Background

Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy.

Objective

This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fluorodeoxyglucose positron emission tomography (FDG-PET) pharmacodynamics, and biomarker explorations for the combination of pan-PI3K inhibitor copanlisib and allosteric MEK inhibitor refametinib in patients with advanced solid tumors.

Patients and methods

This was an adaptive trial with eight dose cohorts combining dose escalation and varying schedules in repeated 28-day cycles. Patients received copanlisib (0.2–0.8 mg/kg intravenously) intermittently (days 1, 8, 15) or weekly (days 1, 8, 15, 22) each cycle, and refametinib (30–50 mg twice daily orally) continuously or 4 days on/3 days off. Patients with KRAS, NRAS, BRAF, or PI3KCA mutations were eligible for the expansion cohort.

Results

In the dose-escalation (n = 49) and expansion (n = 15) cohorts, the most common treatment-emergent adverse events included diarrhea (59.4%), nausea, acneiform rash, and fatigue (51.6% each). Dose-limiting toxicities included oral mucositis (n = 4), increased alanine aminotransferase/aspartate aminotransferase (n = 3), acneiform rash, hypertension (n = 2 each), and diarrhea (n = 1). MTD was copanlisib 0.4 mg/kg weekly and refametinib 30 mg twice daily. No pharmacokinetic interactions were identified. Decreased tumor FDG uptake and MEK-ERK signaling inhibition were demonstrated during treatment. Best response was stable disease (n = 21); median treatment duration was 6 weeks.

Conclusions

Despite sound rationale and demonstrable pharmacodynamic tumor activity in relevant tumor populations, a dose and schedule could not be identified for this drug combination that were both tolerable and offered clear efficacy in the population assessed.

Clinicaltrials.gov identifier

NCT01392521.

中文翻译：

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PI3K抑制剂Copanlisib结合变构MEK抑制剂Refametinib在晚期癌症患者中的Ib期试验。

背景

PI3K和MAPK信号的双重抑制在概念上是一种有前途的抗癌治疗方法。

目的

这项1b期试验研究了pan-PI3K抑制剂copanlisib和变构药物联合使用的安全性，最大耐受剂量（MTD），推荐的II期剂量，药代动力学，肿瘤反应，氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）药效学和生物标志物探索。 MEK抑制剂瑞法替尼用于晚期实体瘤患者。

患者和方法

这是一项具有适应性的试验，共有8个剂量组，在逐步重复的28天周期中结合了剂量递增和不同的时间表。患者每个周期间歇（第1、8、15天）或每周（第1、8、15、22天）接受帕潘尼西（0.2–0.8 mg / kg静脉内）或瑞法替尼（30-50毫克，每天口服两次）连续或4次天开放/ 3天休息。患有KRAS，NRAS，BRAF或PI3KCA突变的患者符合扩展队列的条件。

结果

在剂量递增（n  = 49）和扩张（n  = 15）队列中，最常见的治疗紧急不良事件包括腹泻（59.4％），恶心，痤疮样皮疹和疲劳（各为51.6％）。剂量限制性毒性包括口腔粘膜炎（n  = 4），丙氨酸氨基转移酶/天冬氨酸氨基转移酶增加（n  = 3），痤疮样皮疹，高血压（n  = 2）和腹泻（n  = 1）。MTD每周一次为copanlisib 0.4 mg / kg，瑞格替尼为30 mg每天两次。没有发现药代动力学相互作用。在治疗过程中，肿瘤FDG摄取减少和MEK-ERK信号抑制得到证实。最好的反应是稳定的疾病（n = 21）; 中位治疗时间为6周。

结论

尽管在相关肿瘤人群中具有合理的原理和可证明的药效学肿瘤活性，但尚不能确定这种药物组合的剂量和方案，该剂量和方案既可耐受，又可在所评估的人群中提供明确的疗效。

Clinicaltrials.gov标识符

NCT01392521。