Phase II study of PS-341 (bortezomib) with or without irinotecan in patients (pts) with advanced gastric adenocarcinomas (AGA)

Abstract

14040 Background: We are conducting a phase II trial of the proteasome inhibitor, PS-341, with or without irinotecan in pts with AGA. The combination of PS-341 and irinotecan has been studied in preclinical tumor models including a murine xenograft model of colon cancer, where the combination achieved significantly more tumor shrinkage than either agent alone. The primary objective of this study is to determine response rates, toxicities, progression-free survival, and overall survival in pts with AGA receiving PS-341 alone or in combination with irinotecan. Methods: All pts had gastric adenocarcinoma beyond the scope of surgical resection, measurable disease, and normal bone marrow, hepatic and renal function. All gave informed consent. In previously untreated patients, PS-341 was administered at 1.3 mg/m2 on days 1, 4, 8, and 11 as IV bolus every 21 days. Irinotecan was administered IV at 125 mg/m2 over 90 mins on days 1 and 8 every 21 days (Arm A). For previously treated patients, PS-341 was administered as a single agent at 1.3mg/m2 on days 1, 4, 8, 11 as an IV bolus every 21 days (Arm B). Radiologic evaluation and tumor measurements were performed every 8 weeks. Results: Thirty-seven pts have been enrolled; 29 are evaluable (4 never treated, 4 TETE). Twenty-two pts were treated in Arm A, and 11 in Arm B. All pts were eligible and the 29 treated pts were fully evaluable. Median age 58 (33–87); 26 males/7 females; median number of cycles received was 2.0. Most common toxicities: Grade 4 cardiac arrest (1), stomach perforation (1), leukopenia (2), diarrhea (1), edema (1); Grade 3 nausea (6), vomiting (7), diarrhea (4), febrile neutropenia (3), thrombocytopenia (6), anemia (6); Grade 5 death (3). Severe toxicities likely attributed to disease progression. Response rate was 33% for Arm A, 9% for Arm B. Progression-free survival was 1.8 mo. in Arm A, 1.4 mo. in Arm B. Median overall survival was 4.8 mo. in Arm A, 5.4 mo. in Arm B. Conclusions: The combination of PS-341 and irinotecan, a non-cisplatin containing therapy, is active in AGA and should be considered a key regimen. Monotherapy with PS-341 has a 9% response rate in this population of pre-treated patients with advanced disease. Accrual to this study is continuing. [Table: see text]

Bortezomib, Paclitaxel, and Carboplatin as a First-Line Regimen for Patients with Metastatic Esophageal, Gastric, and Gastroesophageal Cancer: Phase II Results from the North Central Cancer Treatment Group (N044B)

“…Although this study focused on gastric cancer cell lines, not esophageal, the adjacency of these two organs coupled with established similar treatment approaches suggest these data are in fact relevant even to the latter. Third, favorable, mounting clinical evidence in patients with other solid tumor malignancies suggests that this agent merits further study in patients with esophageal cancer [7,8,9]. Ocean and others treated 36 gastric cancer patients with bortezomib alone versus bortezomib plus irinotecan [7].…”

“…Third, favorable, mounting clinical evidence in patients with other solid tumor malignancies suggests that this agent merits further study in patients with esophageal cancer [7,8,9]. Ocean and others treated 36 gastric cancer patients with bortezomib alone versus bortezomib plus irinotecan [7]. The latter regimen yielded a 44% response rate, and the former a 9% response rate.…”

Targeted therapies in the treatment of gastric cancer

“…The cohort of patients treated with the combination presented significant activity with a PR rate of 28% and a median PFS of 3.5 months, whereas in patients treated with bortezomib alone the RR was 0% and the median PFS 1.4 months. 75 The preliminary results from gene profile analysis of eight paired tumor samples showed that the expression of 643 genes significantly changed after bortezomib treatment and 42% of the genes changed by Ն twofold between pretreatment and on treatment. The pathways that were significantly upregulated and downregulated were the apoptotic, PI3K and MAPK signaling pathways.…”

Novel Therapeutic Developments Other Than EGFR and VEGF Inhibition in Colorectal Cancer

“…The proteasome inhibitor Bortezomib (Velcade ® , PS-341; Janssen-Cilag Ltd., High Wycombe, U.K.) is proving valuable in the management of certain hematological malignancies, notably myeloma, and has encouraging preclinical and early clinical evidence of activity in solid tumors [67][68][69][70]. Phase I and II studies in CRC have included combination with 5-FU/LV, capecitabine, irinotecan, and FOLFOX [71,72]. However, the phase II trial with irinotecan in irinotecan-refractory CRC was halted because of poor activity.…”