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
| ISRCTN | ISRCTN21727048 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN21727048 |
| EudraCT/CTIS number | 2017-002762-44 |
| ClinicalTrials.gov number | NCT03455140 |
| Secondary identifying numbers | 37340 |
- Submission date
- 12/03/2018
- Registration date
- 27/03/2018
- Last edited
- 15/02/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Plain English summary of protocol
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 an 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?
Jodie Hodgson
parc@trials.bham.ac.uk
Contact information
Scientific
Cancer Research UK Clinical Trials Unit (CRCTU)
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
| Phone | +44 (0)121 414 9235 |
|---|---|
| parc@trials.bham.ac.uk |
Study information
| Study design | Non-randomized; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| 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 |
| Study acronym | PARC |
| Study objectives | 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(s) | Leicester South Research Ethics Committee, 05/03/2018, ref: 18/EM/0024 |
| Health condition(s) or problem(s) studied | 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 1600 U/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 |
| Pharmaceutical study type(s) | |
| Phase | Phase I/II |
| Drug / device / biological / vaccine name(s) | 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 | Current secondary outcome measures as of 02/02/2023: 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 doses 1, 5, 9, 17 & 25 6. Arginine concentrations in blood, bone marrow, and CSF samples prior to doses 1, 5, 9, 17 & 25 Previous 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 doses 1, 4, 8, 16 and 24 6. Arginine concentrations in blood, bone marrow, and CSF samples prior to doses 1, 4, 8, 16 and 24 |
| Overall study start date | 26/01/2017 |
| Completion date | 16/10/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 1 Year |
| Upper age limit | 24 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 64; UK Sample Size: 18 |
| Total final enrolment | 49 |
| Key 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 |
| Key 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 |
| Date of first enrolment | 16/04/2018 |
| Date of final enrolment | 01/12/2021 |
Locations
Countries of recruitment
- Australia
- Denmark
- England
- Germany
- Ireland
- Italy
- Netherlands
- Scotland
- Spain
- United Kingdom
Study participating centres
Birmingham
B4 6NH
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Manchester
M13 9WL
United Kingdom
Sutton
SM2 5PT
United Kingdom
Bristol
BS2 8BJ
United Kingdom
Leeds
LS1 3EX
United Kingdom
Crumlin
Drimnagh
Dublin
D12 V004
Ireland
Parkville
Victoria
3052
Australia
Randwick
Sydney
NSW 2031
Australia
Westmead
Sydney
NSW 2145
Australia
North Adelaide
SA 5006
Australia
Subiaco
Perth
WA 6008
Australia
Utrecht
3584 CS
Netherlands
Glasgow
G51 4TF
United Kingdom
Sponsor information
University/education
c/o Dr Birgit Whitman
Research Governance and Ethics Manager
The University of Birmingham
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)7814650003 |
|---|---|
| researchgovernance@contacts.bham.ac.uk | |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
No information available
Results and Publications
| Intention to publish date | 01/07/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | 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. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Basic results | version 1.0b | 23/02/2023 | 27/02/2023 | No | No |
| HRA research summary | 26/07/2023 | No | No | ||
| Results article | 31/01/2024 | 15/02/2024 | Yes | No |
Additional files
Editorial Notes
15/02/2024: Publication reference added.
27/02/2023: Basic results corrected.
02/02/2023: The following changes were made to the trial record:
1. The secondary outcome measures were updated.
2. The trial participating centres were updated to add Princess Maxima Center for pediatric oncology and Royal Hospital for Children Glasgow and remove Great Ormond Street Hospital for Children, Rigshospitalet, John Hunter Children’s Hospital, and Lady Cilento Children’s Hospital.
3. Sponsor details updated.
23/01/2023: Basic results and total final enrolment added.
02/12/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/12/2020 to 01/12/2021.
2. The overall trial end date was changed from 16/10/2021 to 16/10/2022.
3. The intention to publish date was changed from 01/07/2022 to 01/07/2023.
4. Contact details updated.
09/07/2020: The trial contact details have been made publicly visible.
24/04/2020: The recruitment end date was changed from 16/04/2020 to 01/12/2020.
12/06/2019: ClinicalTrials.gov number added.
27/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Children's Cancer and Leukaemia; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue, Cancer/ Malignant neoplasms of thyroid and other endocrine glands, Cancer/ Malignant neoplasms of eye, brain and other parts of central nervous system, Cancer/ Malignant neoplasms of mesothelial and soft tissue" to "Relapsed/refractory cancers of Children and young adults" following a request from the NIHR.
