Download PDF
CC BY-NC-ND 4.0 · Endosc Int Open 2022; 10(12): E1517-E1525
DOI: 10.1055/a-1949-7730
Original article

Early phase trial of intracystic injection of large surface area microparticle paclitaxel for treatment of mucinous pancreatic cysts

Mohamed Othman
1   Gastroenterology and Hepatology Section, Baylor College of Medicine Medical Center, Houston, Texas, United States
,
Kalpesh Patel
1   Gastroenterology and Hepatology Section, Baylor College of Medicine Medical Center, Houston, Texas, United States
,
Somashekar G. Krishna
2   Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
,
Antonio Mendoza-Ladd
3   Division of Gastroenterology, Texas Tech University Health Sciences Center at El Paso, El Paso, Texas, United States
,
Shelagh Verco
4   US Biotest, Inc., San Luis Obispo, California, United States
,
Wasif Abidi
1   Gastroenterology and Hepatology Section, Baylor College of Medicine Medical Center, Houston, Texas, United States
,
James Verco
4   US Biotest, Inc., San Luis Obispo, California, United States
,
Alison Wendt
4   US Biotest, Inc., San Luis Obispo, California, United States
,
Gere diZerega
4   US Biotest, Inc., San Luis Obispo, California, United States
5   NanOlogy, LLC., Fort Worth, Texas, United States
› Author AffiliationsSupported by: NanOlogy, LLC

TRIAL REGISTRATION: Multicenter open-label trial at http://www.clinicaltrials.gov/
› Further Information
Also available at
   Permissions and Reprints

Referred to by:

EUS-guided treatments of pancreatic cystic neoplasms – a call for methodological improvementsEndosc Int Open 2022; 10(12): E1526-E1527
DOI: 10.1055/a-1965-3191

Abstract

Background and study aims Mucinous pancreatic cystic lesions (PCLs) have the potential for malignant transformation, for which the only accepted curative modality is surgery. A novel intracystic therapy with large surface area microparticle paclitaxel (LSAM-PTX) may treat PCLs without local or systemic toxicities. Safety and preliminary efficacy of LSAM-PTX for the treatment of PCLs administered by endoscopic ultrasound-guided fine-needle injection (EUS-FNI) was evaluated.

Patients and methods Ten subjects with confirmed PCLs (size > 1.5 cm) received intracystic LSAM-PTX via EUS-FNI at volumes equal to those aspirated from the cyst in sequential cohorts at 6, 10, and 15 mg/mL in a standard “3 + 3” dose-escalation protocol. The highest dose with acceptable safety and tolerability was taken into the confirmatory phase where nine additional subjects received two injections of LSAM-PTX 12 weeks apart. Subjects were followed for 6 months after initial LSAM-PTX treatment for endpoints including: adverse events (AEs), tolerability, pharmacokinetic analysis of systemic paclitaxel drug levels, and change in cyst volume.

Results Nineteen subjects completed the study. No dose-limiting toxicities, treatment-related serious AEs, or clinically significant laboratory changes were reported. Systemic paclitaxel concentrations did not exceed 3.5 ng/mL at any timepoint measured and fell below 1 ng/mL by Week 2, supporting the lack of systemic toxicity. By Week 24 a cyst volume reduction (10–78 %) was seen in 70.6 % of subjects.

Conclusions Intracystic injection of LSAM-PTX into mucinous PCLs resulted in no significant AEs, a lack of systemic absorption, and resulted in reduction of cyst volume over a 6 month period.

