Primary:* Phase I: to establish the recommended phase II dose (RP2D) of BCT-100 in children andyoung adults as assessed by dose limiting toxicity (DLT) and complete arginine depletion.* Phase II: to determine the activity of single agent BCT-100…
ID
Source
Brief title
Condition
- Other condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Health condition
onbehandelbare en/of terugkerende vorm van kanker: leukemie, hoogradig glioom, neuroblastoom, sarcoom
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase I: the safe and optimal (in terms of arginine depletion) RP2D of BCT-100
as determined by:
oSafety profile as measured by the occurrence/non-occurrence of DLT within 28
daysof treatment with BCT-100. DLTs are defined in section 3.1.2.
oOptimal dose as measured by the complete depletion of arginine. This is
defined asAAD <8µM arginine in the blood after 4 doses of BCT-100.
Secondary outcome
Phase II: disease response (Complete Response (CR) or Partial Response (PR))
after 8 weeks oftreatment with BCT-100 as defined by:
oGroup 1 (Leukaemia): CR, Complete response with incomplete count recovery
(CRi),Complete response without platelet recovery (CRp; ALL only), or PR
determined bybone marrow, peripheral blood count/blasts and extramedullary
disease.(seeAppendix 4 for details; AML criteria based on Cheson et al 2003)
oGroup 2 (Neuroblastoma): CR/PR determined by cross-sectional imaging by CT
orMRI, MIBG scan and bone marrow evaluation using the International
NeuroblastomaResponse Criteria (INRC) (Appendix 7).
oGroup 3 (Sarcoma): CR/PR determined by cross-sectional imaging by CT or
MRIusing RECIST version 1.1 (Appendix 5).
oGroup 4 (High grade glioma): CR/PR determined by cross-sectional imaging by
MRIusing RANO criteria (Appendix 6).
Background summary
Arginine is a semi-essential amino acid required for protein synthesis, cell
division and a number of
intracellular pathways that maintain cell survival. B oth solid and
haematological cancer cells are dependent on extracellular
arginine for survival (arginine auxotrophism) due to the loss of ASS or OTC
recycling enzyme
expression; making them vulnerable to therapeutic arginine depletion.
The most clinically relevant approach to targeting tumour arginine metabolism
is through therapeutic
arginine depletion with a recombinant enzyme. BCT-100 (BioCancer Treatment
International) is a
pegylated recombinant human arginase in which a 5000 MW polyethylene glycol
moiety has been
covalently attached to native human arginase to significant increase the plasma
half-life and sustain
arginine depletion.
Study objective
Primary:
* 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.
* 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.
Secondary:
* 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.
Study design
Phase I aims to determine a safe and optimal (in terms of arginine depletion)
dose of BCT-100 using a
modified 3+3 design in all patients who meet the eligibility criteria
irrespective of disease group.
Phase II will be an expansion study to further evaluate the clinical activity
of BCT-100 in 4 diseasespecific
paediatric populations. Approximately 6 to 18 subjects are estimated for Part
1, and 52
subjects are planned for Part 2 (13 evaluable subjects in each of 4 groups;
evaluable for the purpose
of clinical activity analysis is defined as a subject with a pre-dose and at
least 1 post-dose disease
assessment).
Intervention
BCT-100 should initially be given for 8 weeks, i.e. 8 doses. If approved by the
Chief Investigator,
patients may receive treatment beyond 8 weeks until disease progression or
unacceptable toxicity
BCT-100 should be given on a weekly basis: 100 mL intravenously for 1 hour Dose
is depndant on phase of the stage as well as weight of child.
Study burden and risks
As this is the first time BCT-100 will be used in children and young people the
side-effects and severity of treatment are unknown. However, when used to treat
adults with liver cancer no significant toxicities were identified. The
following side effects were observed:
• Diarrhoea
• Abnormalities in liver function
• Shortness of breath
• Abdominal pain
Treating physician will keep a close eye on patient during treatment and all
side effects will be recorded and managed accordingly.
Radiation risk
patient may require a CT or MIBG scan as part of the disease assessment. These
scans use ionising radiation. This is thought to be associated with a very
small increased risk of developing a second cancer in the future.
Contraception and pregnancy
We don*t know whether BCT-100 will cause significant harm to an unborn child.
Therefore pregnancy must not occur during treatment or within 1 year of
completing treatment.
MIBG scan is repeated at week 8 , 16 24 and at the end of the study for
neuroblastoma patients, in case screening scan was found positive,
This is also the case for bonemarrow sample. In case positive at screening for
cancer cells, bone marrow samples will be repeated and considered additional /
extra research.
Additional blood and bonemarowsamples are combined as much as possible with
standard samplings.
- At screening a second nbobemarow sample is collected. This second sample is
considered extra/additional research.
- Additional /extra bloodsamples are collected for disease analyses and
pharmacodynamics/kinetics : at screening , week 1, 5 9 17 and 25, and at end of
study.
Additional:
Preganancy tests for females of childbearing potential.
Edgbaston 1
Birmingham B15 2TT
GB
Edgbaston 1
Birmingham B15 2TT
GB
Listed location countries
Age
Inclusion criteria
Inclusion Criteria
* Aged 1- <25 years old at the time of study registration
* Histologically confirmed disease in one of the following four groups:
o Group 1 - Acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia
(AML)
o Group 2 - Neuroblastoma
o Group 3 - Sarcoma
o 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 (see section 5.3 for details)
* 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002762-44-NL |
| ClinicalTrials.gov | NCT03455140 |
| CCMO | NL71544.041.19 |