A Phase 3 interventional study of clofarabine (IV formulation) and placebo in Acute Myelogenous Leukemia, sponsored by Genzyme, a Sanofi Company. Completed at 57 sites in 5 countries. Open to participants aged 55 Years and older. Per ClinicalTrials.gov, last updated 2014-04-14.
Sponsored by Genzyme, a Sanofi Company · Phase 3, Interventional, and Treatment
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.
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.
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.
5,441 studies on the registry are indexed under Leukemia; 636 are open to participants now.
This study's enrollment of 326 is above the median of 38 across 4,247 interventional studies indexed under Leukemia.
Browse Leukemia studies →Genzyme, a Sanofi Company is the lead sponsor of 303 studies on the registry; 5 are open to participants now.
Of its 24 completed or terminated interventional studies of FDA-regulated products, 19 (79%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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) · Drug: cytarabine
Participants received placebo administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m\^2 administered as a 2-hour infusion. Patients could receive up to 3 cycles of treatment (induction, re-induction, and consolidation)
Drug: placebo · Drug: cytarabine
clofarabine (IV formulation) infusion 40mg/m\^2 / day up to 3 cycles
Also known as: Clolar®, Evoltra®
placebo (sodium Chloride) 1-hour IV infusion
cytarabine IV infusion 1g/m\^2/day for up to 3 cycles
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.
Time frame: 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.
Time frame: Day 1 (randomization) up to approximately 4 years
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).
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)
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).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
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)
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.
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)
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.
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)
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.
Time frame: 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
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.)
| Milestone | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine |
|---|---|---|
| Started | 163 | 163 |
| Full analysis set | 162 | 158 |
| Received >= 1 study drug (safety set) | 161 | 155 |
| Completed | 41 | 28 |
| Not completed | 122 | 135 |
| Withdrew: Not received either study drug | 1 | 3 |
| Withdrew: Physician decision | 15 | 7 |
| Withdrew: Participant declined treatment | 14 | 3 |
| Withdrew: Adverse event | 17 | 5 |
| Withdrew: Treatment failure | 56 | 102 |
| Withdrew: Disease recurrence | 1 | 2 |
| Withdrew: Death | 14 | 7 |
| Withdrew: Not continue to consolidation | 2 | 0 |
| Withdrew: Withdrawal by subject | 0 | 1 |
| Withdrew: Referred for transplantation | 1 | 0 |
| Withdrew: Aml not centrally confirmed | 1 | 5 |
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.
| months | Clofarabine (IV Formulation) and Cytarabine (FAS) | Placebo and Cytarabine (FAS) | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Overall Survival - Overall and by Calculated Strata (CSR 7-April-11) | 6.6 (5.1 to 9.3) | 6.4 (4.7 to 7.3) | 5.1 (3.5 to 8.7) | 5.5 (4.1 to 7.2) | 8.7 (5.3 to 11.1) | 7.2 (4.6 to 8.9) |
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).
| percentage of participants | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Overall Remission (CR + CRi) | 46.9 | 22.9 | 45.5 | 22.9 | 48.6 | 23.0 |
| Complete Remission (CR) | 35.2 | 17.8 | 33.0 | 18.1 | 37.8 | 17.6 |
| CR with incomplete blood count recovery (CRi) | 11.7 | 5.1 | 12.5 | 4.8 | 10.8 | 5.4 |
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).
| months | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Duration of Remission (DOR) Per IRRP Assessment-Overall and by Calculated Strata (CSR 7-April-11) | 7.6 (5.4 to 11.5) | 3.8 (3.3 to 12.1) | 5.7 (5.3 to 7.7) | 6.3 (2.3 to 7.2) | 11.5 (6.8 to 15.5) | 3.8 (3.3 to NA) |
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).
| months | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Duration of Remission (DOR) Per IRRP Assessment-Overall and by Randomized Strata (CSR 9-July-12) | 7.7 (5.7 to 11.5) | 3.8 (3.3 to 12.1) | 6.7 (4.0 to 8.8) | 6.3 (2.3 to 7.2) | 10.2 (6.8 to 20.2) | 3.8 (3.3 to NA) |
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.
| months | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Disease-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11) | 8.1 (6.7 to 10.3) | 7.0 (3.9 to 12.1) | 5.7 (4.4 to 9.7) | 6.7 (3.9 to 8.1) | 10.3 (7.5 to 15.5) | 9.1 (3.7 to NA) |
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.
| months | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Disease-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12) | 9.5 (6.9 to 15.4) | 7.0 (3.9 to 9.8) | 6.7 (3.9 to 9.7) | 6.7 (3.9 to 8.1) | 15.4 (9.2 to 20.5) | 9.2 (3.7 to 13.1) |
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.
| months | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Event-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11) | 1.9 (1.1 to 2.9) | 1.0 (0.9 to 1.1) | 1.4 (1.0 to 2.9) | 1.0 (0.7 to 1.2) | 2.0 (1.2 to 6.6) | 1.0 (0.9 to 1.2) |
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.
| months | Clofarabine (IV Formulation) and Cytarabine (FAS) | Placebo and Cytarabine (FAS) | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Overall Survival - Overall and by Randomized Strata (CSR 9-July-12) | 6.6 (5.1 to 9.3) | 6.3 (4.7 to 7.3) | 4.8 (2.9 to 7.3) | 6.3 (4.1 to 7.8) | 9.7 (5.9 to 12.7) | 6.6 (4.3 to 8.8) |
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.
