Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic
Conditions
Brief summary
To investigate the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of volasertib in combination with azacitidine in patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) and not candidates for hematopoietic stem cell transplant
Interventions
DRUGAzacitidine
DRUGVolasertib
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients with previously untreated, intermediate-2 or high- risk MDS or CMML not eligible for hematopoietic stem cell transplantation (HSCT) based on documented patients characteristics like age, performance status, concomitant diagnoses, and organ dysfunctions * Further inclusion criteria apply
Exclusion criteria
* Prior or concomitant therapy for higher risk MDS (for example, but not limited to, hypomethylating agents like azacitidine). Note: Prior treatment with erythropoetin (EPO) is allowed up to \> 1 week before treatment with study medication. Patients must have not received MDS therapy since diagnosis of higher-risk MDS. However, previous lenalidomide treatment could have been administered for lower-risk MDS treatment as long as this therapy was discontinued at least \> 4 weeks before initiation of the current study treatment. * Treatment with any investigational drug within 2 weeks before first administration of present trial drug or within less than 5 half lives of the investigational drug before treatment with the present trial drug, whichever is longer. * Second malignancy currently requiring active therapy (except for hormonal/anti-hormonal treatment, e.g. in prostate or breast cancer). * 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 Electrocardiograms (ECGs) taken at screening. * Total bilirubin \> 1.5 x upper limit of normal not related to Gilberts disease, hemolysis, or secondary to MDS. * Aspartate amino transferase (AST) or alanine amino transferase (ALT) \> 2.5 x the upper limit of normal (ULN) Creatinine \> 1.5 x ULN * Active hepatitis B or hepatitis C, or laboratory evidence for a chronic infection (hepatitis test results done in routine diagnostics are acceptable if done within 14 days before first study treatment dose). * HIV infection (HIV test results in routine diagnostics are acceptable if done within 14 days before first study treatment dose). * Severe illness or organ dysfunction involving the kidney, liver or other organ system (e.g. active uncontrolled infection , unstable angina pectoris or history of severe congestive heart failure, clinically unstable cardiac disease or pulmonary disease), which in the opinion of the investigator would interfere with the evaluation of the safety of the study treatment * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determination of the Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose-limiting Toxicity (DLT) in Cycle 1 | 4 weeks | The primary objective of the dose-escalation part of this study was to determine the MTD of volasertib in combination with azacitidine. The MTD was to be identified based on the DLT information collected during the first treatment cycle of each dosing schedule. DLT was defined as a non-haematological drug-related toxicity of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3. The MTD corresponded to the highest dose of volasertib and azacitidine at which the incidence of DLT was ≤17% (i.e. 1/6 patients) during Cycle 1. The planned dose escalation schedules of Part 2 were not completed because the trial was prematurely discontinued. Hence, a final conclusion of the MTD of volasertib in combination with azacitidine cannot be drawn in this trial. Number of patients with DLT in cycle 1 in escalation part is presented to determine MTD. |
| Number of Participants With Dose Limiting Toxicities (DLT) in Cycle 1 | 4 weeks | Number of participants with Dose Limiting Toxicities (DLT) in Cycle 1 (escalation part to determine MTD) is presented . |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Objective Response (OR) | From randomisation until data cut-off (16Dec2016); up to 159 weeks | OR was defined as best overall response of complete remission (CR) or partial remission (PR) defined according to the International Working Group (IWG) 2006 criteria. Complete remission (CR): * Bone marrow: \<5 % myeloblasts with normal maturation of all cell lines\* * Persistent dysplasia will be noted\* * Peripheral blood: * hemoglobin (Hgb) \> 11 Grams Per Decilitre (g/dL) * Platelets \>100 x 109/L * Neutrophils \> 1.0 x 109/L * Blasts 0 % \*Dysplastic changes should consider the normal range of dysplastic changes Partial remission (PR): All CR criteria if abnormal before treatment except: * Bone marrow blasts decreased by \>50% to pre-treatment but still \>5% * Cellularity and morphology not relevant |
Countries
France, Germany
Participant flow
Recruitment details
The trial had 2 parts.
