PDF(Pubmed)
Abstract：
BACKGROUND: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors.
METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed.
RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics.
CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.
METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed.
RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics.
CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.
摘要：
背景：Pamiparib是一种有效的，选择性,聚（ADP-核糖）聚合酶1/2抑制剂，在具有乳腺癌易感性基因突变或其他同源重组缺陷的细胞中证明合成致死性。这项两阶段的1b期研究（NCT03150810）评估了帕米帕里布联合替莫唑胺（TMZ）治疗经组织学证实为局部晚期和转移性实体瘤的成年患者。
方法：口服帕米帕尼60mg，每日2次。在剂量递增阶段，增加剂量的TMZ(40-120mg,每日一次脉冲或20-40mg,每日一次连续),以确定在剂量扩大阶段给药的推荐剂量.主要目标是确定安全性和耐受性，最大耐受/给药剂量，推荐的2期剂量和时间表，以及帕米帕利布与TMZ联合应用的抗肿瘤活性。还评估了帕米帕利布和TMZ的药代动力学和生物标志物。
结果：各阶段，139例患者接受了治疗(剂量递增，n=66；剂量扩大，n=73）。TMZ的最大耐受剂量，在剂量扩张期间给药，是7天脉冲60毫克，每天一次。最常见的治疗引起的不良事件（TEAE）是贫血（剂量递增，56.1%;剂量扩大,63.0%），恶心（剂量递增，54.5%;剂量扩大,49.3%），和疲劳(剂量递增，48.5%;剂量膨胀,47.9%）。在剂量递增阶段，4例患者出现剂量限制性毒性反应(3例中性粒细胞减少,1例中性粒细胞计数减少).没有被认为与研究药物治疗相关的TEAE导致死亡。抗肿瘤活性适中，通过确认的总体反应率(剂量递增，13.8%;剂量扩大,11.6%），中位无进展生存期（3.7和2.8个月），和中位总生存期（10.5和9.2个月）。联合治疗的给药没有明显影响帕米帕利布或TMZ的药代动力学。
结论：帕米帕里布联合TMZ具有可控的安全性。有必要进一步研究这种组合在具有特定DNA损伤修复缺陷的肿瘤类型中的功效。
方法：口服帕米帕尼60mg，每日2次。在剂量递增阶段，增加剂量的TMZ(40-120mg,每日一次脉冲或20-40mg,每日一次连续),以确定在剂量扩大阶段给药的推荐剂量.主要目标是确定安全性和耐受性，最大耐受/给药剂量，推荐的2期剂量和时间表，以及帕米帕利布与TMZ联合应用的抗肿瘤活性。还评估了帕米帕利布和TMZ的药代动力学和生物标志物。
结果：各阶段，139例患者接受了治疗(剂量递增，n=66；剂量扩大，n=73）。TMZ的最大耐受剂量，在剂量扩张期间给药，是7天脉冲60毫克，每天一次。最常见的治疗引起的不良事件（TEAE）是贫血（剂量递增，56.1%;剂量扩大,63.0%），恶心（剂量递增，54.5%;剂量扩大,49.3%），和疲劳(剂量递增，48.5%;剂量膨胀,47.9%）。在剂量递增阶段，4例患者出现剂量限制性毒性反应(3例中性粒细胞减少,1例中性粒细胞计数减少).没有被认为与研究药物治疗相关的TEAE导致死亡。抗肿瘤活性适中，通过确认的总体反应率(剂量递增，13.8%;剂量扩大,11.6%），中位无进展生存期（3.7和2.8个月），和中位总生存期（10.5和9.2个月）。联合治疗的给药没有明显影响帕米帕利布或TMZ的药代动力学。
结论：帕米帕里布联合TMZ具有可控的安全性。有必要进一步研究这种组合在具有特定DNA损伤修复缺陷的肿瘤类型中的功效。
