Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies.

PURPOSE: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. EXPERIMENTAL DESIGN: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxel were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized. RESULTS: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non-dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25 patients evaluable for response, partial responses occurred in 11 (10 non-small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics. CONCLUSIONS: Both schedules of vorinostat (400 mg oral qd x 14 days or 300 mg bd x 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL x min) and paclitaxel (200 mg/m(2)). Encouraging anticancer activity was noted in patients with previously untreated non-small cell lung cancer.

The impact of tumor volume and radiotherapy dose on outcome in previously irradiated recurrent squamous cell carcinoma of the head and neck treated with stereotactic body radiation therapy.

PURPOSE: To assess the effect of stereotactic body radiotherapy (SBRT) dose and tumor volume on outcomes in patients with recurrent, previously irradiated squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: A total of 96 patients with recurrent, previously irradiated squamous cell carcinoma of the head and neck were treated with SBRT using Cyberknife and Trilogy-intensity-modulated radiosurgery. Kaplan-Meier survival analyses were used to estimate locoregional control (LRC) and overall survival rates. Response was evaluated using positron emission tomography/computed tomography or computed tomography and detailed physical examination. RESULTS: The median follow-up for all patients was 14 months (2-39 months). The median dose of prior radiation was 68.4 Gy (32-170 Gy). Patients were divided into 4 SBRT dose groups: I (15-28 Gy/n = 29), II (30-36 Gy/n = 22), III (40 Gy/n = 18), and IV (44-50 Gy/n = 27). The median gross tumor volume (GTV) was 24.3(3) cm (2.5-162 cm). For GTV ≤25 cm(3) (n = 50), complete response rates were 27.8%/30%/45.5%/45.5%, and for GTV >25 cm(3) (n = 46), complete response rates were 20%/25%/42.8%/50% for SBRT groups I-IV, respectively. The 1-/2-/3-year LRC rates for doses 40 to 50 Gy were 69.4%/57.8%/41.1%, respectively, whereas for 15 to 36 Gy, they were 51.9%/31.7%/15.9%, respectively (P = 0.02). The overall 1- and 2-year overall survival rates were 58.9% and 28.4%, respectively. Treatment was well tolerated with no grade 4/5 toxicities. CONCLUSIONS: Dose escalation up to 50 Gy in 5 fractions is feasible with SBRT for recurrent head and neck squamous cell carcinoma. Higher SBRT doses were associated with significantly higher LRC rates. Large tumor volume required higher SBRT doses to achieve optimal response rates compared with smaller tumor volume.

Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer.

PURPOSE Vorinostat, a histone deacetylase inhibitor, exerts anticancer effects by both histone and nonhistone-mediated mechanisms. It also enhances the anticancer effects of platinum compounds and taxanes in non-small-cell lung cancer (NSCLC) cell lines. This phase II randomized, double-blinded, placebo-controlled study evaluated the efficacy of vorinostat in combination with carboplatin and paclitaxel in patients with advanced-stage NSCLC. PATIENTS AND METHODS Patients with previously untreated stage IIIB (ie, wet) or IV NSCLC were randomly assigned (2:1) to carboplatin (area under the curve, 6 mg/mL x min) and paclitaxel (200 mg/m(2) day 3) with either vorinostat (400 mg by mouth daily) or placebo. Vorinostat or placebo was given on days 1 through 14 of each 3-week cycle to a maximum of six cycles. The primary end point was comparison of the response rate. Results Ninety-four patients initiated protocol therapy. Baseline patient characteristics were similar between the two arms. The median number of cycles was four for both treatment arms. The confirmed response rate was 34% with vorinostat versus 12.5% with placebo (P = .02). There was a trend toward improvement in median progression-free survival (6.0 months v 4.1 months; P = .48) and overall survival (13.0 months v 9.7 months; P = .17) in the vorinostat arm. Grade 4 platelet toxicity was more common with vorinostat (18% v 3%; P < .05). Nausea, emesis, fatigue, dehydration, and hyponatremia also were more frequent with vorinostat. CONCLUSION Vorinostat enhances the efficacy of carboplatin and paclitaxel in patients with advanced NSCLC. HDAC inhibition is a promising therapeutic strategy for treatment of NSCLC.

A randomized phase II trial using two different treatment schedules of gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer.

BACKGROUND: Gemcitabine and carboplatin combination therapy is an active and tolerable regimen in the treatment of non-small-cell lung cancer (NSCLC). Twenty-eight- and 21-day regimens without day-15 administration of gemcitabine are common; however, it remains unclear which offers the optimal therapeutic index. METHODS: This trial evaluated two schedules of the combination of gemcitabine and carboplatin: gemcitabine (1100 mg/m on days 1 and 8) plus carboplatin (area under the curve = 5 on day 8) every 28 days, or gemcitabine (1000 mg/m on days 1 and 8) plus carboplatin (area under the curve = 5 on day 1) every 21 days. Eligible patients in this trial had stage IIIB (with malignant pleural effusion) or stage IV NSCLC with no prior chemotherapy. The primary objective was to evaluate progression-free survival, with secondary objectives of overall survival, response rate, and toxicity. RESULTS: One hundred patients were randomized and enrolled from October of 2000 to January of 2002 into this multi-institutional study (48 for the 28-day regimen and 52 for the 21-day regimen). Baseline demographics were well matched, and a majority of patients (85%) enrolled with stage IV disease. Median progression-free survival and response rates were 3.8 months and 22.9%, respectively, with the 28-day regimen, and 4.9 months and 40.4%, respectively, with the 21-day regimen. Median survival was 8.7 months with the 28-day regimen and 8.0 months for the 21-day regimen. One- and 2-year survival rates were 34.7% and 8.7%, respectively, with the 28-day regimen, and 36.5% and 16.8%, respectively, with the 21-day regimen. Differences in progression-free survival (log-rank statistic, p = 0.5786), response rate (Fisher's exact test, p = 0.0859) and overall survival (log-rank statistic, p = 0.3568) were not statistically significant. Grade 3 to 4 hematologic toxicities occurred with a greater frequency in the 21-day regimen. No grade 3 to 4 nonhematologic toxicity (except nausea/vomiting with the 28-day regimen) was observed in more than 10% of patients in either treatment arm. CONCLUSION: Gemcitabine plus carboplatin is active and well tolerated in advanced NSCLC. Both regimens may be considered for further study. Although the 21-day regimen appeared to be associated with preferable outcomes, differences between treatment groups were not statistically significant.