| months | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Event-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12) | 1.9 (1.1 to 2.9) | 1.0 (0.8 to 1.1) | 1.1 (0.8 to 2.5) | 1.0 (0.7 to 1.2) | 2.8 (1.2 to 8.1) | 1.0 (0.8 to 1.2) |
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.
| percentage of participants | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Four-Month Event-free Survival Per IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11) | 37.7 | 16.6 | 35.2 | 16.9 | 40.5 | 16.2 |
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.
| percentage of participants | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Clofarabine and Cytarabine - In Stratum < 6 Months | Placebo and Cytarabine - In Stratum < 6 Months | Clofarabine and Cytarabine In Stratum >= 6 Months | Placebo and Cytarabine In Stratum >= 6 Months |
|---|---|---|---|---|---|---|
| Four-Month Event-free Survival Per IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12) | 38.9 | 17.1 | 31.4 | 17.9 | 47.4 | 16.2 |
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
| participants | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine |
|---|---|---|
| Any Treatment Emergent AE | 161 | 155 |
| Any Related Treatment Emergent AE | 157 | 133 |
| Any Treatment Emergent Grade >=3 AE | 157 | 133 |
| Any Related Treatment Related Grade >=3 AE | 127 | 83 |
| Discontinue of study medication due to AE | 17 | 5 |
| Discontinue of study medication due to related AE | 14 | 3 |
Collected over 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.). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Clofarabine (IV Formulation) and Cytarabine | — | 97/161 (60.2%) | 161/161 (100%) |
| Placebo and Cytarabine | — | 76/155 (49%) | 154/155 (99.4%) |
| Overall | — | 173/316 (54.7%) | 315/316 (99.7%) |
| Event | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Overall |
|---|---|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 25/161 | 19/155 | 44/316 |
| PneumoniaInfections and infestations | 13/161 | 12/155 | 25/316 |
| PyrexiaGeneral disorders | 7/161 | 9/155 | 16/316 |
| SepsisInfections and infestations | 8/161 | 3/155 | 11/316 |
| BacteraemiaInfections and infestations | 7/161 | 3/155 | 10/316 |
| Enterococcal bacteraemiaInfections and infestations | 6/161 | 1/155 | 7/316 |
| Septic shockInfections and infestations | 6/161 | 0/155 | 6/316 |
| Acute myeloid leukaemiaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 4/161 | 5/155 | 9/316 |
| Pneumonia fungalInfections and infestations | 5/161 | 0/155 | 5/316 |
| Renal failure acuteRenal and urinary disorders | 5/161 | 1/155 | 6/316 |
| Event | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Overall |
|---|---|---|---|
| NauseaGastrointestinal disorders | 117/161 | 82/155 | 199/316 |
| DiarrhoeaGastrointestinal disorders | 109/161 | 63/155 | 172/316 |
| Oedema peripheralGeneral disorders | 82/161 | 71/155 | 153/316 |
| ConstipationGastrointestinal disorders | 66/161 | 72/155 | 138/316 |
| VomitingGastrointestinal disorders | 71/161 | 42/155 | 113/316 |
| HeadacheNervous system disorders | 68/161 | 44/155 | 112/316 |
| HypokalaemiaMetabolism and nutrition disorders | 61/161 | 29/155 | 90/316 |
| Febrile neutropeniaBlood and lymphatic system disorders | 58/161 | 35/155 | 93/316 |
| FatigueGeneral disorders | 57/161 | 49/155 | 106/316 |
| Decreased appetiteMetabolism and nutrition disorders | 57/161 | 37/155 | 94/316 |
| Age, Continuous(years) | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Total |
|---|---|---|---|
| Mean | 67.0 ± 6.36 | 67.1 ± 5.82 | 67.0 ± 6.09 |
| Sex: Female, Male(Participants) | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Total |
|---|---|---|---|
| Female | 48 | 57 | 105 |
| Male | 114 | 101 | 215 |
| Ethnicity (NIH/OMB)(Participants) | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Total |
|---|---|---|---|
| Hispanic or Latino | 9 | 6 | 15 |
| Not Hispanic or Latino | 153 | 152 | 305 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 3 | 2 | 5 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 7 | 11 | 18 |
| White | 150 | 142 | 292 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 2 | 3 | 5 |
| Height (cm)(centimeter) | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Total |
|---|---|---|---|
| Mean | 171.5 ± 10.27 | 170.5 ± 8.92 | 171.0 ± 9.62 |
| Weight(kg)(kg) | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Total |
|---|---|---|---|
| Mean | 81.21 ± 17.862 | 83.03 ± 17.281 | 82.11 ± 17.574 |
| Body Surface Area (BSA)(m^2) | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Total |
|---|---|---|---|
| Mean | 1.941 ± 0.2383 | 1.959 ± 0.2338 | 1.950 ± 0.2359 |
| Eastern Cooperative Oncology Group Performance Status(Participants) | Clofarabine (IV Formulation) and Cytarabine | Placebo and Cytarabine | Total |
|---|---|---|---|
| ECOG 0 | 57 | 48 | 105 |
| ECOG 1 | 79 | 92 | 171 |
| ECOG 2 | 26 | 18 | 44 |
1 further baseline measures are reported on the registry.
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