Summary
CA102N is a covalently bound conjugate of modified nimesulide (Nim) and NaHA, the sodium salt of hyaluronic acid (HA). HA is a natural ligand of cluster of differentiation 44 (CD44), which is over-expressed in colorectal cancer (CRC). CA102N is designed to deliver nimesulide directly to the tumor via the interaction of HA and CD44. A Phase 1, 2-part (dose escalation, dose expansion), non-randomized, open-label, first-in-human study of CA102N, as monotherapy and in combination with trifluridine-tipiracil, was conducted in patients with locally advanced or metastatic solid tumors. The CA102N doses evaluated were 0.36 mg/kg, 0.54 mg/kg, and 0.72 mg/kg Nim equivalent. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 as well as serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) throughout the study; secondary endpoints were pharmacodynamics parameters, objective tumor response, and urinary pharmacodynamics markers of target inhibition. Between April 2019 and October 2021, 37 patients were enrolled in 3 US centers. No DLTs were observed in Part 1, and 0.72 mg/kg Nim equivalent was the dose selected for Part 2. In total, 52 TEAEs in 18 patients were CA102N-related; 4 (in 3 patients) were ≥ Grade 3. Exploratory analysis in the dose expansion cohort revealed a median progression-free survival of 3.7 (1.0, 6.77) months. Based on this study, CA102N as monotherapy or in combination with trifluridine-tipiracil, was safe and well-tolerated at the recommended Phase 2 dose of 0.72 mg/kg Nim equivalent in patients with locally advanced or metastatic solid tumors. Preliminary evidence of antitumor activity in CRC warrants further clinical development. (ClinicalTrials.gov registration number: NCT03616574. Registration date: August 6, 2018).
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets generated during and/or analyzed during the current study are available in from the corresponding author on reasonable request.
References
Rainsford KD, Members of the Consensus Report Group on Nimesulide (2006) Nimesulide – a multifactorial approach to inflammation and pain: scientific and clinical consensus. Curr Med Res Opin 22(6):1161–1170
Chandrasekharan N, Simmons DL (2004) The cyclooxygenases. Genome Biol 5(9):1–7
Laurent TC (1987) Biochemistry of hyaluronan. Acta Otolaryngol 104(sup442):7–24
Liu B, Qu L, Yan S (2015) Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity. Cancer Cell Int 15(1):1–6
Oshima M et al (1996) Suppression of intestinal polyposis in ApcΔ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87(5):803–809
Sheng H et al (1997) Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Investig 99(9):2254–2259
Tian G et al (2002) Effect of nimesulide on proliferation and apoptosis of human hepatoma SMMC-7721 cells. World J Gastroenterol 8(3):4838
Jian YS et al (2017) Hyaluronic acid-nimesulide conjugates as anticancer drugs against CD44-overexpressing HT-29 colorectal cancer in vitro and in vivo. Int J Nanomedicine 27(12):2315–2333
Zelenay S et al (2015) Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162(6):1257–1270
Zhao LH et al (2015) CD44v6 expression in patients with stage II or stage III sporadic colorectal cancer is superior to CD44 expression for predicting progression. Int J Clin Exp Pathol 8(1):692–701
Tchaparian EH, Lin L (2017) CA102N, a conjugate of hyaluronic acid (HA) and Nimuselide derivative (H-Nim) interferes with PI3K/Akt/mTOR signaling pathway in colorectal cancer (CRC) cells and inhibits tumor growth in vivo. AACR
Zhang YJ et al (2011) mTOR signaling is involved in indomethacin and nimesulide suppression of colorectal cancer cell growth via a COX-2 independent pathway. Ann Surg Oncol 18(2):580–588
Walter T et al (2020) Systematic review and network meta-analyses of third-line treatments for metastatic colorectal cancer. J Cancer Res Clin Oncol 146(10):2575–2587
Eisenhauer EA et al (2009) New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247
Neale JR, Dean BJ (2008) Liquid chromatography-tandem mass spectrometric quantification of the dehydration product of tetranor PGE-M, the major urinary metabolite of prostaglandin E(2) in human urine. J Chromatogr B Analyt Technol Biomed Life Sci 871(1):72–77
Bessone F (2010) Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? World J Gastroenterol 16(45):5651
Kwon J et al (2019) Nimesulide-induced hepatotoxicity: A systematic review and meta-analysis. PLoS ONE 14(1):e0209264
Donati M et al (2016) Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case–control study in Italy. Br J Clin Pharmacol 82(1):238–248
Mayer RJ et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20):1909–1919
Acknowledgements
This study was supported by Holy Stone Healthcare Co., Ltd., Taipei, Taiwan.
Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study's conception and design. Material preparation/support was performed by Y.C. Chen. The study supervision was performed by S. Pant, T. Dragovich, C. Lieu, A. Jimeno, Y.C. Chen and S. Kopetz. The first draft of the manuscript was written, and reviewed/ revised by Eskouhie Tchaparian and Y.C. Chen. and all authors commented on the previous version of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethical approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University of Colorado Hospital Anschutz Cancer Pavilion, Banner MD Anderson Cancer Center, and University of Texas MD Anderson Cancer Center.
Consent to participate
Informed consent was obtained from all individual participants included in the study.
Competing interests
Financial interests: Eskouhie Tchaparian and Y.C. Chen are employees of Holy Stone Healthcare Co., Ltd., and may own stock/stock options in the company. The authors have no relevant financial or non-financial interests to disclose.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Pant, S., Dragovich, T., Lieu, C. et al. Phase 1 study of the safety, pharmacokinetics, and preliminary efficacy of CA102N as monotherapy and in combination with trifluridine-tipiracil in patients with locally advanced or metastatic solid tumors. Invest New Drugs 41, 25–34 (2023). https://doi.org/10.1007/s10637-022-01308-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-022-01308-5