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Cytarabine in Combination With Arsenic Trioxide vs. Cytarabine Alone in Elderly Patients With Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT00513305
Recruitment Status : Terminated (Study has been stopped by sponsor decision)
First Posted : August 8, 2007
Results First Posted : March 29, 2011
Last Update Posted : August 1, 2012
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Cephalon )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Acute Myeloid Leukemia
Interventions Drug: Arsenic trioxide
Drug: Low-dose cytarabine alone
Enrollment 67
Recruitment Details Seven centers in the United States and one center in Canada. First patient enrolled 12 October 2007; last patient completed protocol-specified treatment 5 July 2009; last patient completed survival follow-up contact 16 December 2009.
Pre-assignment Details  
Arm/Group Title Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Hide Arm/Group Description Cycle 1. 10 mg/m^2 cytarabine was administered subcutaneously (sc) twice daily (bid) on days 1-14. 0.25 mg/kg arsenic trioxide was administered intravenously (iv) on days 1-5 and days 8-12. Cycle 2. A second identical cycle of cytarabine and arsenic trioxide was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine and arsenic trioxide with the doses and schedule identical to the initial cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of arsenic trioxide 0.25 mg/kg iv on days 1 and 4 and cytarabine 10 mg/m^2 sc bid on days 1 through 7 of a 28-day cycle. Cytarabine was administered at a dose of 10 mg/m^2 sc bid from days 1-14 of cycle 1. A second identical cycle of cytarabine treatment was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved a complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine with the doses and schedule identical to the initial treatment cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of cytarabine at 10 mg/m^2 sc bid on days 1-7 of a 28-day cycle. Patients started maintenance treatment within 42 days after platelet count recovery. Maintenance treatment continued for 2 years or until unacceptable toxicity or disease progression.
Period Title: Overall Study
Started 33 34 [1]
Completed 5 7
Not Completed 28 27
Reason Not Completed
Adverse Event             6             2
Death (through Consolidation Treatment)             2             2
Lack of Efficacy             8             13
Withdrawal by Subject             1             2
Disease progression             8             5
Eligible for stem cell transplant             1             0
Hematologic counts did not recover             1             0
Physician Decision             1             0
Persistent hypocellularity             0             1
Sponsor Decision             0             2
[1]
One subject withdrew prior to receiving study medication
Arm/Group Title Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone Total
Hide Arm/Group Description Cycle 1. 10 mg/m^2 cytarabine was administered subcutaneously (sc) twice daily (bid) on days 1-14. 0.25 mg/kg arsenic trioxide was administered intravenously (iv) on days 1-5 and days 8-12. Cycle 2. A second identical cycle of cytarabine and arsenic trioxide was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine and arsenic trioxide with the doses and schedule identical to the initial cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of arsenic trioxide 0.25 mg/kg iv on days 1 and 4 and cytarabine 10 mg/m^2 sc bid on days 1 through 7 of a 28-day cycle. Cytarabine was administered at a dose of 10 mg/m^2 sc bid from days 1-14 of cycle 1. A second identical cycle of cytarabine treatment was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved a complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine with the doses and schedule identical to the initial treatment cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of cytarabine at 10 mg/m^2 sc bid on days 1-7 of a 28-day cycle. Patients started maintenance treatment within 42 days after platelet count recovery. Maintenance treatment continued for 2 years or until unacceptable toxicity or disease progression. Total of all reporting groups
Overall Number of Baseline Participants 33 34 67
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 33 participants 34 participants 67 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
9
  27.3%
7
  20.6%
16
  23.9%
>=65 years
24
  72.7%
27
  79.4%
51
  76.1%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 33 participants 34 participants 67 participants
70.9  (7.1) 71.5  (6.8) 71.2  (6.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 33 participants 34 participants 67 participants
Female
16
  48.5%
17
  50.0%
33
  49.3%
Male
17
  51.5%
17
  50.0%
34
  50.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 34 participants 67 participants
United States 32 32 64
Canada 1 2 3
1.Primary Outcome
Title Percentage of Participants in Complete Remission (CR)
Hide Description The primary efficacy variable was the percentage of subjects in each treatment group who achieved complete remission after treatment with study drug. Complete remission was defined as: 1) Less than 5% blasts in normocellular bone marrow sample. 2) No blasts in bone marrow sample containing Auer rods. 3)Clearance of previous extramedullary disease. 4)Normal values for absolute neutrophil count (at least 1000/microliter), platelet count (at least 100,000/microliter), without platelet transfusions, and in absence of peripheral myeloblasts.
