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Abstract：
Ulixertinib is a novel oral ERK inhibitor that has shown promising single-agent activity in a phase I clinical trial that included patients with RAS-mutant cancers.
We conducted a phase Ib trial combining ulixertinib with gemcitabine and nab-paclitaxel (GnP) for untreated metastatic pancreatic adenocarcinoma. The trial comprised a dose de-escalation part and a cohort expansion part at the recommended phase II dose (RP2D). Primary endpoint was to determine the RP2D of ulixertinib plus GnP and secondary endpoints were to assess toxicity and safety profile, biochemical and radiographic response, progression-free survival (PFS) and overall survival (OS).
Eighteen patients were enrolled. Ulixertinib 600 mg PO twice daily (BID) with GnP was initially administered but was de-escalated to 450 mg BID as RP2D early during dose expansion due to poor tolerability, which ultimately led to premature termination of the study. Common treatment-related adverse events (TRAEs) were anemia, thrombocytopenia, rash and diarrhea. For 5 response evaluable patients, one patient achieved a partial response and 2 patients achieved stable disease. For 15 patients who received the triplet, median PFS and OS were 5.46 and 12.23 months, respectively.
Ulixertinib plus GnP had similar frequency of grade ≥3 TRAEs and potentially efficacy as GnP, however was complicated by a high rate of all-grade TRAEs (ClinicalTrials.gov Identifier: NCT02608229).
We conducted a phase Ib trial combining ulixertinib with gemcitabine and nab-paclitaxel (GnP) for untreated metastatic pancreatic adenocarcinoma. The trial comprised a dose de-escalation part and a cohort expansion part at the recommended phase II dose (RP2D). Primary endpoint was to determine the RP2D of ulixertinib plus GnP and secondary endpoints were to assess toxicity and safety profile, biochemical and radiographic response, progression-free survival (PFS) and overall survival (OS).
Eighteen patients were enrolled. Ulixertinib 600 mg PO twice daily (BID) with GnP was initially administered but was de-escalated to 450 mg BID as RP2D early during dose expansion due to poor tolerability, which ultimately led to premature termination of the study. Common treatment-related adverse events (TRAEs) were anemia, thrombocytopenia, rash and diarrhea. For 5 response evaluable patients, one patient achieved a partial response and 2 patients achieved stable disease. For 15 patients who received the triplet, median PFS and OS were 5.46 and 12.23 months, respectively.
Ulixertinib plus GnP had similar frequency of grade ≥3 TRAEs and potentially efficacy as GnP, however was complicated by a high rate of all-grade TRAEs (ClinicalTrials.gov Identifier: NCT02608229).
摘要：
背景：Ulixertinib是一种新型的口服ERK抑制剂，在包括RAS突变癌症患者的I期临床试验中显示出有希望的单药活性。
方法：我们进行了一项Ib期试验，将ulixertinib联合吉西他滨和nab-紫杉醇（GnP）用于未治疗的转移性胰腺腺癌。该试验包括推荐的II期剂量（RP2D）的剂量递减部分和队列扩展部分。主要终点是确定ulixertinib加GnP的RP2D，次要终点是评估毒性和安全性，生化和放射学反应，无进展生存期（PFS）和总生存期（OS）。
结果：纳入18例患者。最初使用Ulixertinib600mgPO每日两次（BID）与GnP，但由于耐受性差，在剂量扩大期间早期降低至450mgBID作为RP2D，最终导致研究提前终止。常见的治疗相关不良事件（TRAEs）是贫血，血小板减少症,皮疹和腹泻。对于5名可评估反应的患者，1例患者获得部分缓解,2例患者病情稳定.对于接受三联的15名患者，中位PFS和OS分别为5.46和12.23个月,分别。
结论：Ulixertinib联合GnP具有与GnP相似的≥3级TRAE频率和潜在疗效。然而，由于高比率的所有级别的TRAE（ClinicalTrials.gov标识符：NCT02608229）而复杂化。
方法：我们进行了一项Ib期试验，将ulixertinib联合吉西他滨和nab-紫杉醇（GnP）用于未治疗的转移性胰腺腺癌。该试验包括推荐的II期剂量（RP2D）的剂量递减部分和队列扩展部分。主要终点是确定ulixertinib加GnP的RP2D，次要终点是评估毒性和安全性，生化和放射学反应，无进展生存期（PFS）和总生存期（OS）。
结果：纳入18例患者。最初使用Ulixertinib600mgPO每日两次（BID）与GnP，但由于耐受性差，在剂量扩大期间早期降低至450mgBID作为RP2D，最终导致研究提前终止。常见的治疗相关不良事件（TRAEs）是贫血，血小板减少症,皮疹和腹泻。对于5名可评估反应的患者，1例患者获得部分缓解,2例患者病情稳定.对于接受三联的15名患者，中位PFS和OS分别为5.46和12.23个月,分别。
结论：Ulixertinib联合GnP具有与GnP相似的≥3级TRAE频率和潜在疗效。然而，由于高比率的所有级别的TRAE（ClinicalTrials.gov标识符：NCT02608229）而复杂化。
