Plain English Summary
Background and study aims
The aim of this study is to assess 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 treatment options are limited with significant side effects. 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 reduce arginine levels and starve cancer cells – a completely new approach. BCT-100 has been tested in adults and has been shown to be active with almost no side effects. This study will test whether this dose of BCT-100 is also safe and active in children and young adults with relapsed/refractory leukaemia, neuroblastoma, sarcoma and high grade glioma. The study will also look at how BCT-100 is broken down in the body and look for new markers of treatment response.
Who can participate?
Children and young adults (aged 1 to 25) with relapsed cancers (leukaemia, neuroblastoma, sarcoma and high grade gliomas)
What does the study involve?
BCT-100 is given as weekly intravenous infusions (into a vein) over one hour in an outpatient setting. The dose is given at 7 day intervals (+/- 1 day). The dose is increased or decreased based on both safety (side effects) and the successful depletion of arginine in the participants. BCT-100 should at first be given for 8 weeks, i.e. 8 doses, but participants may receive treatment beyond 8 weeks if there is ongoing clinical benefit.
What are the possible benefits and risks of participating?
This study aims to find the dose which balances high effectiveness with few side effects, and this will then be tested in a larger group. This study will test this drug on four different disease types for relapsed/refractory patients. The options for these patients can be limited and often are associated with a large burden of side effects. BCT-100 has been found to be very well tolerated with few side effects. However, this is the first study involving children.
Where is the study run from?
Hospitals in the UK, Italy, Germany, Netherlands, Spain, Ireland, Denmark and Australia
When is the study starting and how long is it expected to run for?
January 2017 to October 2021
Who is funding the study?
1. Cancer Research UK
2. Imagine For Margo - Children without Cancer
Who is the main contact?
Louise Moeller
Trial website
Contact information
Type
Scientific
Primary contact
Ms Louise Moeller
ORCID ID
Contact details
Trial Coordinator
Children’s Cancer Trials Team
Cancer Research UK Clinical Trials Unit (CRCTU)
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0) 121 414 2996
parc@trials.bham.ac.uk
Additional identifiers
EudraCT number
2017-002762-44
ClinicalTrials.gov number
NCT03455140
Protocol/serial number
37340
Study information
Scientific title
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
Acronym
PARC
Study hypothesis
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 and young adults 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 and young adults with relapsed cancers will be recruited over 2 years.
Ethics approval
Leicester South Research Ethics Committee, 05/03/2018, ref: 18/EM/0024
Study design
Non-randomised; Interventional; Design type: Treatment, Drug
Primary study design
Interventional
Secondary study design
Non randomised study
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Relapsed/refractory cancers of Children and young adults
Intervention
There is no randomisation for this single arm trial. BCT-100 is administered as weekly intravenous infusions over one hour which may be administered in an outpatient setting. The dose must be administered at 7 day intervals (+/- 1 day).
For phase I the starting dose will be 1600U/kg and dose escalation/de-escalation is based on both the safety profile (occurrence of DLT) and the successful depletion of arginine in patients. This will establish the phase II recommended dose. BCT-100 should initially be given for 8 weeks, i.e. 8 doses but may receive treatment beyond 8 weeks if there is ongoing clinical benefit. Total trial duration is two years and follow up is minimum one year.
Intervention type
Drug
Phase
Phase I/II
Drug names
Pegylated recombinant human arginase (BCT-100)
Primary outcome measure
Phase I: the safe and optimal (in terms of arginine depletion) RP2D of BCT-100 as determined by:
1. Safety profile as measured by the occurrence/non-occurrence of DLT within 28 days of treatment with BCT-100
2. 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
Phase II: disease response (Complete Response (CR) or Partial Response (PR)) after 8 weeks of treatment with BCT-100 as defined by:
Group 1 (Leukaemia): CR, Complete response with incomplete count recovery (CRi), Complete response without platelet recovery (CRp; Acute Lymphoblastic Leukaemia (ALL) only), or PR determined by bone marrow, peripheral blood count/blasts and extramedullary disease (AML criteria based on Cheson et al 2003)
Group 2 (Neuroblastoma): CR/PR determined by cross-sectional imaging by CT or MRI, MIBG scan and bone marrow evaluation using the International Neuroblastoma Response Criteria (INRC)
Group 3 (Sarcoma): CR/PR determined by cross-sectional imaging by CT or MRI using RECIST version 1.1
Group 4 (High grade glioma): CR/PR determined by cross-sectional imaging by MRI using RANO criteria
Secondary outcome measures
1. Incidence and severity of Adverse Events (AEs) defined by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4 as measured from the date of commencement of protocol defined treatment until 28 days after the administration of the last dose of trial treatment
2. Disease response (CR / PR) at any time during treatment with BCT-100:
Group 1 (Leukaemia): CR, Complete response with incomplete count recovery (CRi), Complete response without platelet recovery (CRp; Acute Lymphoblastic Leukaemia (ALL) only), or PR determined by bone marrow, peripheral blood count/blasts and extramedullary disease (AML criteria based on Cheson et al 2003)
Group 2 (Neuroblastoma): CR/PR determined by cross-sectional imaging by CT or MRI, MIBG scan and bone marrow evaluation using the International Neuroblastoma Response Criteria (INRC)
Group 3 (Sarcoma): CR/PR determined by cross-sectional imaging by CT or MRI using RECIST version 1.1
Group 4 (High grade glioma): CR/PR determined by cross-sectional imaging by MRI using RANO criteria
