Phase I dose escalation study of vinorelbine and topotecan combination chemotherapy in patients with recurrent lung cancer.

BACKGROUND: A platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status. However, platinum-based treatment may be associated with significant toxicities, therefore alternative platinum-free combinations should be investigated. Topotecan is a topoisomerase I inhibitor that exerts its cytotoxic effect through stabilization of the topoisomerase I-DNA complex. Preclinical data suggests synergy between topoisomerase I inhibitors and mitotic spindle poisons. Considerable hematologic toxicities have been reported with topotecan dosed for 5 consecutive days in combination with vinorelbine. Therefore, the aim of this study was to evaluate the optimal dosage and the maximal tolerated dose (MTD) of topotecan and vinorelbine in patients with relapsed or refractory non-small cell or small cell lung cancer administered on an alternate dosing schedule. METHODS: From February, 2004 to March, 2007 eighteen patients with advanced or recurrent NSCLC or SCLC previously treated with chemotherapy were enrolled. Patients were heavily pretreated with 22% having received at least 3 prior lines of chemotherapy. Vinorelbine was administered at a fixed dose (20 mg/m2) and topotecan at escalating doses (2, 2.5, 3, 3.5, and 4 mg/m2) on days 1 and 8 every 21 days. RESULTS: The MTD was not reached in any of the 5 cohorts, with only one dose limiting toxicity (DLT) occurring in cohort 4. Non-hematological toxicities were manageable. One patient had a partial response with four patients (27%) achieving stable disease. The median progression-free and overall survival for all patients, were 2.7 months (95% CI: 1.6, 9.1) and 10.5 months (95% CI: 4.2, 22.7), respectively. CONCLUSION: Vinorelbine and topotecan administered on days 1 and 8 every 21 days is well tolerated without any DLT seen with previously investigated topotecan schedules. This doublet provides a potentially active non-platinum containing doublet for the treatment of patients with advanced SCLC and NSCLC. Vinorelbine and topotecan should therefore be investigated in subsequent phase II studies at a dose of 20 mg/m2 and 4 mg/m2, respectively. TRIAL REGISTRATION NUMBER: NCT00287963.

Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial.

BACKGROUND: COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-kappaB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors. METHODS: Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily. RESULTS: No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease. CONCLUSION: The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated. TRIAL REGISTRATION NUMBER: NCT00290680.

Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo.

In this study, a cationic water-soluble ceramide analog L-threo-C6-pyridinium-ceramide-bromide (L-t-C6-Pyr-Cer), which exhibits high solubility and bioavailability, inhibited the growth of various human head and neck squamous cell carcinoma (HNSCC) cell lines at low IC50 concentrations, independent of their p53 status. Consistent with its design to target negatively charged intracellular compartments, L-t-C6-Pyr-Cer accumulated mainly in mitochondria-, and nuclei-enriched fractions upon treatment of human UM-SCC-22A cells [human squamous cell carcinoma (SCC) of the hypopharynx] at 1 to 6 h. In addition to its growth-inhibitory function as a single agent, the supra-additive interaction of L-t-C6-Pyr-Cer with gemcitabine (GMZ), a chemotherapeutic agent used in HNSCC, was determined using isobologram studies. Then, the effects of this ceramide, alone or in combination with GMZ, on the growth of UM-SCC-22A xenografts in SCID mice was assessed following the determination of preclinical parameters, such as maximum tolerated dose, clearance from the blood, and bioaccumulation. Results demonstrated that treatment with L-t-C6-Pyr-Cer in combination with GMZ significantly prevented the growth of HNSCC tumors in vivo. The therapeutic efficacy of L-t-C6-Pyr-Cer/GMZ combination against HNSCC tumors was approximately 2.5-fold better than that of the combination of 5-fluorouracil/cis-platin. In addition, liquid chromatography/mass spectroscopy analysis showed that the levels of L-t-C6-Pyr-Cer in HNSCC tumors were significantly higher than its levels in the liver and intestines; interestingly, the combination with GMZ increased the sustained accumulation of this ceramide by approximately 40%. Moreover, treatment with L-t-C6-Pyr-Cer/GMZ combination resulted in a significant inhibition of telomerase activity and decrease in telomere length in vivo, which are among downstream targets of ceramide.

Pemetrexed alone and in combination with platinum compounds in the management of malignant mesothelioma.

Malignant pleural mesothelioma is an aggressive but rare malignancy with a dismal prognosis. It is traditionally resistant to chemotherapy. Antifolate agents have recently shown promising data in the treatment of this malignancy. Pemetrexed is a multitargeted antifolate inhibitor of thymidylate synthase and other folate-dependent enzymes that has emerged as one of the most active agents in this disease. Several phase I/II trials of pemetrexed as a single agent or in combination with a platinum drug have demonstrated considerable activity in mesothelioma. In a recently published phase III randomized study, pemetrexed/cisplatin showed a significant improvement in survival, response rate, and quality of life compared with single-agent cisplatin. In addition, several trials reported that folic acid and vitamin B12 supplementation significantly reduced the toxicity observed with the use of pemetrexed without affecting the efficacy of the drug.