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01-03-2018 | Clinical Trial Report

A phase I dose escalation trial of nab-paclitaxel and fixed dose radiation in patients with unresectable or borderline resectable pancreatic cancer

Authors: Jacob E. Shabason, Jerry Chen, Smith Apisarnthanarax, Nevena Damjanov, Bruce Giantonio, Arturo Loaiza-Bonilla, Peter J. O’Dwyer, Mark O’Hara, Kim A. Reiss, Ursina Teitelbaum, Paul Wissel, Jeffrey A. Drebin, Charles Vollmer, Michael Kochman, Rosemarie Mick, Norge Vergara, Nirag Jhala, Abigail Doucette, John N. Lukens, John P. Plastaras, James M. Metz, Edgar Ben-Josef

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2018

Abstract

Purpose

Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced pancreatic carcinoma.

Methods

We performed a phase 1 study using a 3 + 3 dose escalation strategy to determine the safety and tolerability of dose-escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with two cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy.

Results

Nine patients received nab-paclitaxel at a dose level of either 100 mg/m² (n = 3) or 125 mg/m² (n = 6). There were no observed grade 3 gastrointestinal toxicities. One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m² of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%) and neutropenia (11%). No grade 4 toxicities were observed. Following chemoradiotherapy, four patients (borderline resectable, n = 2 and unresectable, n = 2) underwent surgical resection, all with negative margins and with significant treatment effect with limited tumor viability.

Conclusions

The combination of fractionated radiation and weekly full dose nab-paclitaxel was safe and well-tolerated.

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Siegel RL, Miller KD, Jemal A (2016) Cancer statistics. CA Cancer J Clin 66(1):7–30CrossRefPubMed

Hammel P et al (2016) Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 315(17):1844–1853CrossRefPubMed

Loehrer PJ (2011) Sr., et al., Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 29(31):4105–4112CrossRefPubMedPubMedCentral

Iacobuzio-Donahue CA et al (2009) DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 27(11):1806–1813CrossRefPubMedPubMedCentral

Al-Batran SE et al (2014) Nab-paclitaxel for metastatic pancreatic cancer: clinical outcomes and potential mechanisms of action. Oncol Res Treat 37(3):128–134CrossRefPubMed

Cullis J et al (2017) Macropinocytosis of nab-paclitaxel drives macrophage activation in pancreatic cancer. Cancer Immunol Res 5(3):182–190CrossRefPubMed

Wiedenmann N et al (2007) 130-nm albumin-bound paclitaxel enhances tumor radiocurability and therapeutic gain. Clin Cancer Res 13(6):1868–1874CrossRefPubMed

Safran H, Rathore R (2002) Paclitaxel as a radiation sensitizer for locally advanced pancreatic cancer. Crit Rev Oncol Hematol 43(1):57–62CrossRefPubMed

Von Hoff DD et al (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703CrossRef

10.

Alvarez R et al (2013) Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer 109(4):926–933CrossRefPubMedPubMedCentral

11.

Okada KI et al (2017) Phase I study of nab-paclitaxel plus gemcitabine as neoadjuvant therapy for borderline resectable pancreatic cancer. Anticancer Res 37(2):853–858CrossRefPubMed

12.

Fury MG et al (2014) Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III-IVB head and neck squamous cell carcinoma (HNSCC). Ann Oncol 25(3):689–694CrossRefPubMedPubMedCentral

13.

Kaira K et al (2017) Phase I study of nab-paclitaxel plus carboplatin and concurrent thoracic radiotherapy in patients with locally advanced non-small cell lung cancer. Cancer Chemother Pharmacol 79(1):165–171CrossRefPubMed

14.

National Comprehensive Cancer Network. Pancreatic Adenocarcinoma Version 1.2014. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed Feb 2014

15.

Shitara K et al (2017) Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol 2(4):277–287CrossRefPubMed

16.

Ceha HM et al (2000) Feasibility and efficacy of high dose conformal radiotherapy for patients with locally advanced pancreatic carcinoma. Cancer 89(11):2222–2229CrossRefPubMed

17.

Ben-Josef E et al (2012) A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 84(5):1166–1171CrossRefPubMedPubMedCentral

Title: A phase I dose escalation trial of nab-paclitaxel and fixed dose radiation in patients with unresectable or borderline resectable pancreatic cancer
Authors: Jacob E. Shabason
Jerry Chen
Smith Apisarnthanarax
Nevena Damjanov
Bruce Giantonio
Arturo Loaiza-Bonilla
Peter J. O’Dwyer
Mark O’Hara
Kim A. Reiss
Ursina Teitelbaum
Paul Wissel
Jeffrey A. Drebin
Charles Vollmer
Michael Kochman
Rosemarie Mick
Norge Vergara
Nirag Jhala
Abigail Doucette
John N. Lukens
John P. Plastaras
James M. Metz
Edgar Ben-Josef
Publication date: 01-03-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3519-6

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Abstract

Purpose

Methods

Results

Conclusions

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