Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.
Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.
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DOI：
10.1002/cncr.25701
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发表时间：
2011-04-15
期刊：
影响因子：
6.2
通讯作者：
Bast, Robert C., Jr.
中科院分区：
文献类型：
--
作者：
Fu, Siqing;Hu, Wei;Iyer, Revathy;Kavanagh, John J.;Coleman, Robert L.;Levenback, Charles F.;Sood, Anil K.;Wolf, Judith K.;Gershenson, David M.;Markman, Maurie;Hennessy, Bryan T.;Kurzrock, Razelle;Bast, Robert C., Jr.
阿扎胞苷序贯治疗可通过基因组DNA低甲基化诱导表观遗传学沉默基因的重新表达，并逆转上皮性卵巢癌细胞的卡铂耐药性。我们启动了一项Ib-IIa期临床试验，研究阿扎胞苷和卡铂序贯联合治疗铂类耐药或难治性上皮性卵巢癌。经病理学证实的中、高级别上皮性卵巢癌患者，在6个月内（耐药，n = 18）或在铂类药物治疗期间（难治性，n = 12）出现疾病进展，符合入选条件。所有患者都有可测量的疾病。30例患者共接受了163个周期的治疗。该方案在29例可评价患者中产生1例CR、3例PR（ORR：13.8%）和10例SD。对于那些获得临床获益的患者，治疗的中位持续时间为7.5个月。所有患者的中位PFS和OS分别为3.7个月和14个月。铂类耐药患者的ORR为22%，中位PFS为5.6个月，中位OS为23个月。主要毒副反应为疲乏和骨髓抑制。相关研究表明，在治疗期间，4例客观应答者中有3例（75%）外周血白细胞中的DR 4甲基化降低，但13例无应答者中仅5例（38%）。据我们所知，这项研究提供了第一个临床证据表明，低甲基化剂可能部分逆转卵巢癌铂类耐药。低甲基化药物联合卡铂的进一步临床评价是必要的。
Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. We initiated a phase Ib-IIa clinical trial of this sequential combination of azacitidine and carboplatin in platinum-resistant or refractory epithelial ovarian cancer. Patients with pathologically confirmed intermediate- or high-grade epithelial ovarian cancer who had disease progression within 6 months (resistant, n = 18) or during a platinum-based therapy (refractory, n = 12) were eligible. All patients had measurable disease. Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 CR, 3 PR (ORR: 13.8%), and 10 SD among 29 evaluable patients. For those who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median PFS and OS for all patients were 3.7 months and 14 months, respectively. Patients with platinum resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies showed that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 non-responders (38%). To our knowledge, this study provides the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted.
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