ABSTRACT
Background:
The
survival for many
children with relapsed/refractory
cancers remains poor despite advances in
therapies.
Arginine metabolism plays a key
role in the pathophysiology of a number of pediatric
cancers. We
report the first in
child study of a recombinant
human arginase, BCT-100, in
children with relapsed/refractory hematological, solid or CNS
cancers.
Procedure PARC was a single
arm, Phase I/II, international, open label study. BCT-100 was given intravenously over one hour at weekly intervals. The Phase I section utilized a modified 3 + 3 design where escalation/de-escalation was based on both the
safety profile and the complete depletion of
arginine (defined as adequate
arginine depletion; AAD <8µM
arginine in the
blood after 4 doses of BCT-100). The Phase II section was designed to further evaluate the clinical activity of BCT-100 at the pediatric RP2D determined in the Phase I section, by recruitment of
patients with pediatric
cancers into 4 individual groups. A primary evaluation of response was conducted at eight weeks with
patients continuing to receive
treatment until
disease progression or unacceptable
toxicity.
Results:
49
children were recruited globally. The Phase I cohort of the trial established the Recommended Phase II
Dose of 1600U/kg iv weekly in
children, matching that of
adults. BCT-100 was very well tolerated. No responses defined as a CR, CRi or PR were seen in any cohort within the defined 8 week primary evaluation period. However a number of these relapsed/refractory
patients experienced prolonged radiological SD.
Conclusion:
Arginine depletion is a clinically safe and achievable strategy in
children with
cancer. The RP2D of BCT-100 in
children with relapsed/refractory
cancers is established at 1600U/kg intravenously weekly and can
lead to sustained
disease stability in this hard to treat
population.
Clinical trial registration EudraCT, 2017-002762-44; ISRCTN, 21727048; and ClinicalTrials.gov, NCT03455140.