- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02721875
Trial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes
August 8, 2018 updated by: Boehringer Ingelheim
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
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.
Study Overview
Status
Terminated
Conditions
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
1
Phase
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Fukui, Yoshida-gun, Japan, 910-1193
- University of Fukui Hospital
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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).
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Volasertib monotherapy
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Experimental: Volasertib + azacitidine combination
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle
Time Frame: First treatment cycle, up to 28 days
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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.
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First treatment cycle, up to 28 days
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Maximum Tolerated Dose (MTD) of Volasertib
Time Frame: First treatment cycle, up to 28 days
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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.
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First treatment cycle, up to 28 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria
Time Frame: Up to 168 days
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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.
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Up to 168 days
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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
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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).
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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
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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
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Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy).
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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
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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
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Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity of volasertib (AUC0-∞) (for combination).
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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
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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
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Maximum measured plasma concentration of volasertib (Cmax) (for combination).
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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
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
April 28, 2016
Primary Completion (Actual)
June 29, 2016
Study Completion (Actual)
July 29, 2016
Study Registration Dates
First Submitted
March 23, 2016
First Submitted That Met QC Criteria
March 23, 2016
First Posted (Estimate)
March 29, 2016
Study Record Updates
Last Update Posted (Actual)
August 9, 2018
Last Update Submitted That Met QC Criteria
August 8, 2018
Last Verified
August 1, 2018
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1230.43
- 2015-004490-32 (EudraCT Number)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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