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To identify the maximum tolerated dose or recommended dose for further development of volasertib in combination with azacitidine in Japanese patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, and evaluate the safety and tolerability, pharmacokinetics and the preliminary efficacy of this combination.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| A | Experimental | Volasertib escalating doses + azacitidine |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Azacitidine | Drug | Azacitidine (subcutaneous) |
| |
| Volasertib |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | This outcome measure presents number of participants with DLTs in the first cycle for the determination of MTD. DLT was defined as any of the following Adverse Events (AEs) considered to be related to the study drug (Volasertib and/or Azacitidine).
| Up to 57 days. |
| Maximum Tolerated Dose of Volasertib | This outcome measure presents MTD of Volasertib in Combination with Azacitidine. The MTD was defined as the highest dose level at which Dose Limiting Toxicities (DLTs) were reported in not more than 1 in 6 evaluable patients during Cycle 1. | Up to 57 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR) | This outcome measure presents overall Objective Response (CR+PR+mCR). Response to treatment was evaluated according to the International Working Group (IWG) 2006 criteria. Best response was tabulated from all available data, with each patient being classified into one of the categories defined in CR, PR, mCR. |
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Inclusion criteria:
Patients of age >=20 and <=80 years
Patients with primary or treatment-related myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), who are not eligible for hematopoietic stem cell transplantation based on the investigator's judgment, that meet one of the following criteria:
Patients with no prior azacitidine treatment, or with prior azacitidine treatment that meet one of the following criteria:
Eastern Cooperative Oncology Group performance status score 0 or 1 at screening
Signed written informed consent consistent with Good Clinical Practice.
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Boehringer Ingelheim | Boehringer Ingelheim | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boehringer Ingelheim Investigational Site | Aichi, Nagoya | Japan | ||||
| Boehringer Ingelheim Investigational Site |
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| ID | Title | Description |
|---|---|---|
| FG000 | Volasertib 200 mg | The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Drug |
Volasertib escalating doses (intravenous) |
|
| Up to 9 months. |
| Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax) | This outcome measure presents maximum measured concentration of Volasertib 200 mg in plasma (Cmax). | -0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration. |
| Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | This outcome measure presents area under the concentration-time curve of Volasertib 200 mg + Azacitidine 75 mg/m^2 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). | -0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration. |
| Gunma, Maebashi |
| Japan |
| Boehringer Ingelheim Investigational Site | Nagasaki, Nagasaki | Japan |
| Boehringer Ingelheim Investigational Site | Tokyo, Sinagawa-ku | Japan |
| COMPLETED |
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| NOT COMPLETED |
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Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.
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| ID | Title | Description |
|---|---|---|
| BG000 | Volasertib 200 mg | The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | Years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | This outcome measure presents number of participants with DLTs in the first cycle for the determination of MTD. DLT was defined as any of the following Adverse Events (AEs) considered to be related to the study drug (Volasertib and/or Azacitidine).
| MTD Set: This patient set included all patients in the treated set who were evaluable for MTD determination. | Posted | Number | Participants | Up to 57 days. |
|
|
| ||||||||||||||||||||||||||
| Primary | Maximum Tolerated Dose of Volasertib | This outcome measure presents MTD of Volasertib in Combination with Azacitidine. The MTD was defined as the highest dose level at which Dose Limiting Toxicities (DLTs) were reported in not more than 1 in 6 evaluable patients during Cycle 1. | MTD Set: This patient set included all patients in the treated set who were evaluable for MTD determination. | Posted | Number | mg | Up to 57 days. |
|
| |||||||||||||||||||||||||||
| Secondary | Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR) | This outcome measure presents overall Objective Response (CR+PR+mCR). Response to treatment was evaluated according to the International Working Group (IWG) 2006 criteria. Best response was tabulated from all available data, with each patient being classified into one of the categories defined in CR, PR, mCR. | Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine. | Posted | Number | Participants | Up to 9 months. |
|
| |||||||||||||||||||||||||||
| Secondary | Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax) | This outcome measure presents maximum measured concentration of Volasertib 200 mg in plasma (Cmax). | Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | -0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration. |
|
| ||||||||||||||||||||||||||
| Secondary | Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | This outcome measure presents area under the concentration-time curve of Volasertib 200 mg + Azacitidine 75 mg/m^2 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). | Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | -0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration. |
|
|
From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Volasertib 200 mg | The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle. | 2 | 5 | 5 | 5 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Disseminated intravascular coagulation | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
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| Hypersensitivity | Immune system disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
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| Pyelonephritis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
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| Dehydration | Metabolism and nutrition disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Acute kidney injury | Renal and urinary disorders | MedDRA 18.1 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
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| Neutropenia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
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| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Arrhythmia | Cardiac disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Eyelids pruritus | Eye disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Enterocolitis | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Stomatitis | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Tongue coated | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Injection site reaction | General disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Peripheral swelling | General disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Hepatic function abnormal | Hepatobiliary disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Hypersensitivity | Immune system disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Paronychia | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
| |
| Pharyngitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
| |
| Contusion | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA 18.1 | Systematic Assessment |
| |
| Aspartate aminotransferase increased | Investigations | MedDRA 18.1 | Systematic Assessment |
| |
| Blood alkaline phosphatase increased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| Blood creatine phosphokinase increased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| Blood creatinine increased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| Gamma-glutamyltransferase increased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| Haemoglobin decreased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| Neutrophil count decreased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| Platelet count decreased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| Weight decreased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| White blood cell count decreased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA 18.1 | Systematic Assessment |
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| Dehydration | Metabolism and nutrition disorders | MedDRA 18.1 | Systematic Assessment |
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| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 18.1 | Systematic Assessment |
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| Iron overload | Metabolism and nutrition disorders | MedDRA 18.1 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Dysgeusia | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
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| Renal impairment | Renal and urinary disorders | MedDRA 18.1 | Systematic Assessment |
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| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
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| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
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| Drug eruption | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Purpura | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Systematic Assessment |
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Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boehringer Ingelheim Call Center | Boehringer Ingelheim | 1-800-243-0127 | clintriage.rdg@boehringer-ingelheim.com |
| ID | Term |
|---|---|
| D009190 | Myelodysplastic Syndromes |
| D015477 | Leukemia, Myelomonocytic, Chronic |
| ID | Term |
|---|---|
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D054437 | Myelodysplastic-Myeloproliferative Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D001374 | Azacitidine |
| C541363 | BI 6727 |
| ID | Term |
|---|---|
| D001372 | Aza Compounds |
| D009930 | Organic Chemicals |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
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