Leukemia, Myeloid, Acute
Conditions
Brief summary
To investigate the efficacy, safety, and pharmacokinetics of intravenous volasertib + subcutaneous low dose cytarabine in patients \>= 65 years of age with previously untreated acute myeloid leukaemia, ineligible for intensive remission induction therapy
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \>= 65years. 2. Cytologically/histologically confirmed acute myeloid leukaemia (AML) according to WHO classification; (except for acute promyelocytic leukaemia (APL). 3. Previously untreated AML (except for hydroxyurea and/or corticosteroid therapy for no more than 28 days (cumulative)). Previous therapy for Myelodysplastic Syndrome (MDS) is allowed. 4. Investigator considers patient ineligible for intensive remission induction therapy based on documented medical reasons (e.g. disease characteristics like AML genetics, type of AML (de novo or secondary), and patient characteristics like performance score, concomitant diagnoses, organ dysfunctions). 5. Patient is eligible for Low-Dose Cytarabine (LDAC) treatment. 6. Eastern co-operative oncology group (ECOG) performance score \<= 2 at screening. 7. Signed and dated written informed consent by start date of Screening visit in accordance with Good Clinical Practice (GCP) and local legislation.
Exclusion criteria
1. Prior or concomitant chemotherapy for AML (with the exception of hydroxyurea and/or corticosteroid therapy for no more than 28 days (cumulative)). Please note that any prior therapy for MDS is allowed. 2. Treatment with any investigational drug within 2 weeks before first administration of present trial drug. 3. Acute promyelocytic leukaemia (French-American-British (FAB) classification subtype M3). 4. Current clinical central nervous system (CNS) symptoms deemed by the investigator to be related to leukaemic CNS involvement (no lumbar puncture required, clinical assessment per investigator´s judgement is sufficient). 5. Hypersensitivity to one of the trial drugs or the excipients. 6. Severe illness or organ dysfunction involving the heart, kidney, liver or other organ system (e.g. active infection, clinically relevant impairment of cardiac function, severe heart failure/cardiac insufficiency, unstable angina pectoris or history of recent myocardial infarction), which in the opinion of the investigator precludes treatment with LDAC. 7. Corrected QT interval according to Fridericia (QTcF) prolongation \> 470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the mean of the 3 Electrocardiogram (ECGs) taken at screening. 8. Total bilirubin \> 3 x upper limit of normal (ULN). 9. Creatinine clearance (CLcr) \< 30 ml/min (estimated creatinine clearance by the Cockcroft-Gault (C-G) equation) . 10. Active hepatitis B or hepatitis C, or laboratory evidence for a chronic infection. 11. HIV infection. 12. Second malignancy currently requiring active therapy (except for hormonal/anti-hormonal treatment e.g. in prostate or breast cancer). 13. Any significant concurrent psychiatric disorder or social situation that according to the investigator´s judgement would compromise patient´s safety or compliance, interfere with consent, study participation, or interpretation of study results. 14. Known or suspected active alcohol or drug abuse. 15. Patient unable to comply with the protocol, in the opinion of the investigator. 16. Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second medically acceptable method of contraception during the trial and for a minimum of 6 months after study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response (OR) | Response assessment was performed at the end of every 2nd cycle, (i.e. at the end of Cycle 2, 4, 6, 8, etc., and at end of treatment), i.e. up to 52 months. | OR is the number of patients who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi), where OR was based on the best response attained during the treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization until death due to any cause, up to 1557 days. | OS is the key secondary endpoint and was measured from the date of randomization until death from any cause. Patients who were lost to follow-up were censored on the last date they were known to be alive. |
| Event-free Survival (EFS) | From randomization until disease progression or relapse or death from any cause, up to 1557 days. | EFS was measured from the date of randomisation to the date of progression or relapse, or death from any cause, whichever occurred first. |
| Relapse-free Survival (RFS) | From randomization until disease progression or relapse or death from any cause, up to 1557 days. | RFS was defined only for patients who achieved best overall response of CR or CRi; it was measured from the date of achievement of a remission until the date of relapse or death from any cause. Patients not known to have relapsed or died at last follow-up were censored on the date they were last examined. |
Countries
Argentina, Austria, Belgium, Brazil, Canada, Czechia, Finland, France, Germany, Greece, Hungary, India, Italy, Japan, Mexico, Netherlands, Norway, Poland, Portugal, Russia, South Africa, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
