Phase II study of the farnesyl transferase inhibitor r115777 in patients with advanced non-small-cell lung cancer
Phase II study of the farnesyl transferase inhibitor r115777 in patients with advanced non-small-cell lung cancer
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DOI：
10.1200/jco.2003.09.075
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发表时间：
2003-05-01
影响因子：
45.3
通讯作者：
Vokes, EE
中科院分区：
文献类型：
--
作者：
Adjei, AA;Mauer, A;Vokes, EE
目的：这项 11 期研究旨在确定 RI 15777（一种法尼基转移酶抑制剂）在晚期非小细胞肺癌患者一线治疗中的疗效和药效学。 患者和方法：44 名可测量的 IIIB 期（胸腔积液）或 IV 期疾病患者接受了 193 个疗程（中位数为 2.0；范围为 I 至 22），其中R115777 300 mg，每日口服两次，每 28 天中的 21 天。治疗前和治疗后 8 天收集颊粘膜样本和外周血单核细胞 (PBMC)，以评估体内法尼基转移酶的抑制作用。结果：没有记录到客观的完全或部分反应。 7 名患者（16%；95% 置信区间 [CI]，8% 至 31%）疾病稳定期超过 6 个月。中位生存期为 7.7 个月（95% Cl，6.5 至 10.5），进展时间为 2.7 个月（95% Cl，1.9 至 3.1）。最严重的毒性是中性粒细胞减少症（9% 3 级，7% 4 级），最常见的毒性是贫血（50% 1 或 2 级，5% 3 级）和厌食症（50% 1 或 2 级，2% 3 级）。 25% 的患者出现轻度周围神经病变。 83% 的患者有法尼基转移酶抑制的证据。结论：单药 11115777 在晚期 NSCLC 患者中耐受性良好，但临床活性极低。体内法尼基化的抑制作用得到一致记录。基于法尼基转移酶抑制剂与标准化疗药物组合的有希望的结果，该药物在 NSCLC 中的未来研究应与全身化疗相结合。
Purpose: This phase 11 study was undertaken to define the efficacy and pharmacadynamics of RI 15777, a farnesyl transferase inhibitor, in the first-line treatment of patients with advanced non-small-cell lung cancer.Patients and Methods: Forty-four patients with measurable stage IIIB (pleural effusion) or stage IV disease received 193 courses of treatment (median, 2.0; range, I to 22) with R115777 300 mg administered orally twice daily for 21 of every 28 days. Buccal mucosa samples and peripheral blood mononuclear cells (PBMCs) were collected before and after 8 days of treatment to evaluate inhibition of farnesyl transferase in Vivo.Results: No objective complete or partial responses were documented. Seven patients (16%; 95% confidence interval [CI], 8% to 31%) had disease stabilization for greater than 6 months. Median survival was 7.7 months (95% Cl, 6.5 to 10.5) and time to progression was 2.7 months (95% Cl, 1.9 to 3.1). The most severe toxicity was neutropenic (9% grade 3, 7% grade 4) and the most common toxicities were anemia (50% grade 1 or 2, 5% grade 3) and anorexic (50% grade 1 or 2, 2% grade 3). Mild peripheral neuropathy occurred in 25% of patients. Evidence of farnesyl transferase inhibition was documented in 83% of patients.Conclusion: Single-agent 11115777 was well tolerated in patients with advanced NSCLC, but demonstrated minimal clinical activity. Inhibition of farnesylation in vivo was consistently documented. On the basis of promising results of farnesyl transferase inhibitor combinations with standard chemotherapy agents, future studies of this agent in NSCLC should be in combination with systemic chemotherapy.