Supplementary material



Publication History

Received: 19 April 2022

Accepted after revision: 20 September 2022

Article published online:
15 December 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Farrell JJ. Prevalence, diagnosis and management of pancreatic cystic neoplasms: current status and future directions. Gut Liver 2015; 9: 571-589
    CrossrefPubMedSearch in Google Scholar
  • 2 de Jong K, Nio CY, Hermans JJ. et al. High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations. Clin Gastroenterol Hepatol 2010; 8: 806-811
    CrossrefPubMedSearch in Google Scholar
  • 3 Valsangkar NP, Morales-Oyarvide V, Thayer SP. et al. 851 resected cystic tumors of the pancreas: a 33-year experience at the Massachusetts General Hospital. Surgery 2012; 152: S4-12
    CrossrefPubMedSearch in Google Scholar
  • 4 Scheiman JM, Hwang JH, Moayyedi P. American Gastroenterological Association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology 2015; 148: 824-848
    CrossrefPubMedSearch in Google Scholar
  • 5 Tanaka M, Fernandez-Del Castillo C, Kamisawa T. et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology 2017; 17: 738-753
    CrossrefPubMedSearch in Google Scholar
  • 6 Tanaka M, Fernandez-del Castillo C, Adsay V. et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012; 12: 183-197
    CrossrefPubMedSearch in Google Scholar
  • 7 de Pretis N, Mukewar S, Aryal-Khanal A. et al. Pancreatic cysts: Diagnostic accuracy and risk of inappropriate resections. Pancreatology 2017; 17: 267-272
    CrossrefPubMedSearch in Google Scholar
  • 8 Basar O, Yuksel O, Yang DJ. et al. Feasibility and safety of microforceps biopsy in the diagnosis of pancreatic cysts. Gastrointest Endosc 2018; 88: 79-86
    CrossrefPubMedSearch in Google Scholar
  • 9 Blaszczak AM, Krishna SG. Endoscopic diagnosis of pancreatic cysts. Curr Opin Gastroenterol 2019; 35: 448-454
    CrossrefPubMedSearch in Google Scholar
  • 10 Tacelli M, Celsa C, Magro B. et al. Diagnostic performance of endoscopic ultrasound through-the-needle microforceps biopsy of pancreatic cystic lesions: Systematic review with meta-analysis. Dig Endosc 2020; 32: 1018-1030
    CrossrefPubMedSearch in Google Scholar
  • 11 Westerveld DR, Ponniah SA, Draganov PV. et al. Diagnostic yield of EUS-guided through-the-needle microforceps biopsy versus EUS-FNA of pancreatic cystic lesions: a systematic review and meta-analysis. Endosc Int Open 2020; 8: E656-E667
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Kovacevic B, Klausen P, Rift CV. et al. Clinical impact of endoscopic ultrasound-guided through-the-needle microbiopsy in patients with pancreatic cysts. Endoscopy 2021; 53: 44-52
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Pitman MB, Genevay M, Yaeger K. et al. High-grade atypical epithelial cells in pancreatic mucinous cysts are a more accurate predictor of malignancy than "positive" cytology. Cancer Cytopathol 2010; 118: 434-440
    CrossrefPubMedSearch in Google Scholar
  • 14 Park JW, Jang JY, Kang MJ. et al. Mucinous cystic neoplasm of the pancreas: is surgical resection recommended for all surgically fit patients?. Pancreatology 2014; 14: 131-136
    CrossrefPubMedSearch in Google Scholar
  • 15 Pusateri AJ, Krishna SG. Pancreatic cystic lesions: pathogenesis and malignant potential. Diseases 2018; 6: 50
    CrossrefPubMedSearch in Google Scholar
  • 16 Krishna SG. Endoscopic ultrasound-guided confocal endomicroscopy requires high-quality imaging and interpretation for diagnostic evaluation of pancreatic cystic lesions. Endosc Int Open 2020; 8: E310-E311
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Oh HC, Seo DW, Lee TY. et al. New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection. Gastrointest Endosc 2008; 67: 636-642
    CrossrefPubMedSearch in Google Scholar
  • 18 Oh HC, Seo DW, Kim SC. et al. Septated cystic tumors of the pancreas: is it possible to treat them by endoscopic ultrasonography-guided intervention?. Scand J Gastroenterol 2009; 44: 242-247
    CrossrefPubMedSearch in Google Scholar
  • 19 Oh HC, Seo DW, Song TJ. et al. Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts. Gastroenterology 2011; 140: 172-179
    CrossrefPubMedSearch in Google Scholar
  • 20 DeWitt JM, Al-Haddad M, Sherman S. et al. Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel. Endoscopy 2014; 46: 457-464
