Takhar Harminder S, Singhal Nimit, Gowda Raghu, Penniment Michael, Takhar Parineet, Brown Michael P
aCancer Clinical Trials Unit bDepartment of Medical Oncology cDepartment of Radiation Oncology dDepartment of Medical Imaging, Royal Adelaide Hospital eCentre for Cancer Biology, SA Pathology and University of South Australia fDiscipline of Medicine, University of Adelaide, Adelaide, Australia.
Anticancer Drugs. 2015 Nov;26(10):1069-77. doi: 10.1097/CAD.0000000000000282.
Panobinostat is a radiosensitizing agent and targets the epigenetics of malignancy. This phase I study evaluated the safety and efficacy of combining oral panobinostat with radiotherapy (RT) or chemoradiotherapy (CRT) in patients with inoperable stage III non-small-cell lung cancer. This study had a parallel dose-escalating design combining oral panobinostat twice a week (dose escalations 20, 30, 45 mg) with either palliative RT (group A) or radical CRT (group B) using a standard chemotherapy protocol of cisplatin and etoposide. In group A (RT), nine recruited patients received treatment with oral panobinostat (doses 20, 30, 45 mg) with RT. Two serious adverse events, rapid atrial fibrillation and tracheo-oesophageal fistula, were not attributable to study treatment. The most common grade 3/4 toxicities were thrombocytopenia and lymphopenia, which resolved promptly after cessation of panobinostat. The disease control rate was 66%, the progression-free survival was 3 months and the median overall survival was 9 months. In group B (CRT), panobinostat dose was not escalated beyond 20 mg because of infection-related complications. Serious adverse events included opportunistic infection associated with treatment-related lymphopenia and febrile neutropenia without a source. One patient had cerebral infarct that was not attributed to study treatment. All patients achieved a partial response to treatment. At 33 months of follow-up, all patients were still alive. Panobinostat can be combined with palliative-dose RT at doses up to 45 mg twice a week with tolerable toxicity. Dose-limiting toxicities prevented the dose escalation of the panobinostat with CRT.
帕比司他是一种放射增敏剂，作用于恶性肿瘤的表观遗传学。这项I期研究评估了口服帕比司他联合放疗（RT）或放化疗（CRT）治疗不可切除的III期非小细胞肺癌患者的安全性和疗效。本研究采用平行剂量递增设计，将每周两次口服帕比司他（剂量递增为20、30、45mg）与使用顺铂和依托泊苷标准化疗方案的姑息性放疗（A组）或根治性CRT（B组）相结合。在A组（RT）中，9名入组患者接受了口服帕比司他（剂量为20、30、45mg）联合RT治疗。有两例严重不良事件，快速心房颤动和气管食管瘘，与研究治疗无关。最常见的3/4级毒性是血小板减少和淋巴细胞减少，在停用帕比司他后迅速缓解。疾病控制率为66%，无进展生存期为3个月，中位总生存期为9个月。在B组（CRT）中，由于感染相关并发症，帕比司他剂量未超过20mg。严重不良事件包括与治疗相关的淋巴细胞减少相关的机会性感染和不明原因的发热性中性粒细胞减少。1例患者发生脑梗死，与研究治疗无关。所有患者对治疗均获得部分缓解。在33个月的随访中，所有患者均存活。帕比司他可与姑息剂量的RT联合使用，每周两次，剂量高达45mg，毒性可耐受。剂量限制性毒性阻止了帕比司他与CRT联合使用时的剂量递增。