Time Frame From baseline through Day 70. Assessments were performed on Day 21 in cycle 1, no later than Day 56 of cycle 1 or 2 (if applicable), and no later than Day 70 of cycle 1 or 2 (if applicable) or at any other time at the discretion of the investigator
Hide Outcome Measure Data
Hide Analysis Population Description
Intention to treat (ITT) Analysis Set
Arm/Group Title Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Hide Arm/Group Description:
Cycle 1. 10 mg/m^2 cytarabine was administered subcutaneously (sc) twice daily (bid) on days 1-14. 0.25 mg/kg arsenic trioxide was administered intravenously (iv) on days 1-5 and days 8-12. Cycle 2. A second identical cycle of cytarabine and arsenic trioxide was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine and arsenic trioxide with the doses and schedule identical to the initial cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of arsenic trioxide 0.25 mg/kg iv on days 1 and 4 and cytarabine 10 mg/m^2 sc bid on days 1 through 7 of a 28-day cycle.
Cytarabine was administered at a dose of 10 mg/m^2 sc bid from days 1-14 of cycle 1. A second identical cycle of cytarabine treatment was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved a complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine with the doses and schedule identical to the initial treatment cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of cytarabine at 10 mg/m^2 sc bid on days 1-7 of a 28-day cycle. Patients started maintenance treatment within 42 days after platelet count recovery. Maintenance treatment continued for 2 years or until unacceptable toxicity or disease progression.
Overall Number of Participants Analyzed 33 34
Measure Type: Number
Unit of Measure: Percentage of participants in CR
15.2 8.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose Cytarabine Plus Arsenic Trioxide, Low-dose Cytarabine Alone
Comments The hypothesis of equal complete remission rates between the two treatment groups was tested using a 2-sided, normal approximation to the difference in binomial proportions test with two-sided alpha equal to 0.05.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.425
Comments The p-value is from the Pearson chi-square test for testing the equality of two binomial proportions, assuming normal approximation of the binomial proportions.
Method Chi-squared
Comments There were no adjustments for covariates. Since the primary endpoint was prespecified, no adjustment for multiplicity of endpoints was introduced
2.Secondary Outcome
Title Number of Participants Who Died or Were Censored by 24 Months
Hide Description This measure (time to death or censor) was defined for all enrolled subjects from the date of randomization until death from any cause. If a subject was not known to have died by the end of the followup period, observation of overall survival was censored on the date the patient was last known to be alive. The number of participants who died or were censored is presented here. (Note: all subjects participating in this study had either died or were censored by 24 months.)
Time Frame From Baseline through 24 months following Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Hide Arm/Group Description:
Cycle 1. 10 mg/m^2 cytarabine was administered subcutaneously (sc) twice daily (bid) on days 1-14. 0.25 mg/kg arsenic trioxide was administered intravenously (iv) on days 1-5 and days 8-12. Cycle 2. A second identical cycle of cytarabine and arsenic trioxide was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine and arsenic trioxide with the doses and schedule identical to the initial cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of arsenic trioxide 0.25 mg/kg iv on days 1 and 4 and cytarabine 10 mg/m^2 sc bid on days 1 through 7 of a 28-day cycle.
