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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Leukemia, Neoplasms

Intervention / Treatment
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* Drug: volasertib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: paediatric patients with leukaemia or advanced solid tumours including lymphomas (age 2 - less than 18 years) for whom no further treatment is known Lansky score > 60 for children 2 to less than 12 years Karnofsky score > 60 for children aged 12 or older life expectancy of at least 6 weeks as judged by the investigator parents or legal guardians have given written informed consent and informed assent suitable for the respective age group obtained Exclusion criteria: patient eligible for other anti-leukaemic therapy with curative intent or effective therapy known for solid tumour therapy presence of cardiac disease (LVEF by echocardiography less than 25 %) symptomatic Central Nervous System involvement of the malignant disease primary CNS tumour inadequate lab parameters inadequate venous access QTc prolongation pregnancy, breastfeeding other diseases or CTs that might interfere with evaluation of safety

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All patients<br>Volasertib will be administered as intravenous infusion | Drug: volasertib<br>* intravenous administration on day 1of a treatment course<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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. 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). | Up to 14 days. | 
| Maximum Tolerated Dose of Volasertib | 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. | Up to 14 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Hepatic Injury Defined as Adverse Events of Special Interest (AESI) | 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. | Up to 879 days. | 
| 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 | 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). | Up to 879 days. | 
| The Number of Patients With Changes in Cardiac Activity (Prolonged QTc Interval) Reported as Clinically Relevant Observations | 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. | Up to 879 days. | 
| 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 | 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. | Up to 849 days. | 
| Event-Free Survival (EFS) [in Leukaemia Patients] | 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. | Up to 849 days. | 
| Overall Survival (OS) [in Leukaemia Patients] | 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. | Up to 849 days. | 
| Maximum Measured Concentration (Cmax, Norm) of Volasertib | This outcome measure presents dose normalized maximum measured concentration of Volasertib in plasma (Cmax, norm). | 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. | 
| Trough Concentration (Cpre, 2) of Volasertib | 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. | 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. | 
| Area Under the Concentration-Time Curve (AUC0-∞, Norm) of Volasertib in Plasma | 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. | 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. | 
| Half-Life (t1/2) of Volasertib | This outcome measure presents half-life 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. |