PDF(Pubmed)
Abstract：
Preclinical studies show that activation of AMP kinase by phenformin can augment the cytotoxic effect and RAF inhibitors in BRAF V600-mutated melanoma. We conducted a phase Ib dose-escalation trial of phenformin with standard dose dabrafenib/trametinib in patients with metastatic BRAF V600-mutated melanoma.
We used a 3+3 dose-escalation design which explored phenformin doses between 50 and 200 mg twice daily. Patients also received standard dose dabrafenib/trametinib. We measured phenformin pharmacokinetics and assessed the effect of treatment on circulating myeloid-derived suppressor cells (MDSC).
A total of 18 patients were treated at dose levels ranging from 50 to 200 mg twice daily. The planned dose-escalation phase had to be cancelled because of the COVID 19 pandemic. The most common toxicities were nausea/vomiting; there were two cases of reversible lactic acidosis. Responses were seen in 10 of 18 patients overall (56%) and in 2 of 8 patients who had received prior therapy with RAF inhibitor. Pharmacokinetic data confirmed drug bioavailability. MDSCs were measured in 7 patients treated at the highest dose levels and showed MDSC levels declined on study drug in 6 of 7 patients.
We identified the recommended phase II dose of phenformin as 50 mg twice daily when administered with dabrafenib/trametinib, although some patients will require short drug holidays. We observed a decrease in MDSCs, as predicted by preclinical studies, and may enhance immune recognition of melanoma cells.
This is the first trial using phenformin in combination with RAF/MEK inhibition in patients with BRAF V600-mutated melanoma. This is a novel strategy, based on preclinical data, to increase pAMPK while blocking the MAPK pathway in melanoma. Our data provide justification and a recommended dose for a phase II trial.
We used a 3+3 dose-escalation design which explored phenformin doses between 50 and 200 mg twice daily. Patients also received standard dose dabrafenib/trametinib. We measured phenformin pharmacokinetics and assessed the effect of treatment on circulating myeloid-derived suppressor cells (MDSC).
A total of 18 patients were treated at dose levels ranging from 50 to 200 mg twice daily. The planned dose-escalation phase had to be cancelled because of the COVID 19 pandemic. The most common toxicities were nausea/vomiting; there were two cases of reversible lactic acidosis. Responses were seen in 10 of 18 patients overall (56%) and in 2 of 8 patients who had received prior therapy with RAF inhibitor. Pharmacokinetic data confirmed drug bioavailability. MDSCs were measured in 7 patients treated at the highest dose levels and showed MDSC levels declined on study drug in 6 of 7 patients.
We identified the recommended phase II dose of phenformin as 50 mg twice daily when administered with dabrafenib/trametinib, although some patients will require short drug holidays. We observed a decrease in MDSCs, as predicted by preclinical studies, and may enhance immune recognition of melanoma cells.
This is the first trial using phenformin in combination with RAF/MEK inhibition in patients with BRAF V600-mutated melanoma. This is a novel strategy, based on preclinical data, to increase pAMPK while blocking the MAPK pathway in melanoma. Our data provide justification and a recommended dose for a phase II trial.
摘要：
目的：临床前研究表明，苯乙双胍激活AMP激酶可以增强BRAFV600突变黑色素瘤的细胞毒性作用和RAF抑制剂。我们在转移性BRAFV600突变黑色素瘤患者中进行了苯乙双胍与标准剂量达拉非尼/曲美替尼的Ib期剂量递增试验。
方法：我们使用3+3剂量递增设计，探索了50mg至200mgbid之间的苯乙双胍剂量。患者还接受标准剂量dabrafenib/trametinib。我们测量了苯乙双胍的药代动力学，并评估了治疗对循环髓源性抑制细胞（MDSC）的影响。
结果：18例患者的治疗剂量为50mgbid至200mgbid。由于COVID19大流行，计划的剂量递增阶段不得不取消。最常见的毒性是恶心/呕吐；有2例可逆性乳酸性酸中毒。总体上10/18例患者（56％）和2/8例接受过RAF抑制剂治疗的患者出现了反应。药代动力学数据证实了药物生物利用度。在以最高剂量水平治疗的7名患者中测量MDSC,并且在6/7名患者中显示MDSC水平在研究药物上下降。
结论：我们确定与达拉非尼/曲美替尼一起给药时，推荐的2期苯乙双胍剂量为50mgbid，尽管有些患者需要短暂的药物假期。我们观察到MDSCs减少，正如临床前研究所预测的那样，并可能增强黑色素瘤细胞的免疫识别。
方法：我们使用3+3剂量递增设计，探索了50mg至200mgbid之间的苯乙双胍剂量。患者还接受标准剂量dabrafenib/trametinib。我们测量了苯乙双胍的药代动力学，并评估了治疗对循环髓源性抑制细胞（MDSC）的影响。
结果：18例患者的治疗剂量为50mgbid至200mgbid。由于COVID19大流行，计划的剂量递增阶段不得不取消。最常见的毒性是恶心/呕吐；有2例可逆性乳酸性酸中毒。总体上10/18例患者（56％）和2/8例接受过RAF抑制剂治疗的患者出现了反应。药代动力学数据证实了药物生物利用度。在以最高剂量水平治疗的7名患者中测量MDSC,并且在6/7名患者中显示MDSC水平在研究药物上下降。
结论：我们确定与达拉非尼/曲美替尼一起给药时，推荐的2期苯乙双胍剂量为50mgbid，尽管有些患者需要短暂的药物假期。我们观察到MDSCs减少，正如临床前研究所预测的那样，并可能增强黑色素瘤细胞的免疫识别。
