A Study Evaluating the Safety and Activity of Pegylated Recombinant Human Arginase (BCT-100)

Study Overview
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Brief Summary
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PARC is an international phase I/II trial evaluating the safety and activity of pegylated recombinant human arginase (BCT-100) in children and young people with relapsed/refractory leukaemia, neuroblastoma, sarcoma and high grade gliomas (brain cancers). Currently the outcomes for these patients are poor and the therapeutic options are limited with a significant toxicity burden. Therefore new treatments which work in different ways to standard chemotherapy are urgently needed. Research has shown that arginine (a nutrient) is important in the survival of cancer cells. BCT-100 is a drug which can deplete arginine levels and starve cancer cells - a completely new approach. BCT-100 has been tested in adults and shown to be active with almost no side-effects. This trial will test whether this dose of BCT-100 is also safe and active in children with relapsed/refractory leukaemia, neuroblastoma, sarcoma and high grade glioma. The trial will also study how BCT-100 is broken down in the body and look for new biological markers of treatment response. Up to 64 children with relapsed cancers will be recruited over 2 years.

Official Title
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A Phase I/II Study Evaluating the Safety and Activity of Pegylated Recombinant Human Arginase (BCT-100) in Relapsed/Refractory Cancers of Children and Young Adults

Conditions
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Cancer, Pediatric Solid Tumor, Pediatric AML, Pediatric ALL

Intervention / Treatment
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* Drug: PEG- BCT-100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 1- <25 years old at the time of study registration Histologically confirmed disease in one of the following four groups: Group 1 - Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) Group 2 - Neuroblastoma Group 3 - Sarcoma Group 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 (biopsy at relapse is not mandated). Measurable bone marrow disease (group 1) or at least one evaluable radiological site of disease (group 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 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 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

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 25 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - Leukaemia<br>PEG- BCT-100 in patients with Leukaemia Starting dose 1600U/Kg IV infusion weekly | Drug: PEG- BCT-100<br>* PEGylated recombinant human arginase 1<br>* Other names: rhArg1peg5000;|
| Experimental: Group 2 - Neuroblastoma<br>PEG- BCT-100 in patients with Neuroblastoma Starting dose 1600U/Kg IV infusion weekly | Drug: PEG- BCT-100<br>* PEGylated recombinant human arginase 1<br>* Other names: rhArg1peg5000;|
| Experimental: Group 3 - Sarcomas<br>PEG- BCT-100 in patients with Sarcomas Starting dose 1600U/Kg IV infusion weekly | Drug: PEG- BCT-100<br>* PEGylated recombinant human arginase 1<br>* Other names: rhArg1peg5000;|
| Experimental: Group 4 - High Grade Glioma<br>PEG- BCT-100 in patients with High Grade Gliomas Starting dose 1600U/Kg IV infusion weekly | Drug: PEG- BCT-100<br>* PEGylated recombinant human arginase 1<br>* Other names: rhArg1peg5000;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: to establish the recommended phase II dose (RP2D) of BCT-100 in children and young adults as assessed by dose limiting toxicity (DLT) and complete arginine depletion | Safety profile as measured by the occurrence/non-occurrence of DLT within 28 days of treatment with BCT-100. o Optimal dose as measured by the complete depletion of arginine. This is defined as AAD <8μM arginine in the blood after 3 doses of BCT-100. | 28 days | 
| Phase II: to determine the activity of single agent BCT-100 against relapsed/refractory leukaemia, neuroblastoma, sarcoma and high grade glioma in children and young adults as measured by disease response after 8 weeks. | Disease response (Complete Response (CR) or Partial Response (PR)) after 8 weeks of treatment with BCT-100 | After 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence and severity of Adverse Events (AEs) as Assessed by CTCAE v4 | Incidence and severity of Adverse Events (AEs) defined by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4 | 28 days after treatment completion | 
| Disease response - Leukaemia | Disease response ( CR / PR) according to Cheson criteria | Within 1 year | 
| Disease response - Sarcoma | Disease response ( CR / PR) according to RECIST criteria | Within 1 year | 
| Disease response - High Grade Glioma | Disease response ( CR / PR) according to RANO criteria | Within 1 year | 
| Disease response - Neuroblastoma | Disease response ( CR / PR) according to INCR criteria | Within 1 year | 
| Progression free survival (PFS) |  | Up to three years after registration | 
| Overall survival (OS). |  | Up to three years after registration | 
| Maximum Plasma Concentration [Cmax], of BCT-100 in the paediatric population. |  | Up to 24 weeks | 
| Time to maximum Plasma Concentration [Tmax], of BCT-100 in the paediatric population. |  | Up to 24 weeks | 
| Minimum Plasma Concentration [Cmin], of BCT-100 in the paediatric population. |  | Up to 24 weeks | 
| Area Under the Curve [AUC], of BCT-100 in the paediatric population. |  | Up to 24 weeks | 
| Duration of adequate arginine depletion in blood. | BCT-100 concentration in blood | Up to 24 weeks | 
| Duration of adequate arginine depletion in bone marrow . | BCT-100 concentration in bone marrow | Up to 24 weeks | 
| Duration of adequate arginine depletion in cerebrospinal fluid. | BCT-100 concentration in cerebrospinal fluid | Up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arginine, Arginase, Children, Young Adult