Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan
Received 24 September 2001; revised 7 December 2001; accepted 9 January 2002
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 (1.061.27), P = 0.001 for 174 drugs; odds ratio = 1.16 (1.051.28), 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.
Key words: investigational new drugs, objective response, phase I trial, phase III trial
Introduction
Investigational new drugs (INDs) are evaluated in phase I, II and III trials. The objectives of phase I trials are to evaluate toxicity and determine a recommended dose for phase II trials. The phase II trials are conducted to determine the response rate (RR) in patients with a specific tumor, and therefore as many phase II trials as the number of tumor types are theoretically required. In addition, combinations of an IND with other anticancer agents are also evaluated before the phase III trials, because combination chemotherapy including two to four agents rather than a single agent is commonly used in these trials as well as in clinical practice. The end point of the phase III trials is usually patient survival, and in the limited situation, quality of life. To establish the effectiveness of an IND or a new regimen containing an IND, these end points are assessed in comparison with a reference arm, the standard treatment for the disease [1].
These processes are costly, time-consuming and require considerable patient resources, but only a few drugs are finally established as anticancer drugs. Because any INDs for which intolerable toxicity is not observed in a phase I trial have theoretically been considered suitable for phase II trials [2, 3], the INDs will often undergo several phase II trials, even if they show no activity, before development of the agent is discontinued. Furthermore, several INDs entering phase III trials were ultimately determined to be ineffective. Thus, it is important to decide whether development of an IND should be continued or terminated in the early phase of clinical trials. In order to predict potential drug efficacy from the results of phase I trials, we analyzed the relationship between objective (complete and partial) responses in phase I trials and the final effectiveness of the agents in phase III trials.
Materials and methods
A Medline search using the keywords Neoplasms/Drug Therapy in MeSH and Phase I during the period from 1976 to 1993 yielded 1927 papers. Of these, 547 reported single-agent phase I trials in adult patients with malignancies. A total of 399 trials were selected from the 547, according to the following criteria: (i) trials of cytotoxic agents; (ii) trials of patients with solid tumors; and (iii) trials in which tumor responses were reported. Of the 148 excluded trials, 94 were trials of non-cytotoxic agents, 30 were trials for patients with leukemia, and in 24 antitumor effects were not reported.
Objective tumor response was defined as the disappearance of all known disease or a decrease of at least 50% in total tumor size for at least 4 weeks without the appearance of new lesions. Response rate was determined by the following equation: RR = [(No. responders)/(No. eligible and treated patients)] x 100 (%).
Phase III trials of a regimen including an IND versus a conventional treatment, and phase III trials comparing different IND doses were collected by Medline searches using the keywords phase III, randomized, or compare and a drug name. Of these, a positive study was defined as one in which an IND regimen showed a better RR, progression-free survival, or overall survival than a conventional treatment, or in which an investigational arm showed the same RR, progression-free survival and overall survival, but less toxicity or improved quality of life when compared with a reference arm. A drug was defined as effective if at least one positive study was identified.
For a drug evaluated in two or more phase I trials, the total numbers of patients and responders were compiled. The numbers of responders and RRs were counted for each drug and for each trial. Associations between these response parameters in phase I trials and drug effectiveness in phase III trials were evaluated using logistic regression analyses. The actual calculations were carried out using the STATISTICA (Stat-Soft, Tulsa, OK, USA) software system.
Results
Of the 399 single-agent phase I trials of cytotoxic agents in adult patients with solid tumors, further clinical investigation was not recommended in 36 trials (9.02%) because of severe toxicity. Objective responses were analyzed for the current study in the remaining 363 trials. The median (range) number of patients in a trial was 29 (6139). The total number of agents evaluated in the 363 trials was 174. Median (range) numbers of trials and patients for each agent were two (19) and 52.5 (7334), respectively. The most common class of agents was antimetabolites (24%), followed by alkylating agents (17%) and anthracyclines and their related compounds (13%) (Table 1). The total number of patients enrolled in the 363 trials was 12 686. Of these, 291 ineligible (2.3%) or untreated patients, and 319 patients (2.5%) with leukemia were excluded from the current analysis. Thus, 12 076 patients were the subjects of this study. Tumor types in these patients were lung cancer in 2458 (20.3%), colorectal cancer in 2080 (17.2%), breast cancer in 925 (7.6%), melanoma in 738 (6.1%), sarcoma in 639 (5.3%), head and neck cancer in 566 (4.7%), renal cell cancer in 524 (4.3%), ovarian cancer in 522 (4.3%), gastric cancer in 389 (3.2%), lymphoma in 309 (2.5%), pancreatic cancer in 192 (1.6%), cervical cancer in 165 (1.3%), prostate cancer in 133 (1.1%), bladder cancer in 128 (1.0%), esophageal cancer in 89 (0.7%), brain tumor in 73 (0.6%), others in 889 (7.3%) and not reported in 1260 (10.4%).
