Abstract
4027 Background: Based on our previous observation of topoisomerase 1 (Topo 1) upregulation by MMC in blood mononuclear cells (PBMC) and antitumor activity in refractory esophageal cancer for the combination of MMC and irinotecan, we evaluated efficacy of this concept in chemotherapy naïve pts with esophageal/GE junction adenocarcinomas. Methods: Pts received irinotecan 125 mg/m2 on days 2 and 9, every 4 wks. A randomized phase II design was used to evaluate modulation by either split dose MMC (3 mg/m2, days 1 and 8 [24h prior to irinotecan]) (Arm B) or full dose MMC 6 mg/m2 on day 1 (Arm A). Pts were stratified according to locally advanced (LA) or metastatic disease (MD). Reevaluation and surgical resection was done, when possible, after 2 cycles of therapy. PBMC were collected (RNA PaxGene tubes) pretreatment and at multiple time points during therapy and analyzed for NQ01 and carboxylesterase (CE) gene mutation status, as well as for expression of NQ01, NQ01AS, CE and Topo I genes. Tumor specimens were obtained pretreatment and after 2 courses of therapy for the above mutation/expression analyses. Results: Fifty-two pts (29 MD, 22 LA) have been enrolled. 17 of 37 pts (46%) re-evaluated so far achieved antitumor responses (2 CR, 15 PR) by CT/PET criteria, whereas 12 pts had stable disease and 8 had disease progression as their best response to treatment. Response rate (RR) so far has favored Arm A (2 CR, 8 PR) as compared to Arm B (7 PR). 15 pts underwent successful esophagectomy. No pathological CR occurred, and lymph node involvement was present in 12 pts. Cisplatin/5FU/XRT was administered to all pts with LN involvement at surgery and when feasible to unresectable patients. PBMC Topo 1 analyses are currently available in 12 pts: 4 Arm A, 8 Arm B. Topo 1 induction (≥10 fold from baseline) was present in 3 of 4 pts in Arm A and in 2 of 8 in Arm B. Full laboratory correlates will be presented at the meeting. Conclusions: The combination of MMC and irinotecan in esophageal/GE junction tumors is feasible and clinically active. Data supporting the best schedule of modulation and molecular mechanisms behind this interaction should be available at the completion of this trial. (Supported by NCI R21 CA92956–01) No significant financial relationships to disclose.
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