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Abstract：
BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor.
METHODS: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors. PF-06939999 was administered orally once or twice a day (q.d./b.i.d.) in 28-day cycles. The objectives were to evaluate PF-06939999 safety and tolerability to identify maximum tolerated dose (MTD) and recommended part 2 dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics [changes in plasma symmetric dimethylarginine (SDMA) levels], and antitumor activities.
RESULTS: In part 1 dose escalation, 28 patients received PF-06939999 (0.5 mg q.d. to 6 mg b.i.d.). Four of 24 (17%) patients reported dose-limiting toxicities: thrombocytopenia (n = 2, 6 mg b.i.d.), anemia (n = 1, 8 mg q.d.), and neutropenia (n = 1, 6 mg q.d.). PF-06939999 exposure increased with dose. Steady-state PK was achieved by day 15. Plasma SDMA was reduced at steady state (58%-88%). Modulation of plasma SDMA was dose dependent. No MTD was determined. In part 2 dose expansion, 26 patients received PF-06939999 6 mg q.d. (RP2D). Overall (part 1 + part 2), the most common grade ≥3 treatment-related adverse events included anemia (28%), thrombocytopenia/platelet count decreased (22%), fatigue (6%), and neutropenia (4%). Three patients (6.8%) had confirmed partial response (head and neck squamous cell carcinoma, n = 1; non-small-cell lung cancer, n = 2), and 19 (43.2%) had stable disease. No predictive biomarkers were identified.
CONCLUSIONS: PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection.
METHODS: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors. PF-06939999 was administered orally once or twice a day (q.d./b.i.d.) in 28-day cycles. The objectives were to evaluate PF-06939999 safety and tolerability to identify maximum tolerated dose (MTD) and recommended part 2 dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics [changes in plasma symmetric dimethylarginine (SDMA) levels], and antitumor activities.
RESULTS: In part 1 dose escalation, 28 patients received PF-06939999 (0.5 mg q.d. to 6 mg b.i.d.). Four of 24 (17%) patients reported dose-limiting toxicities: thrombocytopenia (n = 2, 6 mg b.i.d.), anemia (n = 1, 8 mg q.d.), and neutropenia (n = 1, 6 mg q.d.). PF-06939999 exposure increased with dose. Steady-state PK was achieved by day 15. Plasma SDMA was reduced at steady state (58%-88%). Modulation of plasma SDMA was dose dependent. No MTD was determined. In part 2 dose expansion, 26 patients received PF-06939999 6 mg q.d. (RP2D). Overall (part 1 + part 2), the most common grade ≥3 treatment-related adverse events included anemia (28%), thrombocytopenia/platelet count decreased (22%), fatigue (6%), and neutropenia (4%). Three patients (6.8%) had confirmed partial response (head and neck squamous cell carcinoma, n = 1; non-small-cell lung cancer, n = 2), and 19 (43.2%) had stable disease. No predictive biomarkers were identified.
CONCLUSIONS: PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection.
摘要：
背景：蛋白质精氨酸甲基转移酶5（PRMT5）甲基化多种底物在癌症中失调，包括剪接体机械部件。PF-06939999是一种选择性小分子PRMT5抑制剂。
方法：该I期剂量递增和扩展试验（NCT03854227）纳入了患有选定实体瘤的患者。PF-06939999在28天周期中每天口服一次或两次(q.d./b.i.d.)。目的是评估PF-06939999的安全性和耐受性，以确定最大耐受剂量（MTD）和推荐的第2部分剂量（RP2D）。并评估药代动力学（PK），药效学[血浆对称二甲基精氨酸（SDMA）水平的变化]，和抗肿瘤活性。
结果：在第1部分剂量递增中，28例患者接受PF-06939999（0.5mgq.d.至6mgb.i.d.）。24例患者中有4例（17％）报告了剂量限制性毒性：血小板减少症（n=2，6mgb.i.d.），贫血（n=1，8mgq.d.），和中性粒细胞减少症（n=1，6mgq.d.）。PF-06939999暴露量随剂量增加而增加。到第15天达到稳态PK。血浆SDMA在稳态下降低(58%-88%)。血浆SDMA的调节是剂量依赖性的。没有确定MTD。在第二部分剂量扩张中，26例患者接受PF-069399996mgq.d.（RP2D）。总体(第1部分+第2部分),最常见的≥3级治疗相关不良事件包括贫血（28%），血小板减少症/血小板计数减少(22%),疲劳（6%），和中性粒细胞减少症（4%）。3例患者（6.8%）确认部分缓解（头颈部鳞状细胞癌，n=1；非小细胞肺癌，n=2),19例(43.2%)病情稳定。没有发现预测性生物标志物。
结论：PF-06939999在一部分患者中表现出可耐受的安全性和客观的临床反应，表明PRMT5是一个有趣的癌症靶标，具有临床验证。然而,未发现预测性生物标志物.PRMT5在癌症生物学中的作用是复杂的，需要进一步的临床前，机械调查，以确定用于患者选择的预测性生物标志物。
方法：该I期剂量递增和扩展试验（NCT03854227）纳入了患有选定实体瘤的患者。PF-06939999在28天周期中每天口服一次或两次(q.d./b.i.d.)。目的是评估PF-06939999的安全性和耐受性，以确定最大耐受剂量（MTD）和推荐的第2部分剂量（RP2D）。并评估药代动力学（PK），药效学[血浆对称二甲基精氨酸（SDMA）水平的变化]，和抗肿瘤活性。
结果：在第1部分剂量递增中，28例患者接受PF-06939999（0.5mgq.d.至6mgb.i.d.）。24例患者中有4例（17％）报告了剂量限制性毒性：血小板减少症（n=2，6mgb.i.d.），贫血（n=1，8mgq.d.），和中性粒细胞减少症（n=1，6mgq.d.）。PF-06939999暴露量随剂量增加而增加。到第15天达到稳态PK。血浆SDMA在稳态下降低(58%-88%)。血浆SDMA的调节是剂量依赖性的。没有确定MTD。在第二部分剂量扩张中，26例患者接受PF-069399996mgq.d.（RP2D）。总体(第1部分+第2部分),最常见的≥3级治疗相关不良事件包括贫血（28%），血小板减少症/血小板计数减少(22%),疲劳（6%），和中性粒细胞减少症（4%）。3例患者（6.8%）确认部分缓解（头颈部鳞状细胞癌，n=1；非小细胞肺癌，n=2),19例(43.2%)病情稳定。没有发现预测性生物标志物。
结论：PF-06939999在一部分患者中表现出可耐受的安全性和客观的临床反应，表明PRMT5是一个有趣的癌症靶标，具有临床验证。然而,未发现预测性生物标志物.PRMT5在癌症生物学中的作用是复杂的，需要进一步的临床前，机械调查，以确定用于患者选择的预测性生物标志物。
