Acute Myeloid Leukemia
Conditions
Keywords
acute myeloid leukemia, cytarabine, arsenic trioxide.
Brief summary
The primary objective of this study is to determine whether low-dose cytarabine in combination with arsenic trioxide is more effective than low-dose cytarabine alone in achieving complete remission in elderly patients (≥60 years of age) with acute myeloid leukemia.
Interventions
DRUGArsenic trioxide
Arsenic trioxide will be administered intravenously (iv) at a dose of 0.25 mg/kg.
DRUGLow-dose cytarabine alone
Cytarabine will be administered at a dose of 10 mg/m\^2 subcutaneously (sc) twice a day (bid).
Sponsors
Cephalon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The patient has confirmed acute myeloid leukemia (AML). * The patient is unwilling or unable to tolerate conventional induction chemotherapy. * The patient has no comorbid conditions that would limit life expectancy to less than 3 months. * Patient must meet specific laboratory parameters for study inclusion.
Exclusion criteria
\- The patient has had previous cytotoxic chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Previous treatment with low-dose cytarabine is not permitted. * The patient has a QT interval outside of the protocol-specified range. * The patient has laboratory values outside of protocol-specified ranges. * The patient is concurrently treated with cytotoxic therapy, radiation, or investigational agents. * The patient has uncontrolled, severe cardiovascular or pulmonary disease or other uncontrolled medical condition. * The patient has known central nervous system involvement with AML.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Complete Remission (CR) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died or Were Censored by 24 Months | From Baseline through 24 months following Baseline | 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.) |
| Proportion of Participants With Relapse-Free Survival (RFS)Using the Kaplan-Meier Estimate | From Baseline (randomization) through 24 months following Baseline | 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. |
| Number of Participants Who Experienced Early Death | 14 days from start of study drug treatment | 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. |
| Number of Participants Who Experienced Induction (Thirty-Day) Mortality | Up to 30 days following start of study drug treatment | The number of subjects who died from any cause within the first 30 days after the start of study drug treatment is presented here. |
| Proportion of Participants Surviving at 6 Months and 12 Months Using the Kaplan Meier Estimate | Baseline through 12 months | 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. |
Countries
Canada, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Low-dose Cytarabine Plus Arsenic Trioxide 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. | 33 |
| Low-dose Cytarabine Alone 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. | 34 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 2 |
| Overall Study | Death (through Consolidation Treatment) | 2 | 2 |
| Overall Study | Disease progression | 8 | 5 |
| Overall Study | Eligible for stem cell transplant | 1 | 0 |
| Overall Study | Hematologic counts did not recover | 1 | 0 |
| Overall Study | Lack of Efficacy | 8 | 13 |
| Overall Study | Persistent hypocellularity | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Sponsor Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Low-dose Cytarabine Alone | Low-dose Cytarabine Plus Arsenic Trioxide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 27 Participants | 24 Participants | 51 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 9 Participants | 16 Participants |
| Age Continuous | 71.5 years STANDARD_DEVIATION 6.8 | 70.9 years STANDARD_DEVIATION 7.1 | 71.2 years STANDARD_DEVIATION 6.9 |
| Region of Enrollment Canada | 2 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 32 participants | 32 participants | 64 participants |
| Sex: Female, Male Female | 17 Participants | 16 Participants | 33 Participants |
| Sex: Female, Male Male | 17 Participants | 17 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 33 | 33 / 33 |
| serious Total, serious adverse events | 19 / 33 | 21 / 33 |
Outcome results
Primary
Percentage of Participants in Complete Remission (CR)
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
Population: Intention to treat (ITT) Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Cytarabine Plus Arsenic Trioxide | Percentage of Participants in Complete Remission (CR) | 15.2 Percentage of participants in CR |
| Low-dose Cytarabine Alone | Percentage of Participants in Complete Remission (CR) | 8.8 Percentage of participants in CR |
Comparison: 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.p-value: 0.425Chi-squared
Secondary
Number of Participants Who Died or Were Censored by 24 Months
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Cytarabine Plus Arsenic Trioxide | Number of Participants Who Died or Were Censored by 24 Months | 33 Participants |
| Low-dose Cytarabine Alone | Number of Participants Who Died or Were Censored by 24 Months | 34 Participants |
p-value: 0.82995% CI: [0.535, 1.973]Log Rank
Secondary
Number of Participants Who Experienced Early Death
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Cytarabine Plus Arsenic Trioxide | Number of Participants Who Experienced Early Death | 0 Participants |
| Low-dose Cytarabine Alone | Number of Participants Who Experienced Early Death | 2 Participants |
Secondary
Number of Participants Who Experienced Induction (Thirty-Day) Mortality
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Cytarabine Plus Arsenic Trioxide | Number of Participants Who Experienced Induction (Thirty-Day) Mortality | 3 Participants |
| Low-dose Cytarabine Alone | Number of Participants Who Experienced Induction (Thirty-Day) Mortality | 2 Participants |
Secondary
Proportion of Participants Surviving at 6 Months and 12 Months Using the Kaplan Meier Estimate
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low-dose Cytarabine Plus Arsenic Trioxide | Proportion of Participants Surviving at 6 Months and 12 Months Using the Kaplan Meier Estimate | Month 6 (95% Confidence Interval) | 0.626 Proportion of Participants |
| Low-dose Cytarabine Plus Arsenic Trioxide | Proportion of Participants Surviving at 6 Months and 12 Months Using the Kaplan Meier Estimate | Month 12 (95% Confidence Interval) | 12.22 Proportion of Participants |
| Low-dose Cytarabine Alone | Proportion of Participants Surviving at 6 Months and 12 Months Using the Kaplan Meier Estimate | Month 6 (95% Confidence Interval) | 0.649 Proportion of Participants |
| Low-dose Cytarabine Alone | Proportion of Participants Surviving at 6 Months and 12 Months Using the Kaplan Meier Estimate | Month 12 (95% Confidence Interval) | 8.51 Proportion of Participants |
p-value: 0.828995% CI: [0.535, 1.973]Log Rank
Secondary
Proportion of Participants With Relapse-Free Survival (RFS)Using the Kaplan-Meier Estimate
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low-dose Cytarabine Plus Arsenic Trioxide | Proportion of Participants With Relapse-Free Survival (RFS)Using the Kaplan-Meier Estimate | Month 6 (95% Confidence Interval) | 0.818 Proportion of participants |
| Low-dose Cytarabine Plus Arsenic Trioxide | Proportion of Participants With Relapse-Free Survival (RFS)Using the Kaplan-Meier Estimate | Month 3 (95% Confidence Interval) | 0.818 Proportion of participants |
| Low-dose Cytarabine Alone | Proportion of Participants With Relapse-Free Survival (RFS)Using the Kaplan-Meier Estimate | Month 3 (95% Confidence Interval) | 0.800 Proportion of participants |
| Low-dose Cytarabine Alone | Proportion of Participants With Relapse-Free Survival (RFS)Using the Kaplan-Meier Estimate | Month 6 (95% Confidence Interval) | 0.800 Proportion of participants |
p-value: 0.52795% CI: [0.16, 33.343]Log Rank