Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Neoplasms by Histologic Type

Hematologic Diseases

Acute Graft Versus Host Disease

Volasertib will be administered as intravenous infusion

intravenous administration on day 1of a treatment course

volasertib

Boehringer Ingelheim

The present trial will be performed according to an open design to determine the maximum tolerable dose (MTD) by evaluation of dose-limiting toxicity (DLT) of volasertib in paediatric leukaemia and solid tumours in the age group 2 to less than 12 and 12 to less than 18 years. A further objective is to collect data on safety, tolerability, toxicity, efficacy (preliminary activity), pharmacokinetics and pharmacodynamics of volasertib in paediatric cancer patients

Open Dose Escalating Trial to Determine the Maximum Tolerated Dose in Paediatric Patients With Advanced Cancers for Whom no Therapy is Known

Open, Non-controlled, Dose Escalating Phase I Trial to Evaluate the Pharmacokinetics, Pharmacodynamics, Tolerability and Toxicity of Volasertib in Paediatric Patients From 2 Years to Less Than 18 Years of Age With Acute Leukaemia or Advanced Solid Tumour, for Whom no Effective Treatment is Known

This outcome measure presents number of participants with DLTs in the first cycle for the determination of MTD. DLTs were defined as drug related Common Terminology Criteria for Adverse Events (CTCAE) ≥Grade 3 (haematological and nonhaematological) Adverse Events (AEs) with the exception of a) Reduced blood cell count (any grade) without associated clinical complications qualifying for DLT. b) Febrile neutropenia Grade 3. c) Infection Grade 3 with neutrophil count \<1000/mm3. d) Uric acid Grade ≥3. e) Nausea, vomiting and/or diarrhoea managed by adequate therapy (i.e. recovery to CTCAE Grade ≤2).

This outcome measure presents MTD of Volasertib. The MTD was defined as the highest dose level at which DLTs were reported in not more than 1 in 6 evaluable patients during Cycle 1.

This outcome measure presents number of patients with hepatic injury defined as AESI. Hepatic injury was defined by the following alterations of liver parameters: an elevation of Aspartate Transaminase (AST) and/or Alanine Transaminase (ALT) \>3x Upper Limit of Normal (ULN) combined with an elevation of total bilirubin \>2x ULN measured in the same blood sample.

This outcome measure presents number of patients with clinically relevant laboratory value changes of calcium (hyper- and/or hypocalcaemia) as judged by the investigator and reported as AEs, CTCAE Grade ≥3. CTCAE Grade 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

This outcome measure presents the number of patients with changes in cardiac activity (prolonged QTc interval) reported as clinically relevant observations to assess cardiac activity based on Electrocardiogram (ECG) recordings (digital, triplicate) before and at the end of each Volasertib administration and at least at 2 more time points within the first 24 hours after end of the first Volasertib administration. Two methods of heart rate correction of the QT interval were used: the fixed corrections Fridericia's correction (QTcF) and Bazett's correction (QTcB).

SMQ: Standardised Medical Dictionary for Regulatory Activities (MedDRA) query.

This outcome measure includes, CR: Bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary (EM) disease; absolute neutrophil count ≥ 1.0 x 109/L (1000/μL); platelet count ≥80 x 109/L (80000/μL); independence of red blood cells transfusions. CRi: All CR criteria except for residual neutropenia (\<1.0 x 109/L \[1000/μL\]) or thrombocytopenia (\<800 x 109/L \[80000/μL\]), independence of red blood cell transfusions not required. PR: Decrease of bone marrow blast percentage to 5%-25%; decrease of pretreatment bone marrow (baseline) blast percentage by at least 50%; absence of EM disease. SD: Neither qualifies for CR, CRi, PR or PD. PD: At least one of the criteria a) 50% increase in bone marrow blast count over baseline b) 50% increase in peripheral blast count over baseline - evidence of new EM disease - clinically PD based on the judgment of the investigator. Death in aplasia: Deaths occurring ≥7 days after last administration of the trial drug while cytopenic.

EFS was defined as the time from the first infusion of Volasertib to the date of PD or relapse, occurrence of secondary malignancy, or death from any cause, whichever occurred first. EFS was censored at the date of last disease assessment for patients who were not reported with PD, relapse, occurrence of secondary malignancy or death.

Overall survival was defined as time from first infusion of Volasertib to death from any cause. For patients who were lost to follow-up, OS were censored on the last date the patients were known to be alive.

This outcome measure presents dose normalized maximum measured concentration of Volasertib in plasma (Cmax, norm).

This outcome measure presents pre-dose concentration of Volasertib in plasma immediately before administration of the second dose (Cpre,2).

