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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.
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.
| Original language | English |
|---|---|
| Article number | 1296576 |
| Number of pages | 9 |
| Journal | Frontiers in Oncology |
| Volume | 14 |
| DOIs | |
| Publication status | Published - 31 Jan 2024 |
Bibliographical note
Funding:The author(s) declare financial support was received for the research, authorship, and/or publication of this article. We are grateful to Imagine for Margo, and Cancer Research UK (C47669/A24836) for supporting this trial. We thank the University of Birmingham alumni and donors who contributed to the funding of laboratory analyses and Bio-Cancer Treatment International, Hong Kong Science Park, Hong Kong for providing BCT-100 free of charge and providing financial support. Funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Keywords
- arginine
- cancer
- arginase
- pediatric
- relapse
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PARC: A Phase I / II study evaluating the activity of Pegylated recombinant human Arginase (BCT-100) in RElapsed/refractory Cancers of childhood
Mussai, F. (Principal Investigator), Beggs, A. (Co-Investigator), Fenwick, N. (Co-Investigator), Wheatley, K. (Co-Investigator), De Santo, C. (Co-Investigator), Kearns, P. (Co-Investigator) & Slade, D. (Co-Investigator)
Cancer Research Uk, BIO-CANCER TREATMENT INTERNATIONAL LTD, INNOVATIVE THERAPIES FOR CHILDREN WITH CANCER (ITCC)
1/12/17 → 31/03/24
Project: Research