A phase II study of bryostatin-1 and paclitaxel in patients with advanced non-small cell lung cancer
Introduction
Clinical investigation of chemotherapy treatment strategies for advanced non-small cell lung cancer (NSCLC) has studied combinations employing newer agents with a platinum compound (cisplatin or carboplatin)[1]. These agents include: paclitaxel, docetaxel, vinorelbine, gemcitabine, and the camptothecin derivatives. [2], [3]. Recently, a large trial conducted by the Eastern Cooperative Oncology Group (ECOG) compared four chemotherapy regimens in patients with advanced NSCLC [4]. Patients were randomly assigned to receive either cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. The four treatment regimens were not statistically significantly different in terms of response rate or overall survival. The median survival of all eligible patients was 7.9 months with a 1 and 2 year survival rate of 33 and 11%, respectively. These results solidified the role for chemotherapy but also underscore the need for continued clinical research in this area.
Bryostatin-1 is a macrocyclic lactone derived from a marine invertebrate, Bugula Neritina of the phylum Bryozoa, which has demonstrated in vitro anti-tumor properties in both hematologic and solid tumor cell lines. The mechanism of action is related to its ability to activate protein kinase C (PKC). PKC represents a large family of phospholipid-dependent serine/threonine kinases involved in the transduction of intracellular signals that regulate cell growth, differentiation and metabolism [5]. Paradoxically, prolonged exposure of bryostatin-1 eventually leads to the down-regulation of PKC [6]. It is unclear whether PKC activation or inactivation mediates the anti-tumor activity of this agent.
Another possible mechanism for the antineoplastic activity of bryostatin-1 is related to its immunomodulatory effects, having potent immunoenhancing effects on T-lymphocyte function. Bryostatin-1 can induce IL-2 receptor expression on CD4+ and CD8+ T-lymphocytes, and when combined with a calcium ionophore, can stimulate the production of IL-2 and proliferation of T-lymphocytes [7]. In vitro, bryostatin-1 enhances the development of cytotoxic T-cells (CTL) from resting T-lymphocytes and significantly decreases the amount of IL-2 that is needed for the development of CTL [8]. Augmentation of cytotoxicity in vitro appears to be dependent on the concentration of bryostatin-1 used. Only at a concentration of 0.5 ng/ml or less did bryostatin-1 increase IL-2-induced cytotoxicity. Higher concentrations may inhibit the cytotoxic response. In contrast, bryostatin-1 failed to induce LAK activity even in the presence of IL-2 [8].
Whether the immunomodulatory effects of bryostatin-1 contribute to the anti-tumor activity or toxicity of this agent is not clear. Analyses performed as a correlate to a phase I study demonstrated that bryostatin-1 induced the release of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) as detected in the serum [9]. In that study, peak levels of TNF-α were found 2 h post-infusion and peak levels of IL-6 were encountered at 24-h. The authors concluded that IL-6 and TNF-α might be useful in monitoring the biological activity of bryostatin-1.
Pre-clinical in vitro and in vivo studies showed bryostatin-1 to be active alone and in combination with cytotoxic chemotherapy. Pretreatment of tumor cells with bryostatin-1 enhanced the cytotoxicity of many chemotherapeutic agents. However, in the case of paclitaxel, an inhibitory effect was discovered when bryostatin-1 was given first. Upon further study, specific schedule-dependent cytotoxic synergy was seen only when paclitaxel was followed by bryostatin-1 in tumor-bearing mouse models and with a human leukemia cell line [10], [11].
Given this pre-clinical data, the combination of these two agents was studied in the phase I setting by Schwartz et al. [16] with paclitaxel administered first followed by bryostatin-1. The trial studied escalating doses of bryostatin-1 from 15 to 50 μg/m2 in combination with a fixed dose of paclitaxel of 80 mg/m2. Paclitaxel was administered as a 1-h infusion on days 1, 8, 15 with bryostatin-1 as a 1-h infusion on days 2, 9, 16 in accordance with the previously determined schedule-dependent synergy. Grades 1 and 2 myalgia was observed at all dose levels tested but myalgia was not dose-limiting. Responses were reported in a patient with recurrent adenocarcinoma of the esophagus in whom a partial response in the liver was noted, and in a patient with pancreatic cancer who remained on study for at least 7 months. When it was determined that the combination of bryostatin-1 50 μg/m2 and paclitaxel 80 mg/m2 was feasible, the dose of paclitaxel was escalated to 90 mg/m2 and recommended by the National Cancer Institute for phase II evaluation. From this trial, the recommended phase II doses for the combination of paclitaxel and bryostatin-1 were 90 mg/m2 and 50 μg/m2, respectively.
Based on these pre-clinical and phase I data, we undertook a phase II trial of paclitaxel and bryostatin-1 in patients with advanced NSCLC. The treatment regimen was modeled after the aforementioned phase I trial by Schwartz et al. and based on previous studies utilizing weekly paclitaxel at a dose of 90 mg/m2 [12], [13]. Along with testing the efficacy and safety of this drug combination, serum levels of TNF-α and IL-6, as well as the numbers of T-lymphocyte subsets, were measured during treatment to correlate effects on the immune system with toxicity and response.
Section snippets
Study design
This was a multi-institution (participating hospitals in the University of Chicago Phase II Network), open label, phase II study of paclitaxel followed by bryostatin-1 in patients with advanced NSCLC. The University of Chicago Institutional Review Board approved the protocol and all patients signed written informed consent. Eligibility criteria included histologic or cytologic documentation of NSCLC, stage IIIB (pleural effusion) or IV disease, no prior chemotherapy, measurable or evaluable
Patient characteristics
A total of 15 patients with previously untreated advanced NSCLC were accrued to this trial over a one year period between April of 2000 and April of 2001. They had the following characteristics: 53% male (n=8), 47% female (n=7), median age of 59 years (range 50–73), 13% stage IIIB (n=2), and 87% Stage IV (n=13). Fourteen patients had PS of 0 or 1.
Response
Thirty cycles of chemotherapy were administered with a median of 2 per patient (range 1–4). Eleven of the total 15 patients enrolled received greater
Discussion
Based upon pre-clinical and phase I data, a phase II study was undertaken to determine the feasibility of using the combination of bryostatin-1 and paclitaxel in patients with advanced NSCLC. Pre-clinical data established the specific schedule dependency between paclitaxel and bryostatin-1 noting that the combination was significantly more effective when paclitaxel was followed by bryostatin-1. The possible reasons for this schedule-dependent synergy were elegantly determined in a study by
Acknowledgements
The author thanks Livia Szeto, R.N. and Sylvia Watson M.S., R.N. for their nursing expertise, Srecko Vujasin Jr, B.S. for data management, and the University of Chicago Immunologic Monitoring Facility for performing the correlative assays as well as the University of Chicago Phase II Network affiliated hospitals for patient enrollment. Supported by the National Cancer Institute (N01 CM17102-02) and the University of Chicago Cancer Research Center (P30 CA14599-27).
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