Cytarabine was administered at a dose of 10 mg/m^2 sc bid from days 1-14 of cycle 1. A second identical cycle of cytarabine treatment was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved a complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine with the doses and schedule identical to the initial treatment cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of cytarabine at 10 mg/m^2 sc bid on days 1-7 of a 28-day cycle. Patients started maintenance treatment within 42 days after platelet count recovery. Maintenance treatment continued for 2 years or until unacceptable toxicity or disease progression.
Overall Number of Participants Analyzed 33 34
Measure Type: Number
Unit of Measure: Participants
33 34
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose Cytarabine Plus Arsenic Trioxide, Low-dose Cytarabine Alone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.829
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.027
Confidence Interval (2-Sided) 95%
0.535 to 1.973
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Proportion of Participants With Relapse-Free Survival (RFS)Using the Kaplan-Meier Estimate
Hide Description RFS is defined for patients who achieved a complete remission (CR), complete remission with incomplete platelet recovery (CRp), or partial remission(PR), and was measured from the date of attaining CR, CRp, or PR until the date of AML relapse or death from any cause, whichever occurred first. For a patient not known to have relapsed or died by the end of the study followup, observation of relapse free survival was censored on the date of the last followup examination. The Kaplan Meier Estimate of relapse-free survival at Month 3 and Month 6 is presented here.
Time Frame From Baseline (randomization) through 24 months following Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
Population analyzed are the subjects who who achieved a complete remission (CR), complete remission with incomplete platelet recovery (CRp), or partial remission(PR)during the course of the study
Arm/Group Title Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Hide Arm/Group Description:
Cycle 1. 10 mg/m^2 cytarabine was administered subcutaneously (sc) twice daily (bid) on days 1-14. 0.25 mg/kg arsenic trioxide was administered intravenously (iv) on days 1-5 and days 8-12. Cycle 2. A second identical cycle of cytarabine and arsenic trioxide was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine and arsenic trioxide with the doses and schedule identical to the initial cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of arsenic trioxide 0.25 mg/kg iv on days 1 and 4 and cytarabine 10 mg/m^2 sc bid on days 1 through 7 of a 28-day cycle.
Cytarabine was administered at a dose of 10 mg/m^2 sc bid from days 1-14 of cycle 1. A second identical cycle of cytarabine treatment was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved a complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine with the doses and schedule identical to the initial treatment cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of cytarabine at 10 mg/m^2 sc bid on days 1-7 of a 28-day cycle. Patients started maintenance treatment within 42 days after platelet count recovery. Maintenance treatment continued for 2 years or until unacceptable toxicity or disease progression.
Overall Number of Participants Analyzed 21 29
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
Month 3 (95% Confidence Interval)
0.818
(0.447 to 0.951)
0.800
(0.204 to 0.969)
Month 6 (95% Confidence Interval)
0.818
(0.447 to 0.951)
0.800
(0.204 to 0.969)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose Cytarabine Plus Arsenic Trioxide, Low-dose Cytarabine Alone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.527
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 2.310
Confidence Interval (2-Sided) 95%
0.160 to 33.343
Estimation Comments Estimate based on Cox Proportional Hazards Model adjusting for age, Eastern Cooperative Oncology Group (ECOG) status, white blood count and presence of antecedent hematologic disorder.
4.Secondary Outcome
Title Number of Participants Who Experienced Early Death
Hide Description Early death is defined as death from any cause within the first 14 days after start of study drug treatment. The number of patients in each study group who experienced early death is presented here.
Time Frame 14 days from start of study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Hide Arm/Group Description:
Cycle 1. 10 mg/m^2 cytarabine was administered subcutaneously (sc) twice daily (bid) on days 1-14. 0.25 mg/kg arsenic trioxide was administered intravenously (iv) on days 1-5 and days 8-12. Cycle 2. A second identical cycle of cytarabine and arsenic trioxide was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine and arsenic trioxide with the doses and schedule identical to the initial cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of arsenic trioxide 0.25 mg/kg iv on days 1 and 4 and cytarabine 10 mg/m^2 sc bid on days 1 through 7 of a 28-day cycle.
