Moore Kathleen N, Hong David S, Patel Manish R, Pant Shubham, Ulahannan Susanna V, Jones Suzanne, Meric-Bernstam Funda, Wang Judy S, Aljumaily Raid, Hamilton Erika P, Wittchen Erika S, Wang Xuejing, Lin Aimee Bence, Bendell Johanna C
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 920 Stanton L Young Blvd WP2350, Oklahoma City, OK, 73104, USA.
Sarah Cannon Research Institute, Nashville, TN, USA.
Target Oncol. 2021 Sep;16(5):569-589. doi: 10.1007/s11523-021-00835-0. Epub 2021 Sep 24.
The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy.
The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations.
This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib-drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8). Alternate dose schedules/regimens intended to mitigate toxicity and maximize dose exposure and efficacy were also explored in sub-parts.
In Part A, the maximum tolerated dose (MTD) of prexasertib in combination with cisplatin (75 mg/m) was declared at 80 mg/m, with cisplatin administered on Day 1 and prexasertib on Day 2 of a 21-day cycle. The overall objective response rate (ORR) in Part A was 12.7%, and 28 of 55 evaluable patients (50.9%) had a decrease in target lesions from baseline. The most frequent treatment-related adverse events (AEs) in Part A were hematologic, with the most common being white blood cell count decreased/neutrophil count decreased, experienced by 73.0% (any grade) and 66.7% (grade 3 or higher) of patients. In Part B, an MTD of 70 mg/m was established for prexasertib administered in combination with cetuximab (500 mg /m), both administered on Day 1 of a 14-day cycle. The overall ORR in Part B was 4.9%, and 7 of 31 evaluable patients (22.6%) had decreased target lesions compared with baseline. White blood cell count decreased/neutrophil count decreased was also the most common treatment-related AE (56.1% any grade; 53.7% grade 3 or higher). In Parts A and B, hematologic toxicities, even with the addition of prophylactic granulocyte colony-stimulating factor, resulted in frequent dose adjustments (> 60% of patients). In Part C, evaluation of prexasertib + pemetrexed was halted due to dose-limiting toxicities in two of the first three patients; MTD was not established. In Part D, the MTD of prexasertib in combination with 5-fluorouracil (label dose) was declared at 40 mg /m, both administered on Day 1 of a 14-day cycle. In Part D, overall ORR was 12.5%.
This study demonstrated the proof-of-concept that prexasertib can be combined with cisplatin, cetuximab, and 5-fluorouracil. Schedule was a key determinant of the tolerability and feasibility of combining prexasertib with these standard-of-care agents. Reversible hematologic toxicity was the most frequent AE and was dose-limiting. Insights gleaned from this study will inform future combination strategies for the development of prexasertib and next-generation CHK1 inhibitors. CLINICALTRIALS.
NCT02124148 (date of registration 28 April 2014).
在之前的试验中，检查点激酶1（CHK1）抑制剂普瑞西替尼单药治疗显示出适度的抗肿瘤活性，这表明可能需要与化疗或其他靶向药物联合使用以最大化疗效。
本研究旨在确定普瑞西替尼与顺铂、西妥昔单抗、培美曲塞或5-氟尿嘧啶联合用于晚期和/或转移性癌症患者的II期推荐剂量和给药方案，并总结这些联合用药的初步抗肿瘤活性。
这项Ib期、非随机、开放标签研究包括剂量递增阶段，有多个亚组评估不同的普瑞西替尼-药物联合方案：A部分，普瑞西替尼+顺铂（n = 63）；B部分，普瑞西替尼+西妥昔单抗（n = 41）；C部分，普瑞西替尼+培美曲塞（n = 3）；D部分，普瑞西替尼+5-氟尿嘧啶（n = 8）。在各亚组中还探索了旨在减轻毒性、最大化剂量暴露和疗效的交替给药方案/疗程。
在A部分，普瑞西替尼与顺铂（75 mg/m²）联合使用时，最大耐受剂量（MTD）确定为80 mg/m²，在21天周期的第1天给予顺铂，第2天给予普瑞西替尼。A部分的总体客观缓解率（ORR）为12.7%，55例可评估患者中有28例（50.9%）靶病灶较基线缩小。A部分最常见的治疗相关不良事件（AE）是血液学方面的，最常见的是白细胞计数减少/中性粒细胞计数减少，73.0%（任何级别）和66.7%（3级或更高级别）的患者出现该情况。在B部分，普瑞西替尼与西妥昔单抗（500 mg/m²）联合使用时，MTD确定为70 mg/m²，均在14天周期的第1天给药。B部分的总体ORR为4.9%，31例可评估患者中有7例（22.6%）靶病灶较基线缩小。白细胞计数减少/中性粒细胞计数减少也是最常见的治疗相关AE（56.1%任何级别；53.7% 3级或更高级别）。在A部分和B部分，即使添加预防性粒细胞集落刺激因子，血液学毒性仍导致频繁的剂量调整（>60%的患者）。在C部分，由于前三例患者中有两例出现剂量限制性毒性，普瑞西替尼+培美曲塞的评估停止；未确定MTD。在D部分，普瑞西替尼与5-氟尿嘧啶（标记剂量）联合使用时，MTD确定为40 mg/m²，均在14天周期的第1天给药。在D部分，总体ORR为12.5%。
本研究证明了普瑞西替尼可与顺铂、西妥昔单抗和5-氟尿嘧啶联合使用的概念验证。给药方案是普瑞西替尼与这些标准治疗药物联合使用时耐受性和可行性的关键决定因素。可逆性血液学毒性是最常见的AE，也是剂量限制性的。从本研究中获得的见解将为普瑞西替尼和下一代CHK1抑制剂的未来联合策略提供参考。临床试验。
NCT02124148（注册日期2014年4月28日）。
