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

• ClinicalTrials.gov Identifier: NCT00513305
• Recruitment Status: Terminated
• First Posted: August 8, 2007
• Results First Posted: March 29, 2011
• Last Update Posted: August 1, 2012
• Sponsor: Cephalon
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Low-dose Cytarabine Plus Arsenic Trioxide	Low-dose Cytarabine Alone	Total
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
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

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants in Complete Remission (CR)
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

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT) Analysis Set

Arm/Group Title	Low-dose Cytarabine Plus Arsenic Trioxide	Low-dose Cytarabine Alone
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

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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-dose Cytarabine Plus Arsenic Trioxide	Low-dose Cytarabine Alone
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

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
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

Outcome Measure Data

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
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)

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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-dose Cytarabine Plus Arsenic Trioxide	Low-dose Cytarabine Alone
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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-dose Cytarabine Plus Arsenic Trioxide	Low-dose Cytarabine Alone
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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-dose Cytarabine Plus Arsenic Trioxide	Low-dose Cytarabine Alone
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)

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.

Adverse Events

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
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	--/--		--/--
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
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

Limitations and Caveats

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.

More Information

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
• 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