Patients aged 65 years or more with previously untreated acute myeloid leukaemia, who are ineligible for intensive remission induction therapy were recruited in the phase III randomised, double-blind, placebo-controlled, parallel group study.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended a specialist sites which ensured that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria was violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Low-dose Cytarabine Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle. | 222 |
| Volasertib + Low-dose Cytarabine Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle. | 444 |
| Total | 666 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 41 | 165 |
| Overall Study | Death | 6 | 13 |
| Overall Study | Disease progression / relapse | 123 | 156 |
| Overall Study | Not treated | 1 | 4 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Reason not listed | 34 | 63 |
| Overall Study | Sponsor terminated trial | 0 | 4 |
| Overall Study | Withdrawal by Subject | 15 | 38 |
Baseline characteristics
| Characteristic | Volasertib + Low-dose Cytarabine | Total | Placebo + Low-dose Cytarabine |
|---|---|---|---|
| Age, Continuous | 75.2 Years STANDARD_DEVIATION 5.4 | 75.3 Years STANDARD_DEVIATION 5.2 | 75.5 Years STANDARD_DEVIATION 4.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 26 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 399 Participants | 593 Participants | 194 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 29 Participants | 47 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 74 Participants | 113 Participants | 39 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 38 Participants | 63 Participants | 25 Participants |
| Race (NIH/OMB) White | 328 Participants | 486 Participants | 158 Participants |
| Sex: Female, Male Female | 203 Participants | 290 Participants | 87 Participants |
| Sex: Female, Male Male | 241 Participants | 376 Participants | 135 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 40 / 222 | 138 / 439 |
| other Total, other adverse events | 203 / 222 | 404 / 439 |
| serious Total, serious adverse events | 163 / 222 | 380 / 439 |
Outcome results
Primary
Objective Response (OR)
OR is the number of patients who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi), where OR was based on the best response attained during the treatment period.
Time frame: Response assessment was performed at the end of every 2nd cycle, (i.e. at the end of Cycle 2, 4, 6, 8, etc., and at end of treatment), i.e. up to 52 months.
Population: The randomised set (RS) included all patients who had been randomised at the database snapshot.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Low-dose Cytarabine | Objective Response (OR) | 38 Participants |
| Volasertib + Low-dose Cytarabine | Objective Response (OR) | 123 Participants |
Comparison: This analysis was exploratory and descriptive.p-value: 0.002495% CI: [1.2432, 2.8281]Cochran-Mantel-Haenszel
Secondary
Event-free Survival (EFS)
EFS was measured from the date of randomisation to the date of progression or relapse, or death from any cause, whichever occurred first.
Time frame: From randomization until disease progression or relapse or death from any cause, up to 1557 days.
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Low-dose Cytarabine | Event-free Survival (EFS) | 2.8 Months |
| Volasertib + Low-dose Cytarabine | Event-free Survival (EFS) | 3.3 Months |
Comparison: This analysis was exploratory and descriptive.p-value: 0.671895% CI: [0.8, 1.2]Regression, Cox
Secondary
Overall Survival (OS)
OS is the key secondary endpoint and was measured from the date of randomization until death from any cause. Patients who were lost to follow-up were censored on the last date they were known to be alive.
Time frame: From randomization until death due to any cause, up to 1557 days.
Population: RS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Low-dose Cytarabine | Overall Survival (OS) | 6.5 Months |
| Volasertib + Low-dose Cytarabine | Overall Survival (OS) | 5.6 Months |
Comparison: This analysis was exploratory and descriptive.p-value: 0.757195% CI: [0.8, 1.2]Regression, Cox
Secondary
Relapse-free Survival (RFS)
RFS was defined only for patients who achieved best overall response of CR or CRi; it was measured from the date of achievement of a remission until the date of relapse or death from any cause. Patients not known to have relapsed or died at last follow-up were censored on the date they were last examined.
Time frame: From randomization until disease progression or relapse or death from any cause, up to 1557 days.
Population: All patients in the RS who achieved best overall response of CR or CRi.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Low-dose Cytarabine | Relapse-free Survival (RFS) | 18.7 Months |
| Volasertib + Low-dose Cytarabine | Relapse-free Survival (RFS) | 13.1 Months |
95% CI: [0.7, 2.7]Regression, Cox