Saif, M. W.

10062 Background: 17-AAG is a benzoquinone ansamycin that binds to and inhibits the HSP90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0–2, and adequate hematologic, hepatic, renal and cardiac functions received CNF1010 by 1 h intravenous infusion, twice-a-week, three weeks out of four, starting at 6 mg/m2 per dose. Doses were escalated sequentially in single pts (6 and 12 mg/m2) and 3–6 pts (≥ 25 mg/m2) cohorts according to a modified Fibonacci’s schema. Plasma pharmacokinetic (PK) profiles were obtained on days 1 and 18. Biomarkers were measured in PBMC’s (HSP70) and plasma (HER-2 ectodomain (HER-2 ECD)). Results: 30 pts (M/F: 14/16; median age 63, range 48–78) with colorectal cancer (11), pancreatic cancer (5), melanoma (5), ovarian (2), others (7) were treated with a median of 2 courses (range: 1–10). There was no dose-limiting toxicity up to 175 mg/m2. One pt at 175 mg/m2 died on study, but drug relation was unclear. Grade 1–2 gastrointestinal toxicities (nausea, vomiting, diarrhea) and serum creatinine elevation were observed. Severe toxicities (grade 3 but no grade 4) consisted of reversible hepatic enzyme elevation, hyperbilirubinemia, fatigue, anemia and hyperglycemia. There were no hematological toxicities. Plasma 17-AAG PK appeared dose-proportional (AUC, Cmax); CL (17 L/h/m2) and t1/2 (5.2 h) were dose independent and unchanged after repeated dosing (day 18). Post-treatment increases in HSP70 were observed in PBMCs and decreases in plasma HER-2 ECD were observed at doses ≥ 83 mg/m2. Minor tumor regressions were seen in 1 pt with duodenal cancer (83 mg/m2), 1 pt with gastric carcinoid (175 mg/m2) and 1 pt with melanoma (175 mg/m2). Conclusion: The threshold of biologic activity for CNF1010 administered by a twice a week schedule appears to be 83 mg/m2. This dosing regimen appears to be optimal and supported by the pharmacokinetic and pharmacodynamic data. The MTD has not yet been determined. Dose escalation of CNF1010 continues at 225 mg/m2. [Table: see text]

4606 Background: Preclinical studies have indicated that TP is one of the most useful markers of tumor response to capecitabine; with elevated TP expression resulting in higher intratumor levels of 5-FU. TP level in the tumor may be associated directly with survival and may be up-regulated by XRT. Methods: Twenty patients (pts) who had newly diagnosed locally advanced pancreatic cancer, age ≥ 19 years, ECOG PS 0–2, and adequate organ function received 50.4 Gy XRT with capecitabine 1,600 mg/m2 M-F x 6 wks determined from our phase I study (JCO, Dec 2005). Following capecitabine-XRT, stable and responding pts received capecitabine 2,000mg/m2 x 14 days every 3 wks till progression. Restaging was performed every 9 wks. Tumor specimens were procured with EUS-FNA prior and week 2 after starting capecitabine-XRT to evaluate TP mRNA levels by RT-PCR. Results: TP levels were elevated post-XRT when compared to pre-XRT TP (p= 0.01). Each of the 20 pts had at least one observation of TP. Mean TP level of each pt was obtained by averaging the pre-XRT and post-XRT TP levels. If one value was missing, then the other value was used for the mean TP level. Mean TP level was significantly associated with survival using the Cox proportional hazards model (p= 0.0072). Pts were separated into two groups - those with high baseline TP level and those with lower TP level with a cut off value of 213.85 using median of mean TP level. It was observed that group with higher TP levels had better survival as compared to the group with lower TP levels. However, the survival curves of these two groups crossed over after 18 months. Conclusions: Our study suggests that the higher the TP level in tumor post-XRT, the better the survival. This is most probably due to a higher accumulation of 5-FU in tumor due to up-regulation of TP. Possible explanation for the two groups crossing over after 18 months may include heterogeneity in TP due to a difference in pharmacogenomics or idiosyncratic drug toxicity profile of capecitabine. Further studies of long-term effects of treatment with a larger number of pts are needed to study exact effects of capecitabine and XRT, and to evaluate the differential role of TP with survival. [Table: see text]