Myelodysplastic Syndromes
Conditions
Brief summary
The objectives of this trial are to evaluate the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics and preliminary efficacy of volasertib in two dosing schedules of intravenous volasertib as monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome (MDS) after hypomethylating agents (HMA) treatment failure.
Interventions
DRUGVolasertib
DRUGAzacitidine
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
* Patients 18 years and older with diagnosis of WHO classification-defined primary or treatment-related myeloid neoplasms classified as follows: * Refractory anaemia with excess blasts (RAEB)-1 (5%-9% marrow blasts) or * RAEB-2 (10%-19% marrow blasts or 5% - 19% peripheral blast) or * Chronic Myelomonocytic Leukaemia (CMML) (5%-19% blasts) with white blood cell (WBC) count \<13000/mm3 or * Acute Myeloid Leukaemia (AML) (20%-29% marrow blasts, i.e., RAEB-t according to French-American-British \[FAB\] classification) with WBC count \<10000/mm3 * Patients classified as intermediate, high or very high-risk according to Revised - International Prognostic Scoring System (IPSS-R) at the time of enrolment * Patients who have received a maximum of 24 cycles of frontline HMA treatment prior to enrolment. * Patients must have received a minimum prior dosing schedule of either: * Azacitidine 75 mg/m2 x 5 days per cycle or 50 mg/m2 x 7 days per cycle, or * Decitabine 20 mg/m2 x 5 days per cycle, or * SGI-110 60 mg/m2 x 5 days per cycle * Patients must meet either one of the following criteria: * Progressive disease (PD, according to 2006 International Working Group (IWG) criteria) at any time after initiation of the prior HMA treatment, or * Relapse after initial complete (CR) or partial remission (PR) or haematological improvement (HI) (according to 2006 IWG criteria); or * Failure to achieve complete or partial remission or HI (according to 2006 IWG) with no evidence of progression (i.e., Stable Disease \[SD\]) after at least six cycles of prior azacitidine treatment or at least four cycles of other prior HMA treatment. * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 at screening * Signed written informed consent consistent with International Conference of Harmonization Good Clinical Practice (ICH-GCP) and local legislation
Exclusion criteria
* Prior systemic therapy (including investigational drugs) for MDS, CMML or AML within 14 days before treatment with study medication. * Patients requiring intervention for white blood cell count control with hydroxyurea, chemotherapy, or leukapheresis. * Prior exposure to more than one line of HMA based treatment. * Prior exposure to volasertib or other polo-kinase inhibitors * Patients who were unable to tolerate prior HMA treatment * Patients with history of hematopoietic stem cell transplant (HSCT) * Known hypersensitivity to the trial drugs or its excipients * Second malignancy currently requiring active therapy (except for hormonal/anti-hormonal treatment, e.g., in prostate or breast cancer). * QTcF value \>470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle | First treatment cycle, up to 28 days | DLT was defined as any of the following adverse events (AEs) considered to be related to study drug: 1. Common terminology criteria for adverse events (CTCAE) v4.03 ≥Grade 3 drug related non- haematological toxicity, excluding; ≥Grade 3 untreated nausea, vomiting or diarrhea. Any laboratory abnormality - not considered clinically significant by investigator or resolved spontaneously or could have been recovered with appropriate treatment within 7 days. Grade 3 infection which could be recovered with appropriate treatment within 7 days. Azacitidine injection site reaction or complications related to azacitidine injection. 2. Febrile neutropenia as defined by CTCAE which could not recovered with appropriate treatment within 7 days. 3. Inability to deliver full dose of volasertib according to the assigned dose level within Cycle 1 due to drug-related AEs. 4. Haematological DLTs. 5. Any other drug-related AEs that resulted in the delay of starting new treatment cycle for ≥4 weeks. |
| Maximum Tolerated Dose (MTD) of Volasertib | First treatment cycle, up to 28 days | The MTD was defined as the highest dose with less than 35% risk of the true dose limiting toxicities (DLT) rate being above 0.33 for schedule A, and the highest dose with less than 40% risk of the true DLT rate being above 0.33 for schedule B. The phase I dose-finding was to be guided by a Bayesian 2-parameter logistic regression model (BLRM) with overdose control in each schedule separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy) | PK samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration | Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy). |
| Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria | Up to 168 days | Objective response defined as best overall response of complete remission, partial remission or haematological improvement according to the International Working Group 2006 criteria. It is based on Complete remission (CR): Bone marrow: \<=5% myeloblasts with normal maturation of all cell lines, Peripheral blood: Hemoglobin \>=11 Grams Per Decilitre (g/dL), Platelets \>=100 x 109/L, Neutrophils \>=1.0 x 109/L, Blasts 0%. Peripheral blood responses had to last at least 4 weeks to qualify for CR. Partial remission (PR): All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by \>=50% to baseline but still \>5%, Cellularity and morphology not relevant. Peripheral blood responses must last at least 4 weeks to qualify for PR. Haematological improvement (HI): HI was evaluated in patients with abnormal pretreatment values based on Erythroid response, Platelet response, Neutrophil response. Peripheral blood responses had to last at least 8 weeks to qualify for HI. |
| Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Combination) | PK samples were to be taken at 5 minutes before drug administration (167:55) and 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after first drug administration of Azacitidine | Maximum measured plasma concentration of volasertib (Cmax) (for combination). |
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity of Volasertib (AUC0-∞) (for Combination) | PK samples were to be taken at 5 minutes before drug administration (167:55) and 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after first drug administration of Azacitidine | Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity of volasertib (AUC0-∞) (for combination). |
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Measured Time Point tz of Volasertib (AUC0-tz) (for Monotherapy) | Pharmacokinetic (PK) samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration | Area under the plasma concentration-time curve over the time interval from zero to the last measured time point tz of volasertib (AUC0-tz) (for monotherapy). |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Volasertib Monotherapy Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle | 1 |
| Volasertib + Azacitidine Combination Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle | 0 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Progressive disease/relapse | 1 | 0 |
Baseline characteristics
| Characteristic | Volasertib Monotherapy | Total |
|---|---|---|
| Age, Continuous | 69 Years | 69 Years |
| Sex: Female, Male Female | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 1 / 1 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Volasertib
The MTD was defined as the highest dose with less than 35% risk of the true dose limiting toxicities (DLT) rate being above 0.33 for schedule A, and the highest dose with less than 40% risk of the true DLT rate being above 0.33 for schedule B. The phase I dose-finding was to be guided by a Bayesian 2-parameter logistic regression model (BLRM) with overdose control in each schedule separately.
Time frame: First treatment cycle, up to 28 days
Population: Treated Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Volasertib Monotherapy | Maximum Tolerated Dose (MTD) of Volasertib | NA Milligram (mg)/ meter square (m2) |
Primary
Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle
DLT was defined as any of the following adverse events (AEs) considered to be related to study drug: 1. Common terminology criteria for adverse events (CTCAE) v4.03 ≥Grade 3 drug related non- haematological toxicity, excluding; ≥Grade 3 untreated nausea, vomiting or diarrhea. Any laboratory abnormality - not considered clinically significant by investigator or resolved spontaneously or could have been recovered with appropriate treatment within 7 days. Grade 3 infection which could be recovered with appropriate treatment within 7 days. Azacitidine injection site reaction or complications related to azacitidine injection. 2. Febrile neutropenia as defined by CTCAE which could not recovered with appropriate treatment within 7 days. 3. Inability to deliver full dose of volasertib according to the assigned dose level within Cycle 1 due to drug-related AEs. 4. Haematological DLTs. 5. Any other drug-related AEs that resulted in the delay of starting new treatment cycle for ≥4 weeks.
Time frame: First treatment cycle, up to 28 days
Population: Treated Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Volasertib Monotherapy | Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle | 0 Participants |
Secondary
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity of Volasertib (AUC0-∞) (for Combination)
Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity of volasertib (AUC0-∞) (for combination).
Time frame: PK samples were to be taken at 5 minutes before drug administration (167:55) and 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after first drug administration of Azacitidine
Population: Due to premature discontinuation of the trial no patient is recruited for combination therapy.
Secondary
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Measured Time Point tz of Volasertib (AUC0-tz) (for Monotherapy)
Area under the plasma concentration-time curve over the time interval from zero to the last measured time point tz of volasertib (AUC0-tz) (for monotherapy).
Time frame: Pharmacokinetic (PK) samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration
Population: All evaluable patients were to be included in the PK analysis. Patients who were considered as not evaluable were to be listed with their individual plasma concentrations and individual PK parameters; however, they were not to be included in descriptive statistics for plasma concentrations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Volasertib Monotherapy | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Measured Time Point tz of Volasertib (AUC0-tz) (for Monotherapy) | Cycle 1 - Day 1 | 2480 Nanogram(ng)*hour(h)/milliliter(mL) |
| Volasertib Monotherapy | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Measured Time Point tz of Volasertib (AUC0-tz) (for Monotherapy) | Cycle 1 - Day 8 | 5460 Nanogram(ng)*hour(h)/milliliter(mL) |
Secondary
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Combination)
Maximum measured plasma concentration of volasertib (Cmax) (for combination).
Time frame: PK samples were to be taken at 5 minutes before drug administration (167:55) and 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after first drug administration of Azacitidine
Population: Due to premature discontinuation of the trial no patient is recruited for combination therapy.
Secondary
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy)
Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy).
Time frame: PK samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration
Population: All evaluable patients were to be included in the Pharmacokinetic (PK) analysis. Patients who were considered as not evaluable were to be listed with their individual plasma concentrations and individual PK parameters; however, they were not to be included in descriptive statistics for plasma concentrations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Volasertib Monotherapy | Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy) | Cycle 1 - Day 1 | 467 Nanogram(ng)*/milliliter(mL) |
| Volasertib Monotherapy | Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy) | Cycle 1 - Day 8 | 553 Nanogram(ng)*/milliliter(mL) |
Secondary
Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria
Objective response defined as best overall response of complete remission, partial remission or haematological improvement according to the International Working Group 2006 criteria. It is based on Complete remission (CR): Bone marrow: \<=5% myeloblasts with normal maturation of all cell lines, Peripheral blood: Hemoglobin \>=11 Grams Per Decilitre (g/dL), Platelets \>=100 x 109/L, Neutrophils \>=1.0 x 109/L, Blasts 0%. Peripheral blood responses had to last at least 4 weeks to qualify for CR. Partial remission (PR): All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by \>=50% to baseline but still \>5%, Cellularity and morphology not relevant. Peripheral blood responses must last at least 4 weeks to qualify for PR. Haematological improvement (HI): HI was evaluated in patients with abnormal pretreatment values based on Erythroid response, Platelet response, Neutrophil response. Peripheral blood responses had to last at least 8 weeks to qualify for HI.
Time frame: Up to 168 days
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Volasertib Monotherapy | Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria | Yes | 0 Participants |
| Volasertib Monotherapy | Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria | No | 1 Participants |