- Email: [email protected]
Phase I and II trials of novel anti-cancer agents: Endpoints, efficacy and existentialism
Annals of Oncology 9: 1047-1052, 1998. © 1998 Kluwer Academic Publishers. Printed in the Netherlands.
Special article Phase I and II trials of novel anti-cancer agents: Endpoints, efficacy and existentialism
E. A. Eisenhauer Invesligational New Drug Program, NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada
Key words: phase I, phase II, response, toxicity
Introduction
Decades of work in the laboratory aimed at uncovering genetic and other causes of malignant disease have yielded a tremendous amount of knowledge. Thus this is a time of unprecedented opportunity with many novel targets to pursue in cancer therapeutics. At the level of the cell, targets in cytoplasmic and cell surface signaling molecules, processes of cell cycle control, and mutations or lack of expression of suppressor genes have all yielded multiple new agents for evaluation. Similarly, at the extra cellular level, there are large numbers of novel drugs designed to limit tumor penetration and metastasis and agents which directly inhibit angiogenesis. Finally, vaccines to overcome immune tolerance of cancer are being developed. This unprecedented volume of new agents presents us with numerous challenges. The first, very practical, challenge is to efficiently organize ourselves to quickly investigate the long list of drugs coming into the clinic, so that those that are without potential are discarded and those that have potential in improving outcome are accurately identified for further study. The second major challenge relates to a need to reevaluate the conceptual framework we have used for cancer treatment. Although the ultimate goal of cancer therapy, to prolong survival or cure this disease, will not change, our understanding of the mechanism of action of the some of these new agents will cause us to shift our treatment approach. If certain novel agents are not expected to cause tumor regression, the familiar paradigm of giving as high a dose as possible in rounds of cyclical therapy will need to be shifted to one of repeated smaller doses adequate to inhibit the target, but not sufficient to produce serious toxic effects (Figure 1). This paradigm shift leads us to challenges at the phase I and II level of drug development with respect to how we select dose and how to detect efficacy if it truly exists. Thus it is timely to reflect on several issues with respect to phase I and II trial
design. What measures in these clinical trials are possible? Which measures are plausible in providing surrogate assessments of efficacy? Will any be meaningful in terms of the ultimate survival of the patient? As the title suggests, this paper will review some of the challenges of cancer drug development today reflecting on elements of endpoints, efficacy and existentialism. An endpoint is that which can be measured to assist in reaching the stated trial goal; efficacy must reflect meaningful benefit at the level of the patient with the disease. Existentialism is a philosophic theory which emphasizes the existence of an individual as a free agent in determining his or her own development, purpose and meaning. In some ways, the clinical evaluation of many novel agents will require us to engage in new thinking, making use of some of the elements of existentialist thought with respect to assigning purpose and meaning to the design, measurement and interpretation of data.
Goals of phase I and II trials
Despite the fact that novel agents present new challenges in trial design, in reality, the goals of phase I and II clinical trials of these agents will remain the same: phase I trials will determine an appropriate dose and schedule for further evaluation, will describe the pharmacologic behaviour of the drug and its toxic effects. The goal of phase II trials will be to screen agents for evidence of anti-tumor activity. The area that has been generating a great deal of discussion is not the goals of these trials but rather what endpoints are available to assess them. Alternatives to toxicity as endpoints for phase I trials The tradition of utilizing toxicity as the phase I endpoint was born from the observation that for most cytotoxics there is a direct relationship between the dose of a drug
Downloaded from https://academic.oup.com/annonc/article-abstract/9/10/1047/292346 by guest on 07 September 2018
The Michel Clavel lecture, held at the 10th NCI-EORTC Conference on New Drugs in Cancer Therapy, Amsterdam, 16-19 June 1998
1048 urements of surrogates for activity, and assessment of drug levels in plasma. Toxicity is still relevant of course because it may limit dosing on its own, so it cannot be excluded as an endpoint.
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Figure I. Shifting paradigm for cancer drug delivery which may be relevant in the design and endpoints for early clinical studies.
