Experimental therapeutic oncology agents are often combined to circumvent tumor resistance to individual agents. However, most combination trials fail to demonstrate sufficient safety and efficacy to advance to a later phase. This study collected survey data on phase 1 combination therapy trials identified from ClinicalTrials.gov between January 1, 2003 and November 30, 2017 to assess trial design and the progress of combinations toward regulatory approval. Online surveys (N = 289, 23 questions total) were emailed to Principal Investigators (PIs) of early-phase National Cancer Institute and/or industry trials; 263 emails (91%) were received and 113 surveys completed (43%). Among phase 1 combination trials, 24.9% (95%CI: 15.3%, 34.4%) progressed to phase 2 or further; 18.7% (95%CI: 5.90%, 31.4%) progressed to phase 3 or regulatory approval; and 12.4% (95%CI: 0.00%, 25.5%) achieved regulatory approval. Observations of “clinical promise” in phase 1 combination studies were associated with higher rates of advancement past each milestone toward regulatory approval (cumulative OR=11.9; p=0.0002). Phase 1 combination study designs were concordant with Clinical Trial Design Task Force (CTD-TF) Recommendations 79.6% of the time (95%CI: 72.2%, 87.1%). Most discordances occurred where no plausible pharmacokinetic or pharmacodynamic interactions were expected. Investigator-defined “clinical promise” of a combination is associated with progress toward regulatory approval. Although concordance between study designs of phase 1 combination trials and CTD-TF Recommendations was relatively high, it may be beneficial to raise awareness about the best study design to use when no plausible pharmacokinetic or pharmacodynamic interactions are expected.
展开▼
机译:实验治疗肿瘤学代理通常组合以避免对个体剂的肿瘤抗性。然而,大多数组合试验未能表现出足够的安全性和效力,以提高后期阶段。本研究收集了2003年1月1日至2017年1月1日至11月30日至2017年11月30日至11月30日期间从Clinicaltrials.gov鉴定的第1阶段组合治疗试验的调查数据,以评估试验设计和对监管批准的组合进度。在线调查(N = 289,33个问题)通过电子邮件发送给早期国家癌症研究所和/或行业审判的主要调查员(PIS);收到263封电子邮件(91%),完成了113次调查(43%)。在第1相结合试验中,24.9%(95%CI:15.3%,34.4%)进入2阶段或进一步; 18.7%(95%CI:5.90%,31.4%)进展到第3阶段或监管批准; 12.4%(95%CI:0.00%,25.5%)取得了监管批准。第1阶段组合研究中的“临床承诺”的观察与每个里程碑升高的监管批准(累积或= 11.9; p = 0.0002)相关的率与每个里程碑更高的进步。第1阶段组合研究设计与临床试验设计工作队(CTD-TF)建议进行协调79.6%(95%CI:72.2%,87.1%)。在没有预期不合理的药代动力学或药物动力学相互作用的情况下发生了大多数可乐之。调查员定义的组合的“临床承诺”与监管批准的进展相关。虽然第1阶段组合试验和CTD-TF建议的研究设计之间的一致性相对较高,但提高对最佳研究设计的认识可能是有益的,但是当没有预期不合理的药代动力学或药物动力学相互作用时,可以使用。
展开▼