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. 2024 Jan 31:14:1296576.
doi: 10.3389/fonc.2024.1296576. eCollection 2024.

PARC: 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

Nicola Fenwick  1 , Rebekah Weston  1 , Keith Wheatley  1 , Jodie Hodgson  1 , Lynley Marshall  2 , Martin Elliott  3 , Guy Makin  4 , Antony Ng  5 , Bernadette Brennan  4 , Stephen Lowis  5 , Jenny Adamski  6 , John Paul Kilday  4 , Rachel Cox  5 , Mike Gattens  7 , Andrew Moore  8 , Toby Trahair  9 , Milind Ronghe  10 , Martin Campbell  11 , Helen Campbell  4 , Molly W Williams  11 , Maria Kirby  12 , Natasha Van Eijkelenburg  13 , Jennifer Keely  1 , Ugo Scarpa  14 , Victoria Stavrou  14 , Livingstone Fultang  14 , Sarah Booth  14 , Paul Cheng  15 , Carmela De Santo #  14 , Francis Mussai #  6
Affiliations

PARC: 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

Nicola Fenwick et al. Front Oncol. .

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.

Keywords: arginase; arginine; cancer; pediatric; relapse.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
CONSORT Diagram.
Figure 2
Figure 2
(A) Swimmer plot indicating the number of weeks patients received treatment with BCT-100. Disease cohort and response rates indicated by colors and symbols in the key. (B) Overall survival (OS) (C) Progression-free survival (PFS).
Figure 3
Figure 3
(A) Plasma arginine concentrations prior to each dose of BCT-100. Each unique symbol represents an individual patient. Each color represents the tumour subtype, as indicated in the legend. (B–D) Frequency of CD3+ T cells, CD14+ myeloid cells and CD15+ myeloid cells respectively in the blood of patients prior to each dose of BCT-100. Each unique symbol represents an individual patient. Each color represents the tumour subtype, as indicated in the legend.
See this image and copyright information in PMC

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