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Moyer MT, Dye CE, Sharzehi S. et al. Is alcohol required for effective pancreatic cyst ablation? The prospective randomized CHARM trial pilot study. Endosc Int Open 2016; 4: E603-607
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Gomez V, Takahashi N, Levy MJ. et al. EUS-guided ethanol lavage does not reliably ablate pancreatic cystic neoplasms (with video). Gastrointest Endosc 2016; 83: 914-920
    CrossrefPubMedSearch in Google Scholar
  • 23 Choi JH, Seo DW, Song TJ. et al. Long-term outcomes after endoscopic ultrasound-guided ablation of pancreatic cysts. Endoscopy 2017; 49: 866-873
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Attila T, Adsay V, Faigel DO. The efficacy and safety of endoscopic ultrasound-guided ablation of pancreatic cysts with alcohol and paclitaxel: a systematic review. Eur J Gastroenterol Hepatol 2019; 31: 1-9
    CrossrefPubMedSearch in Google Scholar
  • 25 Du C, Chai NL, Linghu EQ. et al. Endoscopic ultrasound-guided injective ablative treatment of pancreatic cystic neoplasms. World J Gastroenterol 2020; 26: 3213-3224
    CrossrefPubMedSearch in Google Scholar
  • 26 Baltezor M, Farthing J, Sittenauer J. et al. Taxane particles and their use. U.S. Patent 9,814,685: Nov. 14, 2017.
    PubMed
  • 27 Verco S, Maulhardt H, Baltezor M. et al. Local administration of submicron particle paclitaxel to solid carcinomas induces direct cytotoxicity and immune-mediated tumoricidal effects without local or systemic toxicity: preclinical and clinical studies. Drug Deliv Transl Res 2021; 11: 1806-1817
    CrossrefPubMedSearch in Google Scholar
  • 28 Maulhardt H, Verco S, Baltezor M. et al. Local administration of large surface area microparticle docetaxel to solid carcinomas induces direct cytotoxicity and immune-mediated tumoricidal effects: preclinical and clinical studies. Drug Deliv Transl Res 2022; In press
    PubMedSearch in Google Scholar
  • 29 Eisenhauer EA, Therasse P, Bogaerts J. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-247
    CrossrefPubMedSearch in Google Scholar
  • 30 Rkein AM, Harrigal C, Friedman AC. et al. Comparison of the accuracy of CT volume calculated by circumscription to prolate ellipsoid volume (bidimensional measurement multiplied by coronal long axis). Acad Radiol 2009; 16: 181-186
    CrossrefPubMedSearch in Google Scholar
  • 31 Chalian H, Seyal AR, Rezai P. et al. Pancreatic mucinous cystic neoplasm size using CT volumetry, spherical and ellipsoid formulas: validation study. JOP 2014; 15: 25-32
    PubMedSearch in Google Scholar
  • 32 Linghu E, Du C, Chai N. et al. A prospective study on the safety and effectiveness of using lauromacrogol for ablation of pancreatic cystic neoplasms with the aid of EUS. Gastrointest Endosc 2017; 86: 872-880
    CrossrefPubMedSearch in Google Scholar
  • 33 Moyer MT, Sharzehi S, Mathew A. et al. The Safety and efficacy of an alcohol-free pancreatic cyst ablation protocol. Gastroenterology 2017; 153: 1295-1303
    CrossrefPubMedSearch in Google Scholar
  • 34 Mills KM, Johnson DM, Middlebrooks M. et al. Possible drug-associated pancreatitis after paclitaxel-cremophor administration. Pharmacotherapy 2000; 20: 95-97
    CrossrefPubMedSearch in Google Scholar
  • 35 Vege SS, Ziring B, Jain R. et al. American Gastroenterological Association Institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology 2015; 148: 819-822
    CrossrefPubMedSearch in Google Scholar
  • 36 Elta GH, Enestvedt BK, Sauer BG. et al. ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts. Am J Gastroenterol 2018; 113: 464-479
    CrossrefPubMedSearch in Google Scholar
  • 37 Krishna SG, Hart PA, Papachristou G. et al. Sa300 Tandem EUS-Guided fine needle injection of intracystic submicron particle paclitaxel (NanoPac) as treatment for Brach-duct IPMN: An interim safety, pharmacokinetic, and efficacy analysis. Gastroenterology 2021; 160: S475-S476
    CrossrefPubMedSearch in Google Scholar
  • 38 Krishna SG, Ardeshna DR, Hart PA. et al. The efficacy of intracystic injection of large surface area microparticle paclitaxel in the management of intraductal papillary mucinous neoplasms: results from an expanded access protocol. Gastrointestinal Endoscopy 2022; 95: AB531-AB532
    CrossrefPubMedSearch in Google Scholar