Investigation of bendamustine HCL in a phase 2 study in women with resistant ovarian cancer.

We investigated the safety and efficacy of 90 mg/m(2) bendamustine HCL, administered intravenously on days 1 and 2 every 28 days in 10 women with platinum and taxane resistant epithelial ovarian cancer. There were no objective tumor responses observed; 2 patients had stable disease. Plasma samples collected at pre-treatment and end of cycle one were analyzed for changes in circulating total cytokeratin 18 and caspase cleaved cytokeratin 18 as exploratory early biomarkers of bendamustine-induced tumor cell death. All patients had measureable levels of both total and cleaved caspase 3 cytokeratin 18, but no relationship with response was possible due to the lack of clinical benefit in treated patients. Due to the high incidence of adverse events and absence of objective responses, only ten patients were treated as predefined by the Simon Two-Stage Design in the protocol. Overall, the regimen was not well tolerated and was associated with fatigue and a greater number of gastrointestinal side effects as compared to previously reported experiences in different patient populations. However, our study subjects did experience less bone marrow suppression. The lack of tolerability could reflect the degree of tumor burden within the peritoneal cavity as well as the high number of prior regimens (median of 5) received by the patients participating in this study.

Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer.

PURPOSE: This phase I trial evaluated intraperitoneal (i.p.) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. EXPERIMENTAL DESIGN: Dose escalation of day 1 i.p. pemetrexed accrued three patients to each of five dose levels (60-1,000 mg/m(2)), along with day 2 i.p. cisplatin (75 mg/m(2)) and day 8 i.p. paclitaxel (60 mg/m(2)). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics of i.p. pemetrexed. RESULTS: Cycles, given every 21 days, had an 80% 6-cycle completion rate. There was minimal grade III toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, two of three patients experienced ≥ grade III and dose-limiting toxicity (DLT; hematologic, infection, gastrointestinal). There was a pharmacokinetic advantage for i.p. pemetrexed with an intraperitoneal:plasma area under the concentration-time curve ratio of 13-fold. Neither analysis of pharmacokinetic nor homocysteine levels explains the unexpected severity of toxicity in those two patients. On the basis of plasma C(24h) levels, the 42 cycles at ≥ 500 mg/m(2) i.p. pemetrexed without DLT, the MTD appears to be 500 mg/m(2). Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months). CONCLUSIONS: This i.p.-only regimen in front-line ovarian cancer is feasible with PFS in line with recent literature. We suggest phase II trials of this regimen in this population with i.p. pemetrexed at 500 mg/m(2). The favorable toxicity profile at doses <1,000 mg/m(2), which needs to be confirmed, appears to compare well with standard combination i.v./i.p. platinum/taxane chemotherapy in this disease.

Overexpression of tumor vascular endothelial growth factor A may portend an increased likelihood of progression in a phase II trial of bevacizumab and erlotinib in resistant ovarian cancer.

PURPOSE: This phase II trial evaluated bevacizumab plus erlotinib in platinum-resistant ovarian cancer; exploratory biomarker analyses, including that of tumor vascular endothelial growth factor A (VEGF-A), were also done. EXPERIMENTAL DESIGN: Forty heavily pretreated patients received erlotinib (150 mg/d orally) and bevacizumab (10 mg/kg i.v.) every 2 weeks until disease progression. Primary end points were objective response rate and response duration; secondary end points included progression-free survival (PFS), toxicity, and correlations between angiogenic protein levels, toxicity, and efficacy. RESULTS: Grade 3 toxicities included skin rash (n = 6), diarrhea (n = 5), fatigue (n = 4), and hypertension (n = 3). Grade 4 toxicities were myocardial infarction (n = 1) and nasal septal perforation (n = 1). Only one grade 3 fistula and one grade 2 bowel perforation were observed. Nine (23.1%) of 39 evaluable patients had a response (median duration, 36.1+ weeks; one complete response), and 10 (25.6%) patients achieved stable disease, for a disease control rate of 49%. Median PFS was 4 months, and 6-month PFS was 30.8%. Biomarker analyses identified an association between tumor cell VEGF-A expression and progression (P = 0.03); for every 100-unit increase in the VEGF-A score, there was a 3.7-fold increase in the odds of progression (95% confidence interval, 1.1-16.6). CONCLUSIONS: Bevacizumab plus erlotinib in heavily pretreated ovarian cancer patients was clinically active and well tolerated. Erlotinib did not seem to contribute to efficacy. Our study raises the intriguing possibility that high levels of tumor cell VEGF-A, capable of both autocrine and paracrine interactions, are associated with resistance to bevacizumab, emphasizing the complexity of the tumor microenvironment.