Elsevier

Clinical Oncology

Volume 21, Issue 6, August 2009, Pages 464-472
Clinical Oncology

Original Article
Phase II Trial of Talabostat and Docetaxel in Advanced Non-small Cell Lung Cancer

https://doi.org/10.1016/j.clon.2009.04.007Get rights and content

Abstract

Aims

Currently available therapies do improve survival in advanced stage non-small cell lung cancer (NSCLC), but only to a limited degree. Talabostat mesilate (PT-100) is an orally available amino boronic dipeptide that specifically inhibits dipeptidyl peptidases (including fibroblast activation protein) and enhances an immune response. The aim of this study was to determine the efficacy and safety of talabostat in NSCLC patients.

Materials and methods

A phase II trial was conducted to evaluate talabostat in combination with docetaxel in patients with advanced NSCLC after failure of previous platinum-based chemotherapy. In total, 42 patients were enrolled.

Results

Talabostat was well tolerated. Two patients achieved a partial response and one achieved a complete response.

Conclusion

There was no evidence that talabostat enhanced the clinical activity of docetaxel in patients with NSCLC.

Introduction

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the USA [1]. When diagnosed in later stages of the disease, prognosis is grim, with an average survival of less than 1 year.

The most commonly used chemotherapeutic regimens are platinum based, consisting of cisplatin or carboplatin combined with another cytotoxic drug and/or, in some cases, with molecular targeted therapies. Standard two-drug regimens provide 1-year survival rates of about 25–35% 2, 3, 4, 5. Molecular targeted therapies have only produced modest gains. The tyrosine kinase inhibitor erlotinib increases survival by a couple of months 6, 7; gefitinib shows no benefit when added to conventional chemotherapy 8, 9. The antivascular endothelial growth factor monoclonal antibody bevacizumab increased 1-year survival to 51% [10], but is applicable to ≤30% of NSCLC patients. Cetuximab is a monoclonal antibody against epidermal growth factor receptor that increases overall survival from 10 to 11.3 months when combined with chemotherapy [11]. Virtually all patients ultimately show disease progression after initial treatment. Standard second-line therapies include docetaxel, pemetrexed and erlotinib 12, 13. However, median survival after second-line therapy remains below 6 months, highlighting the need for more effective options.

Talabostat mesylate (PT-100) is an orally available amino boronic dipeptide that specifically inhibits dipeptidyl peptidases 14, 15, 16. Fibroblast activation protein is a dipeptidyl peptidase expressed by fibroblasts associated with malignant epithelial tumours and healing wounds 14, 17, 18. Currently it is not clear if inhibition of fibroblast activation protein by talabostat is one of the mechanisms that could account for the tumour-specific cytotoxic effects seen in pre-clinical studies.

Talabostat also elicits an immune response. In pre-clinical studies, talabostat increased the production of cytokines in tumour tissue and lymphoid organs, resulting in an enhanced cell response 19, 20, 21. Synergy was also shown with chemotherapy, presumably from tumour antigen exposure secondary to chemotherapy-induced apoptosis, coupled with the immunostimulatory effect of talabostat [22].

Talabostat inhibited tumour growth in mouse models of fibrosarcoma, lymphoma and melanoma 19, 20, 21. Re-challenge with the same tumour cells resulted in tumour-specific immune rejection. Human studies have found talabostat to be well tolerated 23, 24, 25. A phase I trial of talabostat and rituximab in rituximab-resistant lymphoma showed cytokine elevations in most patients, with a partial response in three patients [25]. However, a phase II trial reported that talabostat failed to induce an objective response in metastatic colorectal carcinoma [26].

On the basis of pre-clinical evidence of tumour-specific cytotoxicity and immunostimulatory properties, a phase II trial was conducted to determine the efficacy and safety of talabostat in combination with docetaxel in patients with advanced NSCLC after failure of previous platinum-based chemotherapy.

Section snippets

Study Design

This was an open-label, single-arm, multicentre study of talabostat and docetaxel in patients with advanced NSCLC (stage IIIB/IV). This study was reviewed and approved by the local institutional review boards for each investigational site before initiation. The study was conducted in accordance with current US Food and Drug Administration regulations, good clinical practice, the International Conference on Harmonisation guidelines, the version of the Declaration of Helsinki current at the time

Patient Characteristics

In stage 1, 21 evaluable patients with stage IIIB/IV NSCLC were evaluated for response using computed tomography. As two responses were documented, the study proceeded to stage 2.

In stage 2, an additional 21 evaluable patients were enrolled, for a total sample size of 42 evaluable patients.

A summary of the demographic and baseline disease characteristics for all patients in the ITT and evaluable populations is provided in Table 1. The median age of patients was similar in the ITT and evaluable

Discussion

There were three validated objective responses, two partial responses and one complete response, among the 55 patients in the ITT population for a response rate of 5.5% (3/55). These responses were included in the evaluable population, for a response rate of 7.1% (3/42).

The most frequent adverse events were oedema, fatigue, neutropenia, anaemia, and dyspnoea. Many of these adverse events were considered possibly, probably, or definitely related to docetaxel (23/29 events of fatigue, 22/24

Conflict of interest

Dr Neil Senzer and Dr John Nemunaitis have direct affiliation with Gradalis, in which they both have stock options. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Acknowledgments

The authors would like to thank Drs James Arseneau, Robert Leonard, Stephen Anthony, Barry Berman, Robert March, and Stuart Packer for their participation in patient recruitment and enrolment. The authors would also like to acknowledge Brenda Marr and Susan Mill for their competent and knowledgeable assistance in the preparation of this manuscript.

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