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

• Register: ISRCTN
• Last refreshed on: 27 February 2024
• Main ID: ISRCTN21727048
• Date of registration: 27/03/2018
• Prospective Registration: Yes
• Primary sponsor: University of Birmingham
• Public 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
• 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
• Date of first enrolment: 16/04/2018
• Target sample size: 64
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN21727048
• Study type: Interventional
• Study design: Non-randomized; Interventional; Design type: Treatment, Drug (Treatment)
• Phase: Phase I/II

Countries of recruitment

Australia, Denmark, England, Germany, Ireland, Italy, Netherlands, Scotland, Spain, United Kingdom

Contacts

• Name: Jodie Hodgson

Key inclusion & exclusion criteria

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
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

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Relapsed/refractory cancers of children and young adults
Cancer

Intervention(s)

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.

Primary Outcome(s)

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(s)

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

Secondary ID(s)

NCT03455140

2017-002762-44

37340

Source(s) of Monetary Support

Cancer Research UK; Grant Codes: C47669/A24836, Imagine For Margo - Children without Cancer; Grant Codes: ITCC-062

Ethics review

Status:
Approval date:
Contact:

Old ethics approval format; Leicester South Research Ethics Committee, 05/03/2018, ref: 18/EM/0024

Results

• Results available: Yes
• Date Completed: 16/10/2022