Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukaemia,, AML
Brief summary
The purpose of this study is to assess the efficacy, safety and tolerability of AZD1152 alone and in combination with low dose cytosine arabinoside (LDAC) in comparison with LDAC alone in AML patients.
Sponsors
AstraZeneca
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
* Provision of written informed consent * Newly diagnosed male or female patients aged 60 and over * De Novo or Secondary AML * Not eligible for intensive induction with anthracycline-based combination chemotherapy as a result of at least one of the following:Age ≥75 years; Adverse cytogenetics, e.g., as defined by the MRC Prognostic Groupings; WHO performance status \>2; Organ dysfunction arising from significant co-morbidities not directly linked to leukaemia
Exclusion criteria
* Participation in another clinical study in which an investigational product was received within 14 days before the first dose in this study, or at any time if the patient has not recovered from side-effects associated with that investigational product * Administration of LDAC is clinically contraindicated * Patients with AML of FAB M3 classification Acute Promyelocytic Leukaemia (APL) * Patients with blast crisis of chronic myeloid leukaemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Overall Complete Response for Stage I | IWG Cheson criteria every 28 days from randomization for study duration (24 months, between 2009 - 2011) | Percentage of patients achieving either a complete response (CR) or a confirmed complete remission with incomplete recovery of neutrophils or platelets (confirmed CRi). Per Cheson Criteria: Confirmed complete remission (CRi) is defined as a disappearance of blasts in the peripheral blood; a decrease in bone marrow blasts to \<5% total bone marrow nucleated cells demonstrated in bone marrow aspirate; absence of Auer rods; no persistent extramedullary leukaemia. Complete response (CR) is defined as all requirements to meet CRi and in addition: recovery of neutrophils to ≥1.0 x 109/L and platelets to ≥100 x 109/L; transfusion-independence. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival (DFS) | DFS was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011) | Disease-free Survival is defined as the time from randomisation to relapse or death from any cause. |
| Time To Complete Response (TTCR) | Response was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011) | TTCR is measured as time from randomization to either a complete response (CR) or a confirmed complete remission with incomplete recovery of neutrophils or platelets (confirmed CRi) |
| Duration of Response (DoR): Stage I and Transition Phase | DoR was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011) | DoR was defined for the median of days which showed a confirmed CRi or CR, as the time from first documented evidence of CRi or CR until the first documented sign of disease progression or death. Duration of Response was measured from the Response Start date until evidence of patient relapse or death. Stage I : 45 patients randomized in a 2:1 ratio to AZD1152 or LDAC. Transition phase: enrollment of up to 30 additional patients randomized as per stage I. |
| Percent of Patients With Worsened Trial Outcome Index (TOI) | TOI was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011) | TOI is derived from the sum of the Functional Well Being (FWB), Physical Well Being (PWB) and additional subscales of the FACT-Leu. The TOI subscale consists of 31 items with TOI scores ranging from 0 to 124. The TOI is described as a summary measure of HRQoL. Higher scores indicate better HRQoL. Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL. A response of Worsened was a change from baseline in score of less than or equal to -9. |
| Percent of Patients With Worsened Functional Assessment of Cancer Therapy - Leukaemia (FACT-Leu) Score. | FACT-Leu was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011) | The total FACT-Leu score consists of 44 items with total scores ranging from 0 to 176. Higher scores indicate better HRQoL. Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL. A response of Worsened was a change from baseline in score of less than or equal to -11. |
| Overall Survival (OS) | Assessed from randomisation until the date of death from any cause, assessed up to 24 months | Overall Survival is defined as the median time from randomisation to death from any cause. Patients who were not known to have died at the time of the analysis were censored at the date they were last known to be alive. |
Countries
Australia, France, Germany, Italy, Japan, Romania, Spain, United Kingdom, United States
Participant flow
Recruitment details
First patient was randomized on 22/07/2009 and last patient last visit has occurred on 27/06/2011.
Participants by arm
| Arm | Count |
|---|---|
| AZD1152 1200mg AZD1152 1200 mg, iv, 7 day infusion monotherapy | 48 |
| LDAC 20mg LDAC 20 mg, sc, bd, 10 days (400mg per cycle) | 26 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Death | 28 | 13 |
| Overall Study | Lack of Efficacy | 2 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 5 |
Baseline characteristics
| Characteristic | AZD1152 1200mg | LDAC 20mg | Total |
|---|---|---|---|
| Age, Continuous | 75.3 years STANDARD_DEVIATION 5.79 | 71.5 years STANDARD_DEVIATION 5.75 | 74.0 years STANDARD_DEVIATION 6.03 |
| Sex: Female, Male Female | 23 Participants | 8 Participants | 31 Participants |
| Sex: Female, Male Male | 25 Participants | 18 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 48 | 10 / 26 |
| serious Total, serious adverse events | 23 / 48 | 10 / 26 |
Outcome results
Primary
Percentage of Patients With Overall Complete Response for Stage I
Percentage of patients achieving either a complete response (CR) or a confirmed complete remission with incomplete recovery of neutrophils or platelets (confirmed CRi). Per Cheson Criteria: Confirmed complete remission (CRi) is defined as a disappearance of blasts in the peripheral blood; a decrease in bone marrow blasts to \<5% total bone marrow nucleated cells demonstrated in bone marrow aspirate; absence of Auer rods; no persistent extramedullary leukaemia. Complete response (CR) is defined as all requirements to meet CRi and in addition: recovery of neutrophils to ≥1.0 x 109/L and platelets to ≥100 x 109/L; transfusion-independence.