Cytarabine was administered at a dose of 10 mg/m^2 sc bid from days 1-14 of cycle 1. A second identical cycle of cytarabine treatment was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved a complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine with the doses and schedule identical to the initial treatment cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of cytarabine at 10 mg/m^2 sc bid on days 1-7 of a 28-day cycle. Patients started maintenance treatment within 42 days after platelet count recovery. Maintenance treatment continued for 2 years or until unacceptable toxicity or disease progression.
Overall Number of Participants Analyzed 33 34
Measure Type: Number
Unit of Measure: Participants
0 2
5.Secondary Outcome
Title Number of Participants Who Experienced Induction (Thirty-Day) Mortality
Hide Description The number of subjects who died from any cause within the first 30 days after the start of study drug treatment is presented here.
Time Frame Up to 30 days following start of study drug treatment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Hide Arm/Group Description:
Cycle 1. 10 mg/m^2 cytarabine was administered subcutaneously (sc) twice daily (bid) on days 1-14. 0.25 mg/kg arsenic trioxide was administered intravenously (iv) on days 1-5 and days 8-12. Cycle 2. A second identical cycle of cytarabine and arsenic trioxide was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine and arsenic trioxide with the doses and schedule identical to the initial cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of arsenic trioxide 0.25 mg/kg iv on days 1 and 4 and cytarabine 10 mg/m^2 sc bid on days 1 through 7 of a 28-day cycle.
Cytarabine was administered at a dose of 10 mg/m^2 sc bid from days 1-14 of cycle 1. A second identical cycle of cytarabine treatment was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved a complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine with the doses and schedule identical to the initial treatment cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of cytarabine at 10 mg/m^2 sc bid on days 1-7 of a 28-day cycle. Patients started maintenance treatment within 42 days after platelet count recovery. Maintenance treatment continued for 2 years or until unacceptable toxicity or disease progression.
Overall Number of Participants Analyzed 33 34
Measure Type: Number
Unit of Measure: Participants
3 2
6.Secondary Outcome
Title Proportion of Participants Surviving at 6 Months and 12 Months Using the Kaplan Meier Estimate
Hide Description The duration of overall survival was defined for all patients and was measured from the date of randomization until death from any cause. For a patient who was not known to have died by the end of the follow-up period, observation of overall survival was censored on the date the patient was last known to be alive. The estimate of likelihood of survival at 6 and 12 months after Baseline using the Kaplan Meier Estimate is presented here.
Time Frame Baseline through 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Hide Arm/Group Description:
Cycle 1. 10 mg/m^2 cytarabine was administered subcutaneously (sc) twice daily (bid) on days 1-14. 0.25 mg/kg arsenic trioxide was administered intravenously (iv) on days 1-5 and days 8-12. Cycle 2. A second identical cycle of cytarabine and arsenic trioxide was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine and arsenic trioxide with the doses and schedule identical to the initial cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of arsenic trioxide 0.25 mg/kg iv on days 1 and 4 and cytarabine 10 mg/m^2 sc bid on days 1 through 7 of a 28-day cycle.
Cytarabine was administered at a dose of 10 mg/m^2 sc bid from days 1-14 of cycle 1. A second identical cycle of cytarabine treatment was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved a complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine with the doses and schedule identical to the initial treatment cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of cytarabine at 10 mg/m^2 sc bid on days 1-7 of a 28-day cycle. Patients started maintenance treatment within 42 days after platelet count recovery. Maintenance treatment continued for 2 years or until unacceptable toxicity or disease progression.
