Original ArticlePhase II Trial of Talabostat and Docetaxel in Advanced Non-small Cell Lung Cancer
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.
References (29)
- et al.
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial
Lancet
(2009) The isolation and some properties of dipeptidyl peptidases II and III from porcine spleen
Int J Biochem
(1991)- et al.
Sequence, purification, and cloning of an intracellular serine protease, quiescent cell proline dipeptidase
J Biol Chem
(1999) - et al.
Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts
J Biol Chem
(1999) - et al.
Phase 1 rising multiple-dose study of talabostat (PT-100) in healthy subjects. Abstract #4215. American Society of Hematology (ASH), 46th Annual Meeting. San Diego, CA
Blood
(2004) - et al.
Phase 1 study of talabostat and rituximab in patients with indolent non-Hodgkin's lymphoma with primary resistance to or progression following rituximab. Abstract #1403. American Society of Hematology (ASH), 46th Annual Meeting. San Diego, CA
Blood
(2004) - et al.
Cancer statistics, 2008
CA Cancer J Clin
(2008) - et al.
Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the Cancer and Leukemia Group B (study 9730)
J Clin Oncol
(2005) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials
Br Med J
(1995)- et al.
Are chemotherapy response rates related to treatment-induced survival prolongations in patients with advanced cancer?
J Clin Oncol
(2004)
Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis
J Am Med Assoc
Erlotinib in previously treated non-small-cell lung cancer
N Engl J Med
Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer
J Clin Oncol
Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2
J Clin Oncol
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2022, Advanced Drug Delivery ReviewsCitation Excerpt :This phase II clinical trial demonstrated minimal clinical activity, probably due to incomplete inhibition of the targeted enzyme in CAF [318]. Similarly, minimal clinical outcome was observed when FAP was inhibited with Talabostat alone or in combination with chemotherapeutic drugs [319,320]. Targeting CAF using a monoclonal antibody (mAb) was one of the several approaches used.
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