Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma.

Abstract

BACKGROUND:

The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling.

METHODS:

Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib).

RESULTS:

Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37-6.97) and 9.79 months (95% CI: 7.85-10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment.

CONCLUSIONS:

Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT01088815.

• Authors: Ana De Jesus-Acosta, Elizabeth A Sugar, Peter J O'Dwyer, Ramesh K Ramanathan, Daniel D Von Hoff, Zeshaan Rasheed, Lei Zheng, Asma Begum, Robert Anders, Anirban Maitra, Florencia McAllister, N V Rajeshkumar, Shinichi Yabuuchi, Roeland F de Wilde, Bhavina Batukbhai, Ismet Sahin, Daniel A Laheru
• Journal: British journal of cancer (Br J Cancer) Vol. 122 Issue 4 Pg. 498-505 (02 2020) ISSN: 1532-1827 [Electronic] England
• PMID: 31857726 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• 130-nm albumin-bound paclitaxel
• Albumins
• Anilides
• HhAntag691
• Pyridines
• Deoxycytidine
• Paclitaxel
• Gemcitabine

Topics

• Aged
• Albumins (administration & dosage, adverse effects)
• Anilides (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Pancreatic Ductal (drug therapy, mortality, secondary)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives)
• Female
• Humans
• Male
• Middle Aged
• Paclitaxel (administration & dosage, adverse effects)
• Pancreatic Neoplasms (drug therapy, mortality)
• Progression-Free Survival
• Pyridines (administration & dosage, adverse effects)
• Treatment Outcome
• Gemcitabine
• Pancreatic Neoplasms