Overall Number of Participants Analyzed 33 34
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of Participants
Month 6 (95% Confidence Interval)
0.626
(0.435 to 0.768)
0.649
(0.454 to 0.789)
Month 12 (95% Confidence Interval)
12.22
(4.37 to 16.76)
8.51
(5.72 to 19.65)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Low-dose Cytarabine Plus Arsenic Trioxide, Low-dose Cytarabine Alone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8289
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.027
Confidence Interval (2-Sided) 95%
0.535 to 1.973
Estimation Comments Estimate based on Cox Proportional Hazards Model adjusting for age, Eastern Cooperative Oncology Group (ECOG) status, white blood count and presence of antecedent hematologic disorder.
Time Frame approximately 2 years
Adverse Event Reporting Description Adverse events were collected from the date the ICF was signed through 30 days after the last dose of study drug.
 
Arm/Group Title Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Hide Arm/Group Description Cycle 1. 10 mg/m^2 cytarabine was administered subcutaneously (sc) twice daily (bid) on days 1-14. 0.25 mg/kg arsenic trioxide was administered intravenously (iv) on days 1-5 and days 8-12. Cycle 2. A second identical cycle of cytarabine and arsenic trioxide was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine and arsenic trioxide with the doses and schedule identical to the initial cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of arsenic trioxide 0.25 mg/kg iv on days 1 and 4 and cytarabine 10 mg/m^2 sc bid on days 1 through 7 of a 28-day cycle. Cytarabine was administered at a dose of 10 mg/m^2 sc bid from days 1-14 of cycle 1. A second identical cycle of cytarabine treatment was given to patients with persistent disease identified from a bone marrow sample taken on day 21 of cycle 1. Patients who achieved a complete remission (CR), complete remission with incomplete platelet count recovery (CRp), or partial remission (PR) after 1 or 2 cycles received a 14-day consolidation cycle of cytarabine with the doses and schedule identical to the initial treatment cycle. A recovery period of up to 4 weeks between the attainment of CR, CRp, or PR and the initiation of consolidation treatment was allowed. Patients who completed consolidation treatment started maintenance treatment of cytarabine at 10 mg/m^2 sc bid on days 1-7 of a 28-day cycle. Patients started maintenance treatment within 42 days after platelet count recovery. Maintenance treatment continued for 2 years or until unacceptable toxicity or disease progression.
All-Cause Mortality
Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   19/33 (57.58%)      21/33 (63.64%)    
Blood and lymphatic system disorders     
Febrile neutropenia  2  7/33 (21.21%)  7 9/33 (27.27%)  9
Cardiac disorders     
Cardiac failure congestive  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Cardio-respiratory arrest  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Cardiopulmonary failure  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Left ventricular dysfunction  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Pericardial haemorrhage  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Tachycardia  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Ventricular extrasystoles  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Diarrhoea  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Gastrointestinal haemorrhage  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Proctitis  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Rectal haemorrhage  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Stomatitis  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Vomiting  1  1/33 (3.03%)  1 0/33 (0.00%)  0
General disorders     
Asthenia  1  1/33 (3.03%)  1 1/33 (3.03%)  1
Chills  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Infusion related reaction  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Pyrexia  1  1/33 (3.03%)  1 1/33 (3.03%)  1
Immune system disorders     
Anaphylactic reaction  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Infections and infestations     
