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

Study Overview
=================
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. 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.

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

Conditions
-----------------
Acute Myelogenous Leukemia

Intervention / Treatment
-----------------
* Drug: clofarabine (IV formulation)
* Drug: placebo
* Drug: cytarabine


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

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.) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
acute myelogenous leukemia, acute myeloid leukemia, relapsed AML, refractory AML, clofarabine, cytarabine, CLO341, clolar