Duke University Medical Center, Seeley G. Mudd Bldg 10 Bryan Searle Drive, Box 3505, Durham, NC, 27710, USA.
Genentech-Roche, San Francisco, CA, USA.
Cancer Chemother Pharmacol. 2019 Jun;83(6):1025-1035. doi: 10.1007/s00280-019-03805-6. Epub 2019 Mar 20.
This study was conducted to define the maximum tolerated dose (MTD), recommended phase two dose (RPTD), and toxicities of gemcitabine + dasatinib (GD) and gemcitabine + dasatinib + cetuximab (GDC) in advanced solid tumor patients.
This study was a standard phase I 3 + 3 dose escalation study evaluating two combination regimens, GD and GDC. Patients with advanced solid tumors were enrolled in cohorts of 3-6 to either GD or GDC. Gemcitabine was dosed at 1000 mg/m weekly for 3 of 4 weeks, dasatinib was dosed in mg PO BID, and cetuximab was dosed at 250 mg/m weekly after a loading dose of cetuximab of 400 mg/m. There were two dose levels for dasatinib: (1) gemcitabine + dasatinib 50 mg ± cetuximab, and (2) gemcitabine + dasatinib 70 mg ± cetuximab. Cycle length was 28 days. Standard cycle 1 dose-limiting toxicity (DLT) definitions were used. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities that would increase the risk of toxicity. Serum, plasma, and skin biopsy biomarkers were obtained pre- and on-treatment.
Twenty-five patients were enrolled, including 21 with pancreatic adenocarcinoma. Three patients received prior gemcitabine. Twenty-one patients were evaluable for toxicity and 16 for response. Four DLTs were observed: Grade (Gr) 3 neutropenia (GDC1, n = 1), Gr 3 ALT (GD2, n = 2), and Gr 5 pneumonitis (GDC2, n = 1). Possible treatment-emergent adverse events (TEAEs) in later cycles included: Gr 3-4 neutropenia (n = 7), Gr 4 colitis (n = 1), Gr 3 bilirubin (n = 2), Gr 3 anemia (n = 2), Gr 3 thrombocytopenia (n = 2), Gr 3 edema/fluid retention (n = 1), and Gr 3 vomiting (n = 3). Six of 16 patients (3 of whom were gemcitabine-refractory) had stable disease (SD) as best response, median duration = 5 months (range 1-7). One gemcitabine-refractory patient had a partial response (PR). Median PFS was 2.9 months (95% CI 2.1, 5.8). Median OS was 5.8 months (95% CI 4.1, 11.8). Dermal wound biopsies demonstrated that dasatinib resulted in a decrease of total and phospho-Src levels, and cetuximab resulted in a decrease of EGFR and ERBB2 levels.
The MTD/RPTD of GD is gemcitabine 1000 mg/m weekly for 3 of 4 weeks and dasatinib 50 mg PO BID. The clinical activity of GD seen in this study was modest, and does not support its further investigation in pancreatic cancer.
本研究旨在确定吉西他滨+达沙替尼（GD）和吉西他滨+达沙替尼+西妥昔单抗（GDC）在晚期实体瘤患者中的最大耐受剂量（MTD）、推荐的 II 期剂量（RPTD）和毒性。
这是一项标准的 3+3 剂量递增的 I 期研究，评估了两种联合治疗方案，GD 和 GDC。晚期实体瘤患者按 3-6 人一组入组接受 GD 或 GDC 治疗。吉西他滨每周 1000mg/m 剂量给药，连续 4 周，每周 2 次口服达沙替尼，每次 50mg；西妥昔单抗在给予 400mg/m 的负荷剂量后，每周剂量为 250mg/m。达沙替尼有两个剂量水平：（1）吉西他滨+达沙替尼 50mg±西妥昔单抗，和（2）吉西他滨+达沙替尼 70mg±西妥昔单抗。治疗周期为 28 天。采用标准的 1 周期剂量限制性毒性（DLT）定义。合格患者为患有晚期实体瘤、有足够的器官和骨髓功能、没有增加毒性风险的合并症。在治疗前和治疗期间采集血清、血浆和皮肤活检生物标志物。
共入组 25 例患者，其中 21 例为胰腺腺癌。3 例患者曾接受过吉西他滨治疗。21 例患者可进行毒性评估，16 例患者可进行疗效评估。观察到 4 例 DLT：Gr3 中性粒细胞减少（GDC1，n=1）、Gr3 丙氨酸氨基转移酶升高（GD2，n=2）和 Gr5 肺炎（GDC2，n=1）。后期周期可能出现的治疗相关不良事件（TEAEs）包括：Gr3-4 中性粒细胞减少（n=7）、Gr4 结肠炎（n=1）、Gr3 胆红素升高（n=2）、Gr3 贫血（n=2）、Gr3 血小板减少症（n=2）、Gr3 水肿/体液潴留（n=1）和 Gr3 呕吐（n=3）。16 例患者中有 6 例（其中 3 例为吉西他滨耐药）最佳缓解为疾病稳定（SD），中位缓解持续时间为 5 个月（范围 1-7）。1 例吉西他滨耐药患者获得部分缓解（PR）。中位无进展生存期为 2.9 个月（95%CI 2.1，5.8）。中位总生存期为 5.8 个月（95%CI 4.1，11.8）。皮肤伤口活检显示，达沙替尼导致总和磷酸化Src 水平降低，西妥昔单抗导致 EGFR 和 ERBB2 水平降低。
GD 的最大耐受剂量/推荐 II 期剂量为每周 1000mg/m 的吉西他滨连续 4 周，达沙替尼 50mg 每日口服 2 次。本研究中观察到的 GD 的临床活性温和，不支持其在胰腺癌中的进一步研究。
