Preliminary results from subsets of patients (pts) with advanced gastric cancer (GC) and esophageal carcinoma (EC) in a dose-escalation/expansion study of BGB-A317, an anti-PD-1 monoclonal antibody (mAb)

4072 Background: Present study describes the first phase II study of S-1 including pharmacokinetic and pharmacogenomic evaluation for extra-Japanese Asian population with advanced gastric cancer. Methods: Chemo-naive advanced gastric cancer with measurable disease was enrolled. Initial dose of S-1 was b.i.d. at 35, then 40 mg/m2 according to devised dosing method (range, 90–160 mg/day) for 28 days every 6 weeks. Pharmacokinetic study was performed after 28-day administration at cycle 1 and 3. Microarray based CGH was performed with genomic DNA from peripheral mononuclear cells to detect the toxicity-related genetic changes. Results: When first 31 patients were enrolled, protocol was amended to conduct the study by two steps for additional patients at 40 mg/m2 without dose escalation in initial 31 patients of 35 mg/m2, because these patients showed neither significant nor cumulative toxicity. Of 62 patients enrolled, median relative dose intensity was 0.99. Overall response rate was 19.3% (95% CI, 9.2–29.5). With 558-day follow-up duration, median TTP and OS were 126 and 264 days, respectively. One-year survival rate was 33.9%. Toxicity increased with dose escalation, but there was no grade 4 toxicity. The most common significant toxicity was anemia. Pharmacokinetics parameters were similar to those of Japanese population. In microarray-CGH, we selected 18 genes with different copy numbers of 13 amplified and 5 deleted genes in patients with anemia. Conclusions: Our phase II study showed the feasibility of S-1 in gastric cancer at the dose of 35 mg/m2, and we suggested that selected 18 genes might be candidate markers for predicting anemia with S-1 treatment. No significant financial relationships to disclose.

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Randomized phase II study comparing dose-escalated weekly paclitaxel versus standard dose weekly paclitaxel for patients with previously treated advanced gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4076 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4076-4076

Author(s):

Kohei Shitara ◽

Satoshi Yuki ◽

Daisuke Takahari ◽

Michio Nakamura ◽

Chihiro Kondo ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Phase Ii ◽

Dose Escalation ◽

Standard Dose ◽

Phase Iii ◽

Weekly Paclitaxel ◽

Subset Analysis ◽

Randomized Phase Ii ◽

Previously Treated

4076 Background: Retrospective analyses of neutropenia during chemotherapy of weekly paclitaxel (wPTX) suggested better overall survival (OS) among patients with neutropenia. We conducted a randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Methods: Ninety-patients with AGC that progressed during one or more previous chemotherapy regimens were randomized to a standard dose of wPTX (80 mg/m2, standard dose arm) or an escalated dose of wPTX (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2 on day 15 unless severe toxicity nor neutropenia<1.5 x 109/L is observed, escalated dose arm) to assess superiority with a one-sided alpha of 0.3 and a power of 0.8. Results: The primary endpoint of median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs. 9.6 months; hazard ratio [HR], 0.75; 95% CI, 0.45-1.22; one-sided P=0.12). Median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs. 2.5 months, HR, 0.55; 95% CI, 0.34-0.90; P=0.017). Objective response rate was 30.3% with dose-escalation and 17.1% with standard dose (P=0.2). The disease control rate (DCR) was significantly higher with dose-escalation (78.8% vs. 48.6%, P=0.009). Subset-analysis according to stratification factors including ECOG PS, presence of measurable lesions and lines of previous chemotherapy indicated that OS benefit of the dose escalation is more prominent in PS 0-1 patients (N=81, median 13.6 vs. 9.8 months, HR 0.68, 95% CI 0.41-1.11) than PS2 patients with significant interaction (p=0.01) Conclusions: Dose escalated wPTX was associated with sufficiently longer OS in patients with pretreated AGC. In addition, significant longer PFS and higher DCR associated with dose-escalation and subset analysis according PS warrant further investigations in phase III trials, especially in patients with favorable PS patients. Clinical trial information: UMIN000004055.

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