A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas.
A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas.
复制标题
DOI：
10.1158/1078-0432.ccr-11-2821
复制
发表时间：
2012-03-15
期刊：
影响因子：
--
通讯作者：
Doroshow JH
中科院分区：
文献类型：
--
作者：
Kummar S;Ji J;Morgan R;Lenz HJ;Puhalla SL;Belani CP;Gandara DR;Allen D;Kiesel B;Beumer JH;Newman EM;Rubinstein L;Chen A;Zhang Y;Wang L;Kinders RJ;Parchment RE;Tomaszewski JE;Doroshow JH
低剂量、节拍剂量口服烷化剂环磷酰胺具有良好的耐受性，对多种肿瘤类型有效。聚（ADP-核糖）聚合酶（PARP）抑制可增强环磷酰胺在临床前模型中的作用。我们对难治性实体瘤和淋巴恶性肿瘤患者进行了 PARP 抑制剂 veliparib 和节拍环磷酰胺的 I 期试验。目的是确定该组合的安全性和最大耐受剂量（MTD）；表征 veliparib 的药代动力学；测量肿瘤活检和外周血单核细胞 (PBMC) 中的聚 (ADP-核糖) (PAR)（PARP 的产物）；并测量 PBMC 和循环肿瘤细胞 (CTC) 中的 DNA 损伤标记 γH2AX。环磷酰胺以 21 天为一个周期，每日一次，与 veliparib 联合每日一次，持续 7、14 或 21 天。共有 35 名患者入组。研究治疗耐受性良好，MTD 确定为 veliparib 60 mg 联合环磷酰胺 50 mg 每日一次。七名患者有部分缓解；另外六名患者的疾病稳定了至少六个周期。在不同剂量水平的 PBMC 中（至少 50%）和肿瘤活检（至少 80%），PAR 显着降低；给药后评估的 9 名患者中有 7 名的 CTC 中 γH2AX 水平升高。 veliparib 与节拍环磷酰胺的组合具有良好的耐受性，并且在 BRCA 突变患者的亚组中显示出有希望的活性。该组合与单药环磷酰胺相比的 II 期试验正在进行中，用于治疗 BRCA 阳性卵巢癌、三阴性乳腺癌和低度淋巴瘤。
Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. Poly(ADP-ribose) polymerase (PARP) inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics; measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMCs); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTCs). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels; γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared to single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.