Abscess bacterial  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Bacteraemia  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Catheter site cellulitis  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Cellulitis  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Neutropenic infection  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Neutropenic sepsis  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Pneumonia  1  3/33 (9.09%)  3 3/33 (9.09%)  3
Pneumonia fungal  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Sepsis  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Septic shock  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Staphylococcal bacteraemia  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Metabolism and nutrition disorders     
Dehydration  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Failure to thrive  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Fluid overload  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Hyponatraemia  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Hypophagia  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Musculoskeletal and connective tissue disorders     
Arthritis  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Pain in jaw  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Non-small cell lung cancer  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Tumour lysis syndrome  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Nervous system disorders     
Haemorrhage intracranial  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Syncope  1  0/33 (0.00%)  0 1/33 (3.03%)  1
Renal and urinary disorders     
Renal failure  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Renal failure acute  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Respiratory, thoracic and mediastinal disorders     
Lung infiltration  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Pulmonary oedema  1  1/33 (3.03%)  1 1/33 (3.03%)  1
Respiratory distress  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Respiratory failure  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Vascular disorders     
Capillary leak syndrome  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Hypotension  1  1/33 (3.03%)  1 1/33 (3.03%)  1
Shock  1  1/33 (3.03%)  1 0/33 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
2
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Low-dose Cytarabine Plus Arsenic Trioxide Low-dose Cytarabine Alone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   33/33 (100.00%)      33/33 (100.00%)    
Blood and lymphatic system disorders     
Anaemia  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Febrile neutropenia  1  9/33 (27.27%)  9 16/33 (48.48%)  16
Neutropenia  1  3/33 (9.09%)  3 3/33 (9.09%)  3
Pancytopenia  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Splenomegaly  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Thrombocytopenia  1  5/33 (15.15%)  5 0/33 (0.00%)  0
Cardiac disorders     
Atrial fibrillation  1  0/33 (0.00%)  0 3/33 (9.09%)  3
Cardiac failure congestive  1  1/33 (3.03%)  1 3/33 (9.09%)  3
Pericardial effusion  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Sinus tachycardia  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Tachycardia  1  6/33 (18.18%)  6 10/33 (30.30%)  10
Ventricular extrasystoles  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Ventricular tachycardia  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Eye disorders     
Vision blurred  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Gastrointestinal disorders     
Abdominal distension  1  7/33 (21.21%)  7 5/33 (15.15%)  5
Abdominal pain  1  7/33 (21.21%)  7 4/33 (12.12%)  4
Abdominal pain lower  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Abdominal pain upper  1  1/33 (3.03%)  1 4/33 (12.12%)  4
Constipation  1  14/33 (42.42%)  14 11/33 (33.33%)  11
Diarrhoea  1  21/33 (63.64%)  21 14/33 (42.42%)  14
Dyspepsia  1  3/33 (9.09%)  3 3/33 (9.09%)  3
Dysphagia  1  3/33 (9.09%)  3 2/33 (6.06%)  2
Gingival bleeding  1  4/33 (12.12%)  4 2/33 (6.06%)  2
Haematochezia  1  1/33 (3.03%)  1 5/33 (15.15%)  5
Haemorrhoids  1  4/33 (12.12%)  4 1/33 (3.03%)  1
