Ramani Vinod K, Gayen Srimonta, Naik Radheshyam
Preventive Oncology Healthcare Global Bangalore India.
Developmental Biology and Genetics Indian Institute of Science Bangalore India.
Health Sci Rep. 2025 Jan 23;8(1):e70233. doi: 10.1002/hsr2.70233. eCollection 2025 Jan.
Sensitivity to immune checkpoint inhibitor (ICI) therapy depends in part on the genetic and epigenetic makeup of cancer cells, and CD8 T-lymphocytes that mediate immune responses. Epigenetics are heritable reversible changes in gene expression that occur without any changes in the nuclear DNA sequence or DNA copy number.
i. To determine if non-cytotoxic oral azacytidine when combined with pembrolizumab can improve ORRs of ICI treatment in patients with recurrent/metastatic tumors of head and neck region.
i. To evaluate the clinical effectiveness endpoints and toxicity of oral azacytidine when combined with pembrolizumab. ii. To assess the induction of a T-cell response among the study subjects. iii. To examine the hypotheses on the predictive biomarkers of response to pembrolizumab, and the mechanisms of resistance.
Our trial is a Phase 2 randomized study of immunotherapy drug pembrolizumab given in combination with azacitidine (HMA). The intervention model includes "Parallel assignment," with the primary purpose of the trial being treatment. The primary effectiveness endpoint is overall RECIST-defined response. To accomplish this goal, 232 patients will be randomized 1:1 (116 in each arm), respectively, to azacitidine plus pembrolizumab or pembrolizumab only groups.
In this trial, molecular profiling of tumor and peripheral blood samples will be conducted which will enable in gaining biological insights for survival benefit. The expected primary outcome assessed at a time frame of 2 years includes the objective response rate of patients measured as per RECIST 1.1 criteria. The secondary outcomes assessed at 2 years include progression-free survival, time to progression, overall survival, and incidence of treatment-emergent adverse events.
The findings of this trial will have translational implications, in terms of immune reprogramming induced by epigenetic therapy among a subset of advanced H & N cancer patients in a clinical setting.
对免疫检查点抑制剂（ICI）治疗的敏感性部分取决于癌细胞的遗传和表观遗传组成，以及介导免疫反应的CD8 T淋巴细胞。表观遗传学是指基因表达中可遗传的可逆变化，这种变化不伴随核DNA序列或DNA拷贝数的任何改变。
i. 确定非细胞毒性口服阿扎胞苷与帕博利珠单抗联合使用时，能否提高头颈部复发性/转移性肿瘤患者ICI治疗的客观缓解率（ORR）。
i. 评估口服阿扎胞苷与帕博利珠单抗联合使用时的临床有效性终点和毒性。ii. 评估研究对象中T细胞反应的诱导情况。iii. 检验关于帕博利珠单抗反应预测生物标志物及耐药机制的假设。
我们的试验是一项帕博利珠单抗与阿扎胞苷（一种血液系统恶性肿瘤药物）联合使用的2期随机研究。干预模型包括“平行分组”，试验的主要目的是治疗。主要有效性终点是根据实体瘤疗效评价标准（RECIST）定义的总体反应。为实现这一目标，232名患者将按1:1随机分组（每组116名），分别进入阿扎胞苷加帕博利珠单抗组或仅帕博利珠单抗组。
在本试验中，将对肿瘤和外周血样本进行分子分析，这将有助于深入了解生存获益的生物学机制。在2年时间框架内评估的预期主要结果包括根据RECIST 1.1标准测量的患者客观缓解率。2年时评估的次要结果包括无进展生存期、疾病进展时间、总生存期以及治疗中出现的不良事件发生率。
在临床环境中，对于一部分晚期头颈部癌症患者，本试验的结果将在表观遗传治疗诱导的免疫重编程方面具有转化意义。
