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

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

doi:10.1038/s41416-019-0683-3

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	498-505
Number of pages	8
Journal	British Journal of Cancer
Volume	122
Issue number	4
DOIs	https://doi.org/10.1038/s41416-019-0683-3
Publication status	Published - 18 Feb 2020
Externally published	Yes

Bibliographical note

Funding information:
The study was sponsored by a Stand Up to Cancer Dream
Team Translational Cancer Research Grant (SU2C grant AACR-DT0509), Viragh Clinical
Cancer Research and the Lustgarten Foundation. Genentech provided drug support

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinomaFinal published version, 469 KBLicence: CC BY

Cite this

De Jesus-Acosta, A., Sugar, E. A., O'Dwyer, P. J., Ramanathan, R. K., Von Hoff, D. D., Rasheed, Z., Zheng, L., Begum, A., Anders, R., Maitra, A., McAllister, F., Rajeshkumar, N. V., Yabuuchi, S., de Wilde, R. F., Batukbhai, B., Sahin, I., & Laheru, D. A. (2020). Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. British Journal of Cancer, 122(4), 498-505. https://doi.org/10.1038/s41416-019-0683-3

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title = "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.",

author = "{De Jesus-Acosta}, Ana and Sugar, {Elizabeth A} and O'Dwyer, {Peter J} and Ramanathan, {Ramesh K} and {Von Hoff}, {Daniel D} and Zeshaan Rasheed and Lei Zheng and Asma Begum and Robert Anders and Anirban Maitra and Florencia McAllister and Rajeshkumar, {N V} and Shinichi Yabuuchi and {de Wilde}, {Roeland F} and Bhavina Batukbhai and Ismet Sahin and Laheru, {Daniel A}",

note = "Funding information: The study was sponsored by a Stand Up to Cancer Dream Team Translational Cancer Research Grant (SU2C grant AACR-DT0509), Viragh Clinical Cancer Research and the Lustgarten Foundation. Genentech provided drug support",

year = "2020",

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day = "18",

doi = "10.1038/s41416-019-0683-3",

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volume = "122",

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De Jesus-Acosta, A, Sugar, EA, O'Dwyer, PJ, Ramanathan, RK, Von Hoff, DD, Rasheed, Z, Zheng, L, Begum, A, Anders, R, Maitra, A, McAllister, F, Rajeshkumar, NV, Yabuuchi, S, de Wilde, RF, Batukbhai, B, Sahin, I & Laheru, DA 2020, 'Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma', British Journal of Cancer, vol. 122, no. 4, pp. 498-505. https://doi.org/10.1038/s41416-019-0683-3

Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. / De Jesus-Acosta, Ana; Sugar, Elizabeth A; O'Dwyer, Peter J et al.
In: British Journal of Cancer, Vol. 122, No. 4, 18.02.2020, p. 498-505.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma

AU - De Jesus-Acosta, Ana

AU - Sugar, Elizabeth A

AU - O'Dwyer, Peter J

AU - Ramanathan, Ramesh K

AU - Von Hoff, Daniel D

AU - Rasheed, Zeshaan

AU - Zheng, Lei

AU - Begum, Asma

AU - Anders, Robert

AU - Maitra, Anirban

AU - McAllister, Florencia

AU - Rajeshkumar, N V

AU - Yabuuchi, Shinichi

AU - de Wilde, Roeland F

AU - Batukbhai, Bhavina

AU - Sahin, Ismet

AU - Laheru, Daniel A

N1 - Funding information: The study was sponsored by a Stand Up to Cancer Dream Team Translational Cancer Research Grant (SU2C grant AACR-DT0509), Viragh Clinical Cancer Research and the Lustgarten Foundation. Genentech provided drug support

PY - 2020/2/18

Y1 - 2020/2/18

N2 - 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.

AB - 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.

U2 - 10.1038/s41416-019-0683-3

DO - 10.1038/s41416-019-0683-3

M3 - Article

C2 - 31857726

SN - 0007-0920

VL - 122

SP - 498

EP - 505

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 4

ER -

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

Abstract

Bibliographical note

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