Lip ulceration  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Mouth haemorrhage  1  4/33 (12.12%)  4 3/33 (9.09%)  3
Nausea  1  15/33 (45.45%)  15 9/33 (27.27%)  9
Odynophagia  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Stomatitis  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Tongue ulceration  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Toothache  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Vomiting  1  7/33 (21.21%)  7 7/33 (21.21%)  7
General disorders     
Asthenia  1  7/33 (21.21%)  7 9/33 (27.27%)  9
Catheter site erythema  1  4/33 (12.12%)  4 0/33 (0.00%)  0
Catheter site pain  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Chest pain  1  5/33 (15.15%)  5 6/33 (18.18%)  6
Chills  1  5/33 (15.15%)  5 7/33 (21.21%)  7
Fatigue  1  10/33 (30.30%)  10 9/33 (27.27%)  9
Generalised oedema  1  3/33 (9.09%)  3 1/33 (3.03%)  1
Injection site haematoma  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Injection site reaction  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Mucosal inflammation  1  4/33 (12.12%)  4 2/33 (6.06%)  2
Oedema  1  6/33 (18.18%)  6 0/33 (0.00%)  0
Oedema peripheral  1  16/33 (48.48%)  16 14/33 (42.42%)  14
Pain  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Pyrexia  1  9/33 (27.27%)  9 12/33 (36.36%)  12
Infections and infestations     
Bacteraemia  1  5/33 (15.15%)  5 1/33 (3.03%)  1
Candidiasis  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Cellulitis  1  4/33 (12.12%)  4 2/33 (6.06%)  2
Clostridial infection  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Clostridium difficile colitis  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Enterococcal bacteraemia  1  0/33 (0.00%)  0 3/33 (9.09%)  3
Enterococcal infection  1  0/33 (0.00%)  0 3/33 (9.09%)  3
Fungal skin infection  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Oral candidiasis  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Pneumonia  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Pneumonia fungal  1  0/33 (0.00%)  0 3/33 (9.09%)  3
Sinusitis  1  1/33 (3.03%)  1 3/33 (9.09%)  3
Staphylococcal bacteraemia  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Urinary tract infection  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Injury, poisoning and procedural complications     
Contusion  1  1/33 (3.03%)  1 3/33 (9.09%)  3
Excoriation  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Procedural pain  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Skin laceration  1  0/33 (0.00%)  0 3/33 (9.09%)  3
Transfusion reaction  1  2/33 (6.06%)  2 3/33 (9.09%)  3
Investigations     
Blood creatinine increased  1  3/33 (9.09%)  3 2/33 (6.06%)  2
Blood culture positive  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Breath sounds abnormal  1  3/33 (9.09%)  3 1/33 (3.03%)  1
Cardiac murmur  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Electrocardiogram QT prolonged  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Liver function test abnormal  1  5/33 (15.15%)  5 1/33 (3.03%)  1
Weight decreased  1  4/33 (12.12%)  4 4/33 (12.12%)  4
Weight increased  1  3/33 (9.09%)  3 0/33 (0.00%)  0
Metabolism and nutrition disorders     
Anorexia  1  2/33 (6.06%)  2 4/33 (12.12%)  4
Decreased appetite  1  7/33 (21.21%)  7 7/33 (21.21%)  7
Dehydration  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Gout  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Hyperglycaemia  1  4/33 (12.12%)  4 4/33 (12.12%)  4
Hyperuricaemia  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Hypokalaemia  1  4/33 (12.12%)  4 5/33 (15.15%)  5
Hypomagnesaemia  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Hyponatraemia  1  4/33 (12.12%)  4 6/33 (18.18%)  6
Hypovolaemia  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Arthralgia  1  2/33 (6.06%)  2 7/33 (21.21%)  7
Back pain  1  6/33 (18.18%)  6 3/33 (9.09%)  3
Bone pain  1  2/33 (6.06%)  2 4/33 (12.12%)  4
Joint stiffness  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Muscular weakness  1  5/33 (15.15%)  5 2/33 (6.06%)  2
Musculoskeletal chest pain  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Musculoskeletal pain  1  0/33 (0.00%)  0 4/33 (12.12%)  4
