P38 Phase 1 dose-finding study of epirubicin, oxaliplatin, and S-1 in patients with previously untreated advanced gastric cancer

3030 Background: AMG 706 is an investigational, oral, small molecule multi-kinase inhibitor with both antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF, and Kit receptors. From a phase 1 study (Rosen ASCO 2005; Herbst EORTC 2005), encouraging antitumor activity was seen in pts with TC. In this analysis, we report on the TC subset from the study. Methods: Pts with refractory solid tumors received oral AMG 706 QD (50, 100, 125, 175 mg) or BID (25 mg) intermittently or continuously for 28-day cycles. Study objectives were to assess safety, establish the maximum tolerated dose (MTD), and generate pharmacokinetic profiles of AMG 706 in these pts. Tumor response (modified RECIST) was evaluated at wk 8 and Q12W thereafter. Data from Oct 2005 were analyzed. Results: In this study, 7 of 71 pts enrolled had TC. Baseline demographics for this subset were 4 W/3 M, median (range) age of 58 (41, 78) yrs, ECOG 1 (71%), and all had stage IV disease. Histologies were papillary (3: PTC), follicular (1; FTC), Hürthle cell (1), anaplastic (1), and medullary TC (1; MTC). All pts received prior external radiotherapy, radioiodine, chemotherapy, and/or surgery. Initial doses of AMG 706 were 125 mg and 175 QD and 25 mg BID. The MTD for the study was 125 mg QD. Median (range) time on treatment for the TC pts was 141 (14, 564) days. Treatment-related adverse events are summarized ( table ). Best objective responses were 3 pts with partial response (PR), 3 with stable disease (SD), and 1 with progressive disease. PR was seen in pts with MTC, PTC and FTC. Two pts with PR did not have confirmation of response (1 had a PR during the last assessment). The 3 pts with PR received AMG 706 for 338, 366, and 564 days; 2 pts are still receiving AMG 706. Time to response for these 3 pts were 210, 217, and 304 days. Conclusion: In patients with TC, AMG 706 appears to be relatively well tolerated and displays promising antitumor activity for some pts. Based on these favorable findings, a phase 2 study of AMG 706 for the treatment of advanced TC is ongoing. [Table: see text] [Table: see text]

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Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4559 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4559-4559

Author(s):

C. Kim ◽

J. Lee ◽

Y. Choi ◽

B. Kang ◽

M. Ryu ◽

...

Keyword(s):

Gastric Cancer ◽

Phase I ◽

Dose Level ◽

Dose Finding ◽

Finding Study ◽

Level 3 ◽

Dose Finding Study ◽

Level 1 ◽

Grade 3 ◽

Level 2

4559 Background: We conducted a phase I dose-finding study of sorafenib (S) in combination with capecitabine (X) and cisplatin (P) in patients with previously untreated metastatic or inoperable advanced gastric cancer. Methods: Four dose levels of S, X, and P combination were tested. The doses of S (p.o. daily), X (p.o. on days 1–14), and P (i.v. on day 1) were escalated at the following schedule; level 1: S 400 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 2: S 800 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 3: S 800 mg/d, X 2,000 mg/m2/d, P 80 mg/m2; level 1A: S 800 mg/d, X 1,600 mg/m2/d, P 60 mg/m2. The cycle was repeated every 3 weeks. Dose limiting toxicities (DLTs) were evaluated only in the first cycles and a standard 3+3 dose escalation design was implemented. Results: A total 21 pts were enrolled in the study. No DLTs were observed at dose level 1 (n=3). One DLT (grade 3 diarrhea) was noted at dose level 2 (n=6), and 2 DLTs (two grade 4 neutropenias longer than 5 days in duration) were observed at dose level 3 (n=6), which made the level 3 dose the maximum tolerated dose (MTD). However, at cycle 2 and thereafter at dose level 2, the relative dose intensity (RDI) of S and X could not be maintained (mostly below 80%) due to the frequent dose reductions and cycle delays. So, we explored a new dose level (1A) between dose level 1 and 2. Since no DLTs were found in 6 patients at level 1A with RDI mostly above 80% throughout the treatment period, level 1A was determined as recommended dose (RD). Most frequent grade 3 and 4 hematologic toxicities were neutropenia (25.0% of cycles), and most frequent grade 2 and 3 non-hematologic toxicities were hand-foot syndrome (9.4%), asthenia (7.0%), and anorexia (5.5%). The objective responses were confirmed in 10 out of 16 patients with measurable lesions (62.5%; 95% CI, 38.8–86.2%). With a median follow-up of 8.1 months, estimated median progression-free survival was 10.0 months (95% CI, 1.6–18.4 months) and median overall survival has not been reached. Conclusions: Diarrhea and neutropenia were DLTs in this S, X, and P combination. The dose schedule of sorafenib 400 mg po bid daily with capecitabine 800 mg/m2 po bid on days 1–14, and cisplatin 60 mg/m2 iv on day 1 in every 3 weeks is recommended for further development in AGC. [Table: see text]

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