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Although phase I trials are not designed primarily to evaluate the therapeutic effects of an agent, a few authors have discussed the relationship between the responses observed during phase I trials and clinical drug development. Estey et al. [4] reviewed 187 phase I trials and found that the median phase I RR for active agents in phase II trials was 4.3%, and 2.7% for those inactive in phase II trials, with no significant difference between the two RRs. In contrast, Von Hoff and Turner [5] reviewed 228 phase I trials and found that all of the agents that made it to market had a median of six responders in their phase I trials. They concluded that if no responses were noted in a phase I trial, the agent had a low probability of being marketed. In the present study, we have demonstrated the number of responders and RRs in phase I trials to be important information for predicting potential drug effectiveness in phase III trials. If two or more responders and/or an RR of >5% were noted in a phase I trial, half of such agents will possibly be efficacious against cancer. Of 10 agents without objective responses in phase I trials, nine showed minor responses in this study or objective responses in phase I trials conducted before 1975. Thus, if no tumor shrinkage effect is obtained in a phase I trial, further development of the drug would not be recommended.
Selection of tumor types for phase II trials is another issue to be discussed. The National Cancer Institute clinical drug development program in the 1970s recommended that each drug be evaluated in phase II trials involving at least six different tumor types, including breast, colon and lung cancers, as well as melanoma, acute leukemia and lymphoma [6]. Recent development of a pre-clinical screening system for INDs, using well-characterized tumor cell lines or focusing on well-defined molecular targets, may provide useful and reliable information on the activity of an agent against a particular type of tumor [7]. This study suggested that an IND producing objective responses in patients with lung, breast, ovarian or colorectal cancer may be among the very promising agents for treatment of the respective tumors. Thus, it is reasonable to include patients with various common cancers in phase I trials for exploratory evaluation of the activity of an agent. In contrast, no such association was observed in lymphoma, melanoma, sarcoma or renal-cell carcinoma. Relatively large numbers of patients with melanoma, sarcoma or renal-cell carcinoma have been enrolled in phase I trials, because few standard chemotherapeutic regimens have been established for these tumors. If an objective response is observed in patients with these tumors, however, this would not support going into phase II trials for any type of tumors.
The main limitation of the current study is related to the design of phase I trials, which are not directed at evaluating responses: (i) many patients in phase I trials have no measurable lesion; (ii) the tumor type was not reported in 10.4% (1260 of 12 076) of patients; (iii) the patient population was highly heterogeneous with regard to previous treatment, performance status and disease extent, all of which are thought to influence the response to an agent. For the first reason, we calculated RRs using the number of eligible and treated patients as the denominator in the equation in place of the number of patients evaluable for responses. This substitution is thought to have little influence on the results of our study, because the association between RRs in phase I trials and drug effectiveness in phase III trials did not differ from that between the number of responders and drug effectiveness.
Biases inherent in patient accrual and publication of phase I studies are to be pointed out. More phase I studies and more patient resources are often invested in compounds that demonstrate some responsiveness in phase I studies. These studies are also more likely to be reported or published. Thus, it is a self-fulfilling prophecy that higher RRs will be seen with active agents in phase I studies, especially in published phase I studies. Similarly, once an agent has demonstrated activity in a specific tumor type in phase I studies, there is a skewing of accrued patients with that specific tumor type, which would skew activity away from other tumor types. The definition of effective agents in this study is another issue. It is arbitrary and may not be optimal. We consider at least one positive phase III study to be clear, objective, and easy to confirm, although there remains room for bias in the criteria for a positive study. We evaluated all phase III trials identified by Medline searches regardless of their quality, because the quality of phase III trials is greatly affected by the publication year. Old trials are often of lower quality than more recent trials, but the former can be very important for assessing long-sustained antineoplastic agents. Von Hoff and Turner [5] used marketing of the agent as the definition of an efficacious agent. We did not adopt their definition in this study, because government approval requirements for INDs vary among countries. Therefore, marketing of the agent cannot serve as a standardized criterion. Finally, this retrospective analysis is largely focused on non-specific cytotoxic agents developed in a period that might be very different from the present time. To evaluate recent cytotoxic agents whose molecular target is established, target inhibition as well as tumor responses in phase I studies may be important factors for further development of the agent.
In conclusion, the numbers of responders and RRs in phase I trials of INDs successfully predicted their potential efficacy. The number of responders among lung, ovarian, breast and colorectal cancer cases, but not among lymphoma, melanoma, sarcoma and renal-cell carcinoma cases, was associated significantly with drug efficacy against the respective tumors. Objective responses observed in phase I trials are important for determining the direction of future IND trials.
Acknowledgements
We thank Mihoko Kanazawa for her collection and arrangement of numerous reports on phase I trials.
Footnotes
+ Correspondence to: Dr I. Sekine, Department of Internal Medicine, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. Tel: +81-3-3542-2511; Fax: +81-3-3545-3567; E-mail: isekine@gan2.ncc.go.jp
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