E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relpased/refractory paeditaric cancers: Leukaemias Sarcoma Neuroblastoma High grade glioma (brain cancers) |
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E.1.1.1 | Medical condition in easily understood language |
Children's cancers that have come back or are resistant to treatment. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000830 |
E.1.2 | Term | Acute leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065443 |
E.1.2 | Term | Malignant glioma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029260 |
E.1.2 | Term | Neuroblastoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039494 |
E.1.2 | Term | Sarcoma NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of this trial are to: - establish a safe and active dose of BCT-100 in children and young people - evaluate if BCT-100 is effective against acute leukaemias, neuroblastoma, sarcoma and high grade glioma which have come back (relapsed) or not responded to previous treatment (refractory)as measured by disease response at 8 weeks.
The trial is made of two parts: In the first part, the doctors will be looking for the dose of BCT-100 which is both safe and active in children and young adults. This will involve giving increasing doses of the drug (BCT-100) to patients to find the dose which does not cause significant side effects (known as dose-limiting toxicities) and completely depletes arginine levels. All the doses of BCT-100 used in this trial have found to be safe in adults.
In the second part the trial, the final dose chosen in part 1 will then be given to all patients who take part. Disease response at eight weeks will be measured to determine activity of |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the trial are: • To assess the safety of BCT-100. • To assess disease response at any time during treatment with BCT-100. • To assess progression free survival (PFS) and overall survival (OS). • To determine the pharmacokinetics of BCT-100 in the paediatric population. • To assess the duration and magnitude of arginine depletion.
The exploratory objectives of the trial are: • To collect blood and tumour samples for (future) ethically approved projects.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Aged 1- <25 years old • Histologically confirmed disease in one of the following four cohorts. Patients with and without metastatic lesions are eligible. o Cohort 1 - Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) o Cohort 2 - Neuroblastoma o Cohort 3 - Sarcoma o Cohort 4 - High grade glioma (as defined by 2016 WHO CNS classification) • Radiological or laboratory evidence of disease progression (during or after completion of first line treatment) or any subsequent recurrence • Measurable bone marrow disease (cohort 1) or at least one evaluable radiological site of disease (cohort 2, 3 and 4) • Adequate liver function defined as a total bilirubin <1.5x the upper limit of normal for age and ALT <3x the upper limit of normal for age • Normal ECG • Documented negative pregnancy test for female patients of childbearing potential within 7 days of trial entry • Sexually active patients must agree to use adequate and appropriate contraception while on study drug and for 12 months following treatment discontinuation • Written informed consent given by patient and/or parents/legal representative
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E.4 | Principal exclusion criteria |
• Previous treatment with another therapeutic arginine depleting drug (bacterial or human) or arginase inhibitor • Presence of any ≥ CTCAE grade 3 clinically significant treatment-related toxicity from prior therapies • Pregnant or lactating female • Evidence of uncontrolled infection
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measures of this study are:
1. The safe and optimal recommended dose of BCT-100 for children and young people. Safety profile as measured by the occurrence/non-occurrence of specified dose-limiting toxicities within 28 days of treatment with BCT-100. Optimal dose as measured by the complete depletion of arginine after 3 doses of BCT-100
2. Disease response (Complete Response (CR) or Partial Response (PR))to BCT-100 after eight weeks of treatment with BCT-100. This is defined by the following criteria for each group: Group 1: Modified Cheson criteria Group 2: International Neuroblastoma Response Criteria Group 3: RECIST criteria Group 4: RANO criteria (see protocol for further details)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I Dose-limiting toxicities within 28 days of treatment with BCT-100. Optimal dose as measured by the complete depletion of arginine after 3 doses of BCT-100
Phase II Response at 8 weeks |
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E.5.2 | Secondary end point(s) |
• To assess the safety of BCT-100. • To assess disease response at any time during treatment with BCT-100 • To assess progression free survival (PFS) and overall survival (OS). • To determine the pharmacokinetics of BCT-100 in the paediatric population. • To assess the duration and magnitude of arginine depletion.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Incidence and severity of Adverse Events (AEs) defined by National Cancer Institute Common •Terminology Criteria for Adverse Events (CTCAE) v4 (see Appendix 3) • Disease response ( CR / PR) at any time during treatment with BCT-100 • PFS - median survival at 6 and 12 months • OS - median survival at 6 and 12 months • PK profile of BCT-100 concentration in blood, bone marrow, and CSF - during and at end of treatment • Arginine concentrations in blood, bone marrow, and CSF - during and at end of treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
First in paediatric population |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Denmark |
France |
Germany |
Ireland |
Italy |
Netherlands |
New Zealand |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 29 |