3. Progression free survival, measured using follow up data (patients followed up for at least 1 year)
4. Overall survival, measured using follow up data (patients followed up for at least 1 year)
5. Pharmacokinetic (PK) profile of BCT-100 concentration in blood, bone marrow, and cerebrospinal fluid (CSF) samples prior to dose 1, 4, 8, 16 and 24
6. Arginine concentrations in blood, bone marrow, and CSF samples prior to dose 1, 4, 8, 16 and 24
Overall trial start date
26/01/2017
Overall trial end date
16/10/2021
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Aged 1- <25 years old at the time of study registration
2. Histologically confirmed disease in one of the following four groups:
2.1. Group 1 - Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)
2.2. Group 2 - Neuroblastoma
2.3. Group 3 - Sarcoma
2.4. Group 4 - High grade glioma (as defined by 2016 WHO CNS classification)
3. 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)
4. Measurable bone marrow disease (group 1) or at least one evaluable radiological site of disease (group 2, 3 and 4)
5. 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
6. Documented negative pregnancy test for female patients of childbearing potential within 7 days of trial entry
7. Sexually active patients must agree to use adequate and appropriate contraception while on study drug and for 12 months following treatment discontinuation
8. Written informed consent given by patient and/or parents/legal representative
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 64; UK Sample Size: 18
Participant exclusion criteria
1. Previous treatment with another therapeutic arginine depleting drug (bacterial or human) or arginase inhibitor
2. Presence of any > = CTCAE grade 3 clinically significant treatment-related toxicity from prior therapies
3. Pregnant or lactating female
4. Evidence of uncontrolled infection
Recruitment start date
16/04/2018
Recruitment end date
01/12/2020
Locations
Countries of recruitment
Australia, Denmark, Germany, Ireland, Italy, Netherlands, Spain, United Kingdom
Trial participating centre
Birmingham Children’s Hospital
Steelhouse Lane
Birmingham
B4 6NH
United Kingdom
Trial participating centre
Addenbrooke’s Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Trial participating centre
Royal Manchester Children's Hospital
Oxford Road
Manchester
M13 9WL
United Kingdom
Trial participating centre
Great Ormond Street Hospital for Children
Great Ormond Street
London
WC1N 3JH
United Kingdom
Trial participating centre
The Royal Marsden Hospital
Downs Road
Sutton
SM2 5PT
United Kingdom
Trial participating centre
Bristol Royal Hospital for Children
24 Upper Maudlin St
Bristol
BS2 8BJ
United Kingdom
Trial participating centre
Leeds General Infirmary
Great George St
Leeds
LS1 3EX
United Kingdom
Trial participating centre
Our Lady’s Children’s Hospital
Cooley Road
Crumlin
Drimnagh
Dublin
D12 V004
Ireland
Trial participating centre
Rigshospitalet
Blegdamsvej 9
København
2100
Denmark
Trial participating centre
Royal Children's Hospital, Melbourne
50 Flemington Road
Parkville
Victoria
3052
Australia
Trial participating centre
Sydney Children's Hospital
High St
Randwick
Sydney
NSW 2031
Australia
Trial participating centre
The Children’s Hospital at Westmead
Cnr Hawkesbury Road and Hainsworth Street
Westmead
Sydney
NSW 2145
Australia
Trial participating centre
John Hunter Children’s Hospital
Kookaburra Circuit
New Lambton Heights
Newcastle
NSW 2305
Australia
Trial participating centre
Lady Cilento Children’s Hospital
501 Stanley Street
South Brisbane
Queensland 4101
Australia
Trial participating centre
Women’s and Children’s Hospital
72 King William Rd
North Adelaide
SA 5006
Australia
Trial participating centre
Princess Margaret Hospital
Roberts Rd
Subiaco
Perth
WA 6008
Australia
Funders
Funder type
Charity
Funder name
Cancer Research UK; Grant Codes: C47669/A24836
Alternative name(s)
CRUK
Funding Body Type
private sector organisation
Funding Body Subtype
Other non-profit organizations
Location
United Kingdom
Funder name
Imagine For Margo - Children without Cancer; Grant Codes: ITCC-062
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer reviewed journal.
IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from the Cancer Research UK Clinical Trials Unit (CRCTU) at the University of Birmingham. The (CRCTU) is committed to responsible and controlled sharing of anonymised clinical trial data with the wider research community to maximise potential patient benefit while protecting the privacy and confidentiality of study participants. Participant data and the associated supporting documentation (metadata) will typically be available for all CRCTU clinical trials within 6 months after the publication of the outcome measures unless the trial results are to be used as part of a regulatory submission where release of the data may be delayed or be subject to the approval of a third party. Requests for historical clinical trial data will be dealt with on a case-by-case basis. For trials with long term follow-up, primary outcome data (e.g. response) may be available before secondary outcome data (e.g. survival). Each request will be reviewed independently by the CRCTU Directors in discussion with the Chief Investigator and relevant Trial Management Group and/or independent Trial Steering Committee (as applicable to the trial). In making their decision the Director’s Committee will consider the scientific validity of the request, the qualifications of the research group, the views of the Chief Investigator and trial management and/or steering committees, consent arrangements, the practicality of anonymising the requested data and contractual obligations. Where the CRCTU Directors and appropriate Trial Committees are supportive of the request, and where not already obtained, consent for data transfer will be sought from the Sponsor of the trial before notifying the applicant of the outcome of their request. It is anticipated that applicants will be notified of a decision within 3 months.
Intention to publish date
01/07/2022
Participant level data
Available on request
Basic results (scientific)
Publication list