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

Phase 1

Completed

Conditions: Leukemia
Neoplasms

Interventions: Drug: volasertib

Registration Number: NCT01971476

Lead Sponsor: Boehringer Ingelheim

Brief Summary: 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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
All patients	volasertib	Volasertib will be administered as intravenous infusion

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)	Up to 14 days.	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).
Maximum Tolerated Dose of Volasertib	Up to 14 days.	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.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Hepatic Injury Defined as Adverse Events of Special Interest (AESI)	Up to 879 days.	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.
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	Up to 879 days.	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).
The Number of Patients With Changes in Cardiac Activity (Prolonged QTc Interval) Reported as Clinically Relevant Observations	Up to 879 days.	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.
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	Up to 849 days.	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.
Event-Free Survival (EFS) [in Leukaemia Patients]	Up to 849 days.	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 (OS) [in Leukaemia Patients]	Up to 849 days.	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.
Maximum Measured Concentration (Cmax, Norm) of Volasertib	Cycle 1: -0:05 (hour/s: minute/s) before drug administration and 1:00, 1:30, 3:00, 24:00, 96:00, 216:00 after drug administration. Cycle >=2: -0:05 (hour/s: minute/s) before drug administration and 1:00 after drug administration.	This outcome measure presents dose normalized maximum measured concentration of Volasertib in plasma (Cmax, norm).
Trough Concentration (Cpre, 2) of Volasertib	Cycle 1: -0:05 (hour/s: minute/s) before drug administration and 1:00, 1:30, 3:00, 24:00, 96:00, 216:00 after drug administration. Cycle >=2: -0:05 (hour/s: minute/s) before drug administration and 1:00 after drug administration.	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.
Area Under the Concentration-Time Curve (AUC0-∞, Norm) of Volasertib in Plasma	Cycle 1: -0:05 (hour/s: minute/s) before drug administration and 1:00, 1:30, 3:00, 24:00, 96:00, 216:00 after drug administration. Cycle >=2: -0:05 (hour/s: minute/s) before drug administration and 1:00 after drug administration.	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.
Half-Life (t1/2) of Volasertib	Cycle 1: -0:05 (hour/s: minute/s) before drug administration and 1:00, 1:30, 3:00, 24:00, 96:00, 216:00 after drug administration. Cycle >=2: -0:05 (hour/s: minute/s) before drug administration and 1:00 after drug administration.	This outcome measure presents half-life of Volasertib.

Trial Locations

Locations (5): UNIV UZ Gent
🇧🇪
Gent, Belgium
INS Curie
🇫🇷
Paris, France
University Hospital Motol
🇨🇿
Prague, Czechia
Osp. Pediatrico Bambin Gesù
🇮🇹
Roma, Italy
Universitätsklinikum Köln (AöR)
🇩🇪
Köln, Germany