Myalgia  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Neck pain  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Pain in extremity  1  5/33 (15.15%)  5 2/33 (6.06%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung neoplasm  1  3/33 (9.09%)  3 1/33 (3.03%)  1
Tumour lysis syndrome  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Nervous system disorders     
Dizziness  1  7/33 (21.21%)  7 4/33 (12.12%)  4
Dysarthria  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Dysgeusia  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Headache  1  10/33 (30.30%)  10 4/33 (12.12%)  4
Hypoaesthesia  1  3/33 (9.09%)  3 0/33 (0.00%)  0
Neuropathy peripheral  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Paraesthesia  1  3/33 (9.09%)  3 1/33 (3.03%)  1
Psychiatric disorders     
Anxiety  1  5/33 (15.15%)  5 4/33 (12.12%)  4
Insomnia  1  7/33 (21.21%)  7 3/33 (9.09%)  3
Confusional state  1  4/33 (12.12%)  4 2/33 (6.06%)  2
Depression  1  3/33 (9.09%)  3 1/33 (3.03%)  1
Mental status changes  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Renal and urinary disorders     
Dysuria  1  3/33 (9.09%)  3 5/33 (15.15%)  5
Renal failure acute  1  0/33 (0.00%)  0 4/33 (12.12%)  4
Haematuria  1  1/33 (3.03%)  1 3/33 (9.09%)  3
Oliguria  1  0/33 (0.00%)  0 3/33 (9.09%)  3
Pollakiuria  1  0/33 (0.00%)  0 3/33 (9.09%)  3
Renal failure  1  1/33 (3.03%)  1 3/33 (9.09%)  3
Respiratory, thoracic and mediastinal disorders     
Cough  1  8/33 (24.24%)  8 7/33 (21.21%)  7
Dyspnoea  1  9/33 (27.27%)  9 7/33 (21.21%)  7
Epistaxis  1  3/33 (9.09%)  3 7/33 (21.21%)  7
Pleural effusion  1  3/33 (9.09%)  3 4/33 (12.12%)  4
Rales  1  6/33 (18.18%)  6 4/33 (12.12%)  4
Atelectasis  1  1/33 (3.03%)  1 3/33 (9.09%)  3
Oropharyngeal pain  1  5/33 (15.15%)  5 3/33 (9.09%)  3
Tachypnoea  1  0/33 (0.00%)  0 3/33 (9.09%)  3
Haemoptysis  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Hypoxia  1  3/33 (9.09%)  3 2/33 (6.06%)  2
Lung consolidation  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Pulmonary oedema  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Respiratory alkalosis  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Respiratory distress  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Wheezing  1  3/33 (9.09%)  3 1/33 (3.03%)  1
Dyspnoea exertional  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Pulmonary mass  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Rhinorrhoea  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Rhonchi  1  3/33 (9.09%)  3 0/33 (0.00%)  0
Skin and subcutaneous tissue disorders     
Petechiae  1  10/33 (30.30%)  10 6/33 (18.18%)  6
Hyperhidrosis  1  1/33 (3.03%)  1 5/33 (15.15%)  5
Rash  1  5/33 (15.15%)  5 5/33 (15.15%)  5
Ecchymosis  1  8/33 (24.24%)  8 4/33 (12.12%)  4
Skin lesion  1  5/33 (15.15%)  5 4/33 (12.12%)  4
Erythema  1  5/33 (15.15%)  5 3/33 (9.09%)  3
Night sweats  1  2/33 (6.06%)  2 3/33 (9.09%)  3
Dry skin  1  3/33 (9.09%)  3 2/33 (6.06%)  2
Pruritus  1  6/33 (18.18%)  6 2/33 (6.06%)  2
Rash erythematous  1  2/33 (6.06%)  2 2/33 (6.06%)  2
Blood blister  1  6/33 (18.18%)  6 1/33 (3.03%)  1
Rash maculo-papular  1  2/33 (6.06%)  2 1/33 (3.03%)  1
Purpura  1  2/33 (6.06%)  2 0/33 (0.00%)  0
Vascular disorders     
Hypotension  1  13/33 (39.39%)  13 9/33 (27.27%)  9
Haematoma  1  1/33 (3.03%)  1 3/33 (9.09%)  3
Deep vein thrombosis  1  0/33 (0.00%)  0 2/33 (6.06%)  2
Hypertension  1  1/33 (3.03%)  1 2/33 (6.06%)  2
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
In September 2009, the sponsor decided to stop the study due to difficulty in enrollment. The study was stopped prior to the first planned interim analysis. Most of the analysis planned in the protocol was not performed.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Sponsor's Medical Expert, Clinical Research
Organization: Cephalon, Inc.
Phone: 1-800-896-5855
Responsible Party: Teva Pharmaceutical Industries ( Cephalon )
ClinicalTrials.gov Identifier: NCT00513305     History of Changes
Other Study ID Numbers: C18477/3059/AM/US-CA
First Submitted: August 6, 2007
First Posted: August 8, 2007
Results First Submitted: July 29, 2010
Results First Posted: March 29, 2011
Last Update Posted: August 1, 2012