■进行此Ib期研究是为了确定卡培他滨与alpleisib(磷脂酰肌醇3-激酶催化亚基p110α阻断)联合使用的安全性,并确定最大耐受剂量(MTD)和推荐的II期剂量(RP2D)在标准治疗难以治疗的晚期实体瘤患者中。研究了协同抗肿瘤活性和药代动力学(PK)。
■在标准治疗难以治疗的晚期实体癌患者中进行剂量递增阶段,无论PIK3CA突变。患者每天口服一次alpelisib(200mg和300mg)和每天两次卡培他滨(850mg,1000mg,1250mg口服,第1-14天)每3周。标准“3+3”剂量递增用于定义MTD。评估了alpelisib对卡培他滨PK的影响。
■纳入6例结直肠癌(3例PIK3CA突变)和6例乳腺癌(均为PIK3CA突变)患者。前三名患者的剂量水平为0(alpelisib200mg每日,卡培他滨1,000mg/m2,每天两次)没有剂量限制性毒性(DLTs)。在剂量水平1(alpelisib增加到每天300毫克,卡培他滨1,000mg,每日两次),6例患者中有1例患有DLT(Gr)3级高血糖症.当剂量水平2(alpelisib每天300mg,卡培他滨1,250mg/m2,每天两次)扩大到3名患者,没有患者有DLT。在晚期实体瘤患者中,每天300mg的alpelisib和每天两次的卡培他滨1,250mg/m2的组合被宣布为MTD/RP2D。最常见的不良事件是Gr1-3高血糖(75.0%)。频繁的所有年级,治疗相关的不良事件包括Gr2-3恶心(75.0%),Gr1-2腹泻(50.0%),Gr1-2手足综合征(41.7%),Gr1-2厌食症(41.7%),Gr2粘膜炎(33.3%)。在患有PIK3CA突变型乳腺癌的患者中观察到抗肿瘤活性(总共6名患者中的3名部分反应和3名稳定疾病)。Alpelisib暴露(Cmax和AUC0-12)不受卡培他滨的影响。在alpelisib和卡培他滨之间没有观察到临床相关的药物-药物相互作用。
■alpelisib和卡培他滨的组合通常可以耐受,没有药代动力学相互作用,并在PIK3CA突变晚期癌症患者中显示抗肿瘤活性。
UNASSIGNED: This phase Ib study was performed to determine the safety of combination capecitabine with alpleisib (phosphatidylinositol 3-kinase catalytic subunit p110α blockade) and determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination regimen in patients with advanced solid tumors refractory to standard therapy. The synergistic anti-tumor activity and pharmacokinetics (PK) were investigated.
UNASSIGNED: Dose escalation phases were conducted in patients with advanced solid cancers who were refractory to standard therapy regardless of PIK3CA mutation. Patients were administered orally once daily
alpelisib (200mg and 300mg) and twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) every 3 weeks. Standard \"3 + 3\" dose escalation was used to define the MTD. The effect of
alpelisib on the PK of capecitabine was assessed.
UNASSIGNED: Patients with 6 colorectal cancer (three PIK3CA mutation) and 6 breast cancer (all PIK3CA mutation) were enrolled. The first three patients in dose level 0 (
alpelisib 200mg daily, capecitabine 1,000 mg/m2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 1 (alpelisib increased to 300 mg daily, capecitabine 1,000mg twice daily), one of six patients had DLT (grade (Gr) 3 hyperglycemia). When dose level 2 (alpelisib 300mg daily, capecitabine 1,250 mg/m2 twice daily) was expanded to 3 patients, no patients had DLTs. The combination of
alpelisib 300mg daily and capecitabine 1,250 mg/m2 twice daily was declared as the MTD/RP2D in patients with advanced solid tumors. The most common AEs were Gr 1-3 hyperglycemia (75.0%). Frequent all-grade, treatment-related AEs included Gr 2-3 nausea (75.0%), Gr 1-2 diarrhea (50.0%), Gr 1-2 hand-foot syndrome (41.7%), Gr 1-2 anorexia (41.7%), Gr 2 mucositis (33.3%). Antitumor activity was observed in patients with PIK3CA mutant breast cancer (3 partial response and 3 stable disease of total 6 patients).
Alpelisib exposure (Cmax and AUC0-12) was unaffected by concomitant capecitabine. There were no clinically relevant drug-drug interactions observed between alpelisib and capecitabine.
UNASSIGNED: The combination of alpelisib and capecitabine is generally tolerated, without pharmacokinetic interactions, and shows antitumor activity in patients with PIK3CA mutant advanced cancers.