Time frame: IWG Cheson criteria every 28 days from randomization for study duration (24 months, between 2009 - 2011)
Population: modified Intent to Treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1152 1200mg | Percentage of Patients With Overall Complete Response for Stage I | 35.4 percentage of participants |
| LDAC 20mg | Percentage of Patients With Overall Complete Response for Stage I | 11.5 percentage of participants |
Secondary
Disease Free Survival (DFS)
Disease-free Survival is defined as the time from randomisation to relapse or death from any cause.
Time frame: DFS was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011)
Population: modified Intent to Treat (mITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD1152 1200mg | Disease Free Survival (DFS) | 5.6 months |
| LDAC 20mg | Disease Free Survival (DFS) | NA months |
Secondary
Duration of Response (DoR): Stage I and Transition Phase
DoR was defined for the median of days which showed a confirmed CRi or CR, as the time from first documented evidence of CRi or CR until the first documented sign of disease progression or death. Duration of Response was measured from the Response Start date until evidence of patient relapse or death. Stage I : 45 patients randomized in a 2:1 ratio to AZD1152 or LDAC. Transition phase: enrollment of up to 30 additional patients randomized as per stage I.
Time frame: DoR was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011)
Population: modified Intent to Treat (mITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD1152 1200mg | Duration of Response (DoR): Stage I and Transition Phase | 82 days |
| LDAC 20mg | Duration of Response (DoR): Stage I and Transition Phase | NA days |
Secondary
Overall Survival (OS)
Overall Survival is defined as the median time from randomisation to death from any cause. Patients who were not known to have died at the time of the analysis were censored at the date they were last known to be alive.
Time frame: Assessed from randomisation until the date of death from any cause, assessed up to 24 months
Population: modified Intent to Treat (mITT)
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| AZD1152 1200mg | Overall Survival (OS) | 8.2 months | Full Range 43 |
| LDAC 20mg | Overall Survival (OS) | 4.5 months | Full Range 32 |
Secondary
Percent of Patients With Worsened Functional Assessment of Cancer Therapy - Leukaemia (FACT-Leu) Score.
The total FACT-Leu score consists of 44 items with total scores ranging from 0 to 176. Higher scores indicate better HRQoL. Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL. A response of Worsened was a change from baseline in score of less than or equal to -11.
Time frame: FACT-Leu was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011)
Population: modified Intent to Treat (mITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1152 1200mg | Percent of Patients With Worsened Functional Assessment of Cancer Therapy - Leukaemia (FACT-Leu) Score. | 29.2 percentage of participants |
| LDAC 20mg | Percent of Patients With Worsened Functional Assessment of Cancer Therapy - Leukaemia (FACT-Leu) Score. | 11.5 percentage of participants |
Secondary
Percent of Patients With Worsened Trial Outcome Index (TOI)
TOI is derived from the sum of the Functional Well Being (FWB), Physical Well Being (PWB) and additional subscales of the FACT-Leu. The TOI subscale consists of 31 items with TOI scores ranging from 0 to 124. The TOI is described as a summary measure of HRQoL. Higher scores indicate better HRQoL. Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL. A response of Worsened was a change from baseline in score of less than or equal to -9.
Time frame: TOI was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011)
Population: modified Intent to Treat (mITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1152 1200mg | Percent of Patients With Worsened Trial Outcome Index (TOI) | 31.3 percentage of participants |
| LDAC 20mg | Percent of Patients With Worsened Trial Outcome Index (TOI) | 11.5 percentage of participants |
Secondary
Time To Complete Response (TTCR)
TTCR is measured as time from randomization to either a complete response (CR) or a confirmed complete remission with incomplete recovery of neutrophils or platelets (confirmed CRi)
Time frame: Response was measured every 28 days from randomization for study duration (24 months, between 2009 - 2011)
Population: modified Intent to Treat (mITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD1152 1200mg | Time To Complete Response (TTCR) | 59 days |
| LDAC 20mg | Time To Complete Response (TTCR) | 64 days |