TY - JOUR
T1 - Parc
T2 - 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
AU - Fenwick, Nicola
AU - Weston, Rebekah
AU - Wheatley, Keith
AU - Hodgson, Jodie
AU - Marshall, Lynley
AU - Elliott, Martin
AU - Makin, Guy
AU - Ng, Antony
AU - Brennan, Bernadette
AU - Lowis, Stephen
AU - Adamski, Jenny
AU - Kilday, John Paul
AU - Cox, Rachel
AU - Gattens, Mike
AU - Moore, Andrew
AU - Trahair, Toby
AU - Ronghe, Milind
AU - Campbell, Martin
AU - Campbell, Helen
AU - Williams, Molly W
AU - Kirby, Maria
AU - Van Eijkelenburg, Natasha
AU - Keely, Jennifer
AU - Scarpa, Ugo
AU - Stavrou, Victoria
AU - Fultang, Livingstone
AU - Booth, Sarah
AU - Cheng, Paul
AU - De Santo, Carmela
AU - Mussai, Francis
N1 - Copyright © 2024 Fenwick, Weston, Wheatley, Hodgson, Marshall, Elliott, Makin, Ng, Brennan, Lowis, Adamski, Kilday, Cox, Gattens, Moore, Trahair, Ronghe, Campbell, Campbell, Williams, Kirby, Van Eijkelenburg, Keely, Scarpa, Stavrou, Fultang, Booth, Cheng, De Santo and Mussai.
PY - 2024/1/31
Y1 - 2024/1/31
N2 - 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.
AB - 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.
KW - arginase
KW - arginine
KW - cancer
KW - pediatric
KW - relapse
UR - http://www.scopus.com/inward/record.url?scp=85185340831&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/fc7b2e7e-ead6-3d52-8f55-0bc687339d10/
U2 - 10.3389/fonc.2024.1296576
DO - 10.3389/fonc.2024.1296576
M3 - Article
C2 - 38357205
SN - 2234-943X
VL - 14
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1296576
ER -