I期试验中的客观反应与非特异性细胞毒性研究新药潜在疗效之间的关系。

Relationship between objective responses in phase I trials and potential efficacy of non-specific cytotoxic investigational new drugs.

作者信息

Sekine I, Yamamoto N, Kunitoh H, Ohe Y, Tamura T, Kodama T, Saijo N

机构信息

Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.

出版信息

Ann Oncol. 2002 Aug;13(8):1300-6. doi: 10.1093/annonc/mdf202.

DOI:10.1093/annonc/mdf202

PMID:12181255

Abstract

BACKGROUND

Although the evaluation of new investigational drugs in phase I, II and III trials requires considerable time and patient resources, only a few of these drugs are ultimately established as anticancer drugs.

MATERIALS AND METHODS

We collected papers of phase I trials by a Medline search using the key words 'Neoplasms/Drug Therapy in MeSH' and 'Phase I' for the period from 1976 to 1993. A drug was defined as 'effective' if a regimen including the drug produced positive results in at least one phase III trial. We analyzed the relationship between objective (complete and partial) responses in phase I trials and the effectiveness of agents in phase III trials.

RESULTS

A total of 399 single-agent phase I trials of cytotoxic agents in adult patients with solid tumors were obtained. Further clinical investigation was not recommended in 36 trials (9%) because of severe toxicity. In the remaining 363 trials, 174 drugs were evaluated and the median number of trials for each drug was two (range one to nine). Objective responses were observed in 495 (4.1%) of 12 076 patients, 178 (49%) of 363 trials, and 115 (66%) of 174 drugs. Of the 174 drugs, 48 (28%) were considered to be effective. Percentages of effective drugs rose as the number of responders in phase I trials increased. Logistic regression analyses showed the number of responders to be significantly associated with drug effectiveness [odds ratio = 1.16 (1.06-1.27), P = 0.001 for 174 drugs; odds ratio = 1.16 (1.05-1.28), P = 0.0038 for 363 trials]. Although 10 active drugs failed to produce an objective response in phase I trials, seven of them produced a tumor regression of <50%, and three reportedly produced objective responses in phase I trials conducted before 1975. The numbers of responders among patients with lung, ovarian, breast or colorectal cancer, but not those among patients with lymphoma, melanoma, sarcoma or renal-cell carcinoma, were associated significantly with drug effectiveness against the respective tumors.

CONCLUSIONS

Objective responses observed in phase I trials are important for determining the future development of an anticancer drug.

摘要

背景

尽管在I期、II期和III期试验中评估新的研究性药物需要大量时间和患者资源，但最终只有少数这些药物被确立为抗癌药物。

材料与方法

我们通过医学主题词表（MeSH）中使用关键词“肿瘤/药物疗法”和“I期”在1976年至1993年期间进行Medline检索，收集I期试验的论文。如果包含该药物的方案在至少一项III期试验中产生阳性结果，则将该药物定义为“有效”。我们分析了I期试验中的客观（完全和部分）缓解与III期试验中药物有效性之间的关系。

结果

共获得399项针对成年实体瘤患者的细胞毒性药物单药I期试验。由于严重毒性，36项试验（9%）不建议进一步进行临床研究。在其余363项试验中，评估了174种药物，每种药物的试验中位数为两项（范围为一至九项）。在12076例患者中的495例（4.1%）、363项试验中的178例（49%）以及174种药物中的115种（66%）观察到客观缓解。在这174种药物中，48种（28%）被认为是有效的。随着I期试验中缓解者数量的增加，有效药物的百分比上升。逻辑回归分析显示，缓解者数量与药物有效性显著相关[174种药物的优势比=1.16（1.06 - 1.27），P = 0.001；363项试验的优势比=1.16（1.05 - 1.28），P = 0.0038]。尽管有10种活性药物在I期试验中未产生客观缓解，但其中7种药物使肿瘤缩小<50%，据报道有3种药物在1975年之前进行的I期试验中产生了客观缓解。肺癌、卵巢癌、乳腺癌或结直肠癌患者中的缓解者数量与针对相应肿瘤的药物有效性显著相关，但淋巴瘤、黑色素瘤、肉瘤或肾细胞癌患者中的缓解者数量与药物有效性无关。