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| ID | Type | Description | Link |
|---|---|---|---|
| 2015-004490-32 | EudraCT Number |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Volasertib monotherapy | Experimental |
| |
| Volasertib + azacitidine combination | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Volasertib | Drug |
| ||
| Volasertib |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | First treatment cycle, up to 28 days |
| 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. | First treatment cycle, up to 28 days |
| 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 | 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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Inclusion criteria:
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Boehringer Ingelheim | Boehringer Ingelheim | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Fukui Hospital | Fukui, Yoshida-gun | 910-1193 | Japan |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
All patients who were documented to receive at least one dose of volasertib were defined as the treated set (TS).
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Volasertib + Azacitidine Combination |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 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. | Treated Set | Posted | Number | Participants | First treatment cycle, up to 28 days |
|
From first drug administration until 30 days after the last dose of study medication, up to 94 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 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lower gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cataract | Eye disorders | MedDRA 19.1 | Systematic Assessment |
Trial was prematurely discontinued and only one patient was treated. So it was not possible to draw any conclusion about volasertib monotherapy/with azacitidine, in patients with Myelodysplastic syndrome after Hypomethylating agent treatment failure
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boehringer Ingelheim, Call Center | Boehringer Ingelheim | 1-800-243-0127 | clintriage.rdg@boehringer-ingelheim.com |
| ID | Term |
|---|---|
| D009190 | Myelodysplastic Syndromes |
| ID | Term |
|---|---|
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| C541363 | BI 6727 |
| D001374 | Azacitidine |
| ID | Term |
|---|---|
| D001372 | Aza Compounds |
| D009930 | Organic Chemicals |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
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|
| Azacitidine | Drug |
|
| Up to 168 days |
| 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). | 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 |
| Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy) | 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 |
| 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). | 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) | 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 |
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 |
| BG002 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Description |
|---|
| OG000 | 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 |
| OG001 | 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 |
|
|
| 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. | Treated Set | Posted | Number | Milligram (mg)/ meter square (m2) | First treatment cycle, up to 28 days |
|
|
|
| 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. | Treated Set | Posted | Number | Participants | Up to 168 days |
|
|
|
| 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). | 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. | Posted | Number | Nanogram(ng)*hour(h)/milliliter(mL) | 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 |
|
|
|
| Secondary | Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy) | Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy). | 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. | Posted | Number | Nanogram(ng)*/milliliter(mL) | 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 |
|
|
|
| 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). | Due to premature discontinuation of the trial no patient is recruited for combination therapy. | Posted | 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 |
|
|
| Secondary | Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Combination) | Maximum measured plasma concentration of volasertib (Cmax) (for combination). | Due to premature discontinuation of the trial no patient is recruited for combination therapy. | Posted | 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 |
|
|
| 1 |
| 1 |
| 1 |
| 1 |
| Dental caries | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Oral lichen planus | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Small intestine ulcer | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Infusion site extravasation | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Herpes simplex | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Injection site infection | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
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| Weight decreased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hypertonic bladder | Renal and urinary disorders | MedDRA 19.1 | Systematic Assessment |
|
| Benign prostatic hyperplasia | Reproductive system and breast disorders | MedDRA 19.1 | Systematic Assessment |
|
| Haemorrhage subcutaneous | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Petechiae | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Purpura | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Haematoma | Vascular disorders | MedDRA 19.1 | Systematic Assessment |
|
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.
| D011743 |
| Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |