Forest University School of Medicine
Winston-Salem, North Carolina
France6 sites
Service Maladies du Sang, CHU Angers
Angers
Hopital Claude Huriez CHRU de Lille
Lille
Hopital Edouard Herriot
Lyon
Institut Paoli Calmettes
Marseille
Hopital Hotel Dieu
Nantes
Hopital Purpan
Toulouse
Italy4 sites
Ospedali Riuniti Bergamo
Bergamo
A.O Ospedale Niguarda Ca'Granda
Milan
N.O. San Gerardo
Monza
Azienda Ospedaliera "Antonio Cardarelli"
Naples
Canada3 sites
Juravinski Cancer Center
Hamilton, Ontario
Hopital Maisonneuve-Rosemont
Montreal, Quebec
Saint John Regional Hospital
Saint John, New Brunswick
Germany3 sites
Medizinische Hochschule Hannover, Zentrum fur Innere Medizin, Abt. Haematologie / Onkologie
Hanover
Medizinische Klinik der Technischen, Universität München
Munich
Universitatsklinikum Ulm
Ulm, 89081
About this study
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
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.
Read the 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.
- 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.
- 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
- Being tested
- clofarabine (IV formulation), placebo, cytarabine
- Keywords
- acute myelogenous leukemia, acute myeloid leukemia, relapsed AML, refractory AML, clofarabine, cytarabine, CLO341, clolar
- Medical subject headings
- Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
clofarabine (IV formulation)Drug
Also called Clolar®, Evoltra®
clofarabine (IV formulation) infusion 40mg/m^2 / day up to 3 cycles
placeboDrug
placebo (sodium Chloride) 1-hour IV infusion
cytarabineDrug
cytarabine IV infusion 1g/m^2/day for up to 3 cycles
| Study group | Role | What they receive |
|---|---|---|
| clofarabine (IV formulation) and cytarabine | Experimental | 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 Receives: Drug: clofarabine (IV formulation); Drug: cytarabine |
| placebo and cytarabine | Experimental | 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) Receives: Drug: placebo; Drug: cytarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Day 1 (randomization) up to approximately 4 years
Secondary outcomes (10)
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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Apr 2006 (estimated)
- Study startAug 2006
- Primary completionJan 2012
- Study completionJan 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Acute Myelogenous LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 326 participants (actual)
Sponsor and investigators
- Lead sponsor
- Genzyme, a Sanofi Company
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Monitor, Study director, Genzyme, a Sanofi Company
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00317642
- Sponsor's protocol ID
- CLO34100405
- Other IDs
- 2008-001043-19, 2008
- Status last verified
- Mar 2014
- First submitted
- 24 Apr 2006
- Last updated
- 14 Apr 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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.
PubMed 22585697Ganguly 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 at a glance
From the registry record, last updated by the sponsor on 14 Apr 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00317642
- Acronym / sponsor ID
- CLO34100405
- Conditions
- Acute Myelogenous Leukemia
- Keywords
- acute myelogenous leukemia, acute myeloid leukemia, relapsed AML, refractory AML, clofarabine, cytarabine, CLO341, clolar
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 326 participants (actual)
- Lead sponsor
- Genzyme, a Sanofi CompanyIndustry (pharma, biotech, devices)
- Study start
- Aug 2006
- Primary completion
- Jan 2012 (actual)
- Study completion
- Jan 2012 (actual)
- First posted
- 25 Apr 2006 (estimated)
- Results
- Posted 15 Sep 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
- 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.
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| clofarabine (IV formulation) and cytarabine | Experimental | Drug: clofarabine (IV formulation), Drug: cytarabineParticipants 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 |
| placebo and cytarabine | Experimental | Drug: placebo, Drug: cytarabineParticipants 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) |
Who may qualify
- Ages
- 55 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (12 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| clofarabine (IV formulation)Also: Clolar®, Evoltra®clofarabine (IV formulation) infusion 40mg/m^2 / day up to 3 cycles | Drug | clofarabine (IV formulation) and cytarabine |
| placeboplacebo (sodium Chloride) 1-hour IV infusion | Drug | placebo and cytarabine |
| cytarabinecytarabine IV infusion 1g/m^2/day for up to 3 cycles | Drug | clofarabine (IV formulation) and cytarabine, placebo and cytarabine |
Primary outcome
Overall Survival - Overall and by Calculated Strata (CSR 7-April-11)
Time frame: Day 1 (randomization) up to approximately 4 years
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.
Overall Survival - Overall and by Randomized Strata (CSR 9-July-12)
Time frame: Day 1 (randomization) up to approximately 4 years
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.
10 secondary outcomes
Best Response Per Independent Response Review Panel (IRRP) Assessment - Overall and by Calculated Strata (CSR 7-April-11)
Time frame: Day 12 up to approximately 6 months
Duration of Remission (DOR) Per IRRP Assessment-Overall and by Calculated Strata (CSR 7-April-11)
Time frame: Day 12 to approximately 4 years
Duration of Remission (DOR) Per IRRP Assessment-Overall and by Randomized Strata (CSR 9-July-12)
Time frame: Day 12 to approximately 4 years
Disease-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
Time frame: Day 12 to approximately 4 years
Disease-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
Time frame: Day 12 to approximately 4 years
Event-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
Time frame: Day 1 (randomization) up to approximately 4 years
Event-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
Time frame: 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)
Time frame: Day 1 (randomization) to Day 122
Four-Month Event-free Survival Per IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
Time frame: Day 1 (randomization) to Day 122
Participants With Adverse Events (CSR 7-April-11)
Time frame: 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.)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Apr 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publicationClofarabine + 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.
- Results publicationClofarabine 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.
- Results publication: PubMed 22585697Faderl 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.
- Results publicationGanguly 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.
- Results publicationGanguly 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
Related trials for Acute Myelogenous Leukemia
RecruitingPhase 1
A Study of CHM-029 in Participants With NPM1 Mutated, KMT2A or NUP98 Rearranged AML
AML (Acute Myeloid Leukemia)
RecruitingPhase 2
Testing New Therapies for Patients With Acute Myeloid Leukemia Who Are Newly Diagnosed and Have Not Yet Started Treatment (A MyeloMATCH Treatment Trial)
Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic/Myeloproliferative Neoplasm
Active, not recruitingPhase 2
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
RecruitingPhase 1/2
Venetoclax and CLAG-M for the Treatment of Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms
Acute Biphenotypic Leukemia, Acute Myeloid Leukemia
Not yet recruitingPhase 1
ATRN-119 in Combination With Decitabine in Patients With TP53-Mutated AML or Higher-Risk MDS
Acute Myeloid Leukemia, High-risk Myelodysplastic Syndrome
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Monitor study director
Genzyme, a Sanofi Company
57 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing clofarabine (IV formulation) and cytarabine in people with Acute Myelogenous Leukemia, run by Genzyme, a Sanofi Company at 57 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Apr 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 57 sites in United States, France, Italy, Canada, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Sep 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Survival - Overall and by Calculated Strata (CSR 7-April-11) (time frame: Day 1 (randomization) up to approximately 4 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00317642, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Apr 2014.