Pre-assignment details
Part 1:Starting dose of volasertib 250 mg administered on Day1 and Day15.The dose was escalated in 50 mg steps up to 300 mg.Flat dosing in Part 1. Part 2:volasertib dosing on Day1 in schedule A, on Day7 in schedule B, on Day1+ Day7 in schedule C.Body surface area (BSA) adapted dosing in Part 2. In each cycle, azacitidine was given from Day1 to 7
Participants by arm
| Arm | Count |
|---|---|
| Volasertib 250 mg + Azacitidine (Escalation Cohort)-Part 1 Patients were intravenously administered escalating dose of volasertib 250 milligram (mg) (Volasertib (BI 6727), solution for infusion) on Day 1+15 (28-day cycle) combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 milligram / square meter (mg/m2) once daily on Days 1 to 7 (28- day cycle) | 6 |
| Volasertib 300 mg + Azacitidine (Escalation Cohort)- Part 1 Patients were intravenously administered escalating dose of volasertib 300 mg (Volasertib (BI 6727), solution for infusion) on Day 1+15 (28-day cycle) combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 mg/m2 once daily on Days 1 to 7 (28-day cycle) | 6 |
| Volasertib 250 mg + Azacitidine (Expansion Cohort)- Part 1 Patients were intravenously administered volasertib 250 mg (Volasertib (BI 6727), solution for infusion) on Day 1+15 (28-day cycle) combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 mg/m2 once daily on Days 1 to 7 (28-day cycle) in the expansion cohort | 1 |
| Volasertib 170 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 Patients were intravenously administered escalating dose of volasertib 170 mg/m2 (Volasertib (BI 6727), solution for infusion) on Day 7 combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 mg/m2 once daily on Days 1 to 7 (28-day cycle) | 2 |
| Volasertib 110 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 Patients were intravenously administered escalating dose of volasertib 110 mg/m2 (Volasertib (BI 6727), solution for infusion) on Day1 and Day 7 combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 mg/m2 once daily on Days 1 to 7 (28-day cycle) | 1 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 | 0 | 0 | 1 |
| Overall Study | Other reason | 1 | 2 | 1 | 1 | 0 |
| Overall Study | Progressive disease / relapse | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Volasertib 250 mg + Azacitidine (Escalation Cohort)-Part 1 | Volasertib 300 mg + Azacitidine (Escalation Cohort)- Part 1 | Volasertib 250 mg + Azacitidine (Expansion Cohort)- Part 1 | Volasertib 170 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 | Volasertib 110 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 69.5 years STANDARD_DEVIATION 8.2 | 69.2 years STANDARD_DEVIATION 7.7 | 60.0 years | 64.5 years STANDARD_DEVIATION 13.4 | 81.0 years | 68.9 years STANDARD_DEVIATION 8.5 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 1 Participants | 2 Participants | 0 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 5 / 6 | 1 / 1 | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 6 / 6 | 2 / 6 | 0 / 1 | 0 / 2 | 1 / 1 |
Outcome results
Primary
Determination of the Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose-limiting Toxicity (DLT) in Cycle 1
The primary objective of the dose-escalation part of this study was to determine the MTD of volasertib in combination with azacitidine. The MTD was to be identified based on the DLT information collected during the first treatment cycle of each dosing schedule. DLT was defined as a non-haematological drug-related toxicity of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3. The MTD corresponded to the highest dose of volasertib and azacitidine at which the incidence of DLT was ≤17% (i.e. 1/6 patients) during Cycle 1. The planned dose escalation schedules of Part 2 were not completed because the trial was prematurely discontinued. Hence, a final conclusion of the MTD of volasertib in combination with azacitidine cannot be drawn in this trial. Number of patients with DLT in cycle 1 in escalation part is presented to determine MTD.
Time frame: 4 weeks
Population: MTD set: The MTD set was used for the first treatment cycle (Cycle 1) analysis and excluded any treated patients that missed any dose of trial medication in Cycle 1 for reasons other than DLT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Volasertib 250 mg + Azacitidine (Escalation Cohort)-Part 1 | Determination of the Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose-limiting Toxicity (DLT) in Cycle 1 | NA Milligram (mg) |
| Volasertib 300 mg + Azacitidine (Escalation Cohort)- Part 1 | Determination of the Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose-limiting Toxicity (DLT) in Cycle 1 | NA Milligram (mg) |
| Volasertib 170 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 | Determination of the Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose-limiting Toxicity (DLT) in Cycle 1 | NA Milligram (mg) |
| Volasertib 110 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 | Determination of the Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose-limiting Toxicity (DLT) in Cycle 1 | NA Milligram (mg) |
Primary
Number of Participants With Dose Limiting Toxicities (DLT) in Cycle 1
Number of participants with Dose Limiting Toxicities (DLT) in Cycle 1 (escalation part to determine MTD) is presented .
Time frame: 4 weeks
Population: MTD set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Volasertib 250 mg + Azacitidine (Escalation Cohort)-Part 1 | Number of Participants With Dose Limiting Toxicities (DLT) in Cycle 1 | 1 participants |
| Volasertib 300 mg + Azacitidine (Escalation Cohort)- Part 1 | Number of Participants With Dose Limiting Toxicities (DLT) in Cycle 1 | 1 participants |
| Volasertib 170 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 | Number of Participants With Dose Limiting Toxicities (DLT) in Cycle 1 | 0 participants |
| Volasertib 110 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 | Number of Participants With Dose Limiting Toxicities (DLT) in Cycle 1 | 1 participants |
Secondary
Percentage of Patients With Objective Response (OR)
OR was defined as best overall response of complete remission (CR) or partial remission (PR) defined according to the International Working Group (IWG) 2006 criteria. Complete remission (CR): * Bone marrow: \<5 % myeloblasts with normal maturation of all cell lines\* * Persistent dysplasia will be noted\* * Peripheral blood: * hemoglobin (Hgb) \> 11 Grams Per Decilitre (g/dL) * Platelets \>100 x 109/L * Neutrophils \> 1.0 x 109/L * Blasts 0 % \*Dysplastic changes should consider the normal range of dysplastic changes Partial remission (PR): All CR criteria if abnormal before treatment except: * Bone marrow blasts decreased by \>50% to pre-treatment but still \>5% * Cellularity and morphology not relevant
Time frame: From randomisation until data cut-off (16Dec2016); up to 159 weeks
Population: Efficacy set (ES): All the treated patients without any protocol violations related to efficacy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Volasertib 250 mg + Azacitidine (Escalation Cohort)-Part 1 | Percentage of Patients With Objective Response (OR) | 33.3 percentage of participants |
| Volasertib 300 mg + Azacitidine (Escalation Cohort)- Part 1 | Percentage of Patients With Objective Response (OR) | 20.0 percentage of participants |
| Volasertib 170 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 | Percentage of Patients With Objective Response (OR) | 0.0 percentage of participants |
| Volasertib 110 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 | Percentage of Patients With Objective Response (OR) | 0.0 percentage of participants |
| Volasertib 110 mg/m2 + Azacitidine (Escalation Cohort)- Part 2 | Percentage of Patients With Objective Response (OR) | 0.0 percentage of participants |