The number of participants analysed displays the number of participants with available data at the timepoint of interest.

This outcome measure presents dose normalized area under the concentration-time curve of Volasertib in plasma over the time interval from zero extrapolated to infinity.

This outcome measure presents half-life of Volasertib.

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

2 to <12 Years: Volasertib 200 mg/m2

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

2 to <12 Years: Volasertib 250 mg/m2

The patients were administered Volasertib 300 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

2 to <12 Years: Volasertib 300 mg/m2

The pooled total of patients administered Volasertib 200 mg/m2/250 mg/m2/300 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

2 to <12 Years: Volasertib Pooled Total

12 to <18 Years: Volasertib 200 mg/m2

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 1-day cycle.

12 to <18 Years: Volasertib 250 mg/m2

The pooled total of patients administered Volasertib 200 mg/m2/250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

12 to <18 Years: Volasertib Pooled Total

Volasertib 200 mg/m2

Volasertib 250 mg/m2

Volasertib 300 mg/m2

Total

2 to <12 years

12 to <18 years

Age, Continuous

Female (2 to <12 years)

Male (2 to <12 years)

Female (12 to <18 years)

Male (12 to <18 years)

Sex/Gender, Customized

Treated Set: The treated set consisted of all patients who have received at least 1 dose of trial medication at the time of clinical cut-off.

2 to \<12 years (N=3, 3, 6). 12 to \< 18 years (N=6, 4, 0).

Boehringer Ingelheim Call Center

12 to <18 Years: Volasertib 300 mg/m2

Treated Set: The treated set consisted of all patients who have received at least 1 dose of trial medication at the time of clinical cut-off.

Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)

Maximum Tolerated Dose of Volasertib

Total AEs in grouped category hepatic impairment

Alanine aminotransferase increased

Aspartate aminotransferase increased

Blood alkaline phosphatase increased

Metabolism and nutrition disorders

Hypoalbuminaemia

Hepatobiliary disorders

Hyperbilirubinaemia

Blood bilirubin increased

Gamma-glutamyltransferase increased

Number of Patients With Hepatic Injury Defined as Adverse Events of Special Interest (AESI)

Total AEs clinically relevant changes of calcium

Hypocalcaemia

Hypercalcaemia

Number of Patients With Clinically Relevant Laboratory Value Changes of Calcium (Hyper- and/or Hypocalcaemia) as Judged by the Investigator and Reported as AEs, CTCAE Grade ≥3

Total AEs in the MedDRA SMQ of QT prolongation

Electrocardiogram QT prolonged

Cardiac disorders

Conduction disorder

The Number of Patients With Changes in Cardiac Activity (Prolonged QTc Interval) Reported as Clinically Relevant Observations

Complete remission

CRi*

Partial remission

Stable disease

Progressive disease

Death in aplasia

Not evaluable

Missing

Treated Set: The treated set consisted of all patients who have received at least 1 dose of trial medication at the time of clinical cut-off.

The number of participants analysed displays the number of participants with available data at the timepoint of interest.

Best Overall Response [in Leukaemia Patients]: (Complete Remission (CR)), CR With Incomplete Neutrophil or Platelet Recovery (CRi), Partial Remission (PR), Stable Disease (SD), Progressive Disease (PD) and Death in Aplasia

Event-Free Survival (EFS) [in Leukaemia Patients]

Overall Survival (OS) [in Leukaemia Patients]

Pharmacokinetic Set (PKS): All evaluable patients were included in the PK analysis. A patient was considered to be not evaluable, if the patient had an important protocol violation relevant to the evaluation of PK or had insufficient data.

Maximum Measured Concentration (Cmax, Norm) of Volasertib

Pharmacokinetic Set: All evaluable patients were included in the PK analysis. A patient was considered to be not evaluable, if the patient had an important protocol violation relevant to the evaluation of PK or had insufficient data. The number of participants analysed are the number of participants with available data at the timepoint of interest.

Trough Concentration (Cpre, 2) of Volasertib

Pharmacokinetic Set: All evaluable patients were included in the PK analysis. A patient was considered to be not evaluable, if the patient had an important protocol violation relevant to the evaluation of PK or had insufficient data.

Area Under the Concentration-Time Curve (AUC0-∞, Norm) of Volasertib in Plasma

Half-Life (t1/2) of Volasertib

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour (h) on Day 1 of 14-day cycle.

Spots Global Cancer Trial Database for Open Dose Escalating Trial to Determine the Maximum Tolerated Dose in Paediatric Patients With Advanced Cancers for Whom no Therapy is Known

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