Back to resultsTrial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes
Primary Purpose
Myelodysplastic Syndromes
Status
Terminated
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
Volasertib
Volasertib
Azacitidine
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndromes
Eligibility Criteria
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).
Sites / Locations
- University of Fukui Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Volasertib monotherapy
Volasertib + azacitidine combination
Arm Description
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
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).
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy)
Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy).
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).
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Combination)
Maximum measured plasma concentration of volasertib (Cmax) (for combination).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02721875
Brief Title
Trial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes
Official Title
An Open Label, Phase I Trial of Intravenous Administration of Volasertib as Monotherapy and in Combination With Azacitidine in Patients With Myelodysplastic Syndrome After Hypomethylating Agents Treatment Failure
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Terminated
Study Start Date
April 28, 2016 (Actual)
Primary Completion Date
June 29, 2016 (Actual)
Study Completion Date
July 29, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim
4. Oversight
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
1 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Volasertib monotherapy
Arm Type
Experimental
Arm Title
Volasertib + azacitidine combination
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Volasertib
Intervention Type
Drug
Intervention Name(s)
Volasertib
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Primary Outcome Measure Information:
Title
Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle
Description
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
Title
Maximum Tolerated Dose (MTD) of Volasertib
Description
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
Secondary Outcome Measure Information:
Title
Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria
Description
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
Title
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)
Description
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
Title
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy)
Description
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
Title
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity of Volasertib (AUC0-∞) (for Combination)
Description
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
Title
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Combination)
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boehringer Ingelheim
Organizational Affiliation
Boehringer Ingelheim
Official's Role
Study Chair
Facility Information:
Facility Name
University of Fukui Hospital
City
Fukui, Yoshida-gun
ZIP/Postal Code
910-1193
Country
Japan
12. IPD Sharing Statement
Links:
URL
http://trials.boehringer-ingelheim.com
Description
Related Info
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Trial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes
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