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Figure 2. Preclinical data (idealized) which may exist for some novel agents. See text for explanation of panels A and B.
and its effects on both tumor and toxicity. Thus, toxicity has been seen as a surrogate for doses that might be effective. However, some novel agents may exhibit different relationships between dose and other outcomes as is shown in Figure 2. Although these are 'idealized'curves, they serve to highlight some of the dose-effect relationships which may be seen. In both panels, the effect on the drug target parallels and anticipates the anti-tumor effect, both showing a plateau at a certain dose. These are quite plausible dose-effect relationships for many agents targeting specific molecules or receptors for which there is expected to be a finite number within a tumor cell population. In panel A toxic effects are shown initially to move with the other two parameters but at the point of the plateau in drug targeting effect, toxicity continues to increase. In panel B, toxic effects appear late... well above effective doses. This type of relationship between efficacy and toxicity might be expected if toxic effects are mediated by a different mechanism than the targeted anti-tumor effect. In the setting of the second example, it is clear that increasing doses to toxic levels is not necessary to achieve efficacy. There are several endpoints which may be alternatives to toxicity for agents showing these relationships. These include measurement of target inhibition, meas-
Measurement of effect on the molecular target is particularly appealing because of its rational basis, but the challenges to its use as an endpoint for phase I evaluation are many. The relevant tissue in which to measure target inhibition is tumor and this is seldom available in repeated patient samples. Available tissue, which is usually blood, may not be relevant. At the very least, if blood cells are to be used to evaluate the magnitude of target inhibition, there ought to be evidence from preclinical models that target inhibition in blood cells is a valid marker for efficacy. This is often not the case; furthermore species specificity of molecular inhibitors may make this type of assessment impossible. How one measures the effect on the target is also a subject for debate. Should the target inhibition be measured directly (e.g., decreased production of a specific targeted protein) or indirectly (e.g., measurement of proteins or products 'downstream' from the target itself)? Either approach requires intensive laboratory back-up, and if the measure selected is to be a phase I endpoint, these assays must be done in 'real-time' fashion to allow decisions about subsequent dose escalation. The major weakness of this approach may relate to the target itself. While the preclinical data may suggest that an agent's efficacy is due to it's interaction with a specific target, it is certainly plausible that it may have other, as yet unknown, effects at the cellular level responsible for its anti-tumor activity. Thus the target that we believe is relevant (and may strive to measure) may not be the target that is responsible for anti-tumor effect. The proof of the relevance of many molecular targets, in fact, may only come once they are assessed clinically. Measurement of other surrogates for activity Measurement of other surrogates for activity is another possible endpoint for phase I evaluation. This is of particular interest for immune based treatments where measures of immune response may relate to achievement of effective doses. The major challenge in this context is to define which measures are really related to anti-tumor effect. Preclinical models may help, but immune therapies may have species specific attributes making laboratory determination of the appropriate surrogate difficult. Furthermore, multiple measurements of immune function may generate discordant results leading to confusion about which is the most 'relevant' one for dose and scheduling decisions. Simpler phase I endpoints are those which have been accessible for standardized measurement for many years: blood levels of drug and toxic effects. Although the hypothetical dose effect curves shown in Figure 2
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Measurement of effect on the molecular target
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After phase I: Continue Development? Target Effect:
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Figure 3. Possible outcomes of phase I trials with new endpoints. How to integrate findings of toxicity and target effects in decisions regarding continued development?
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suggest that giving a toxic dose may not be necessary, it would be almost certain that a dose high enough to produce toxic effects will not be too low for efficacy. Furthermore it is reasonable to suppose that blood levels correlating with target inhibition and with efficacy in animal models could be extrapolated to the clinical situation. Even if measures of target inhibition are possible, toxicity and pharmacologic data must still be collected. Provided that some measure of target inhibition as well as usual blood level and toxicity information can be obtained, how will these results be integrated into decisions about the future development of a new agent? Figure 3 illustrates the various outcome scenarios possible following completion of phase I trials. In the presence of dose limiting toxicity plus evidence of target inhibition in relevant tissue, further drug development ought to proceed. The same decision would likely be made if dose-related target inhibition were achieved without severe toxicity. The observation of neither toxic effects nor evidence of inhibition would undoubtedly lead to concern about the continued evaluation of the compound. The most difficult of all scenarios, I believe, is when dose limiting toxicity is seen but no inhibition at the target level has been noted. Here, given the fact that we can sometimes be wrong in our assessment of the true target, the decision to go forward with the drug into phase II or III evaluation should depend upon the strength of the preclinical efficacy data and whether there are unique features to the agent. So what should be done today in designing phase I trials? My views are simple and summarized in Table 1. We should measure toxicity, blood levels and if possible target effect. Ideally the trial should be designed with two MTD's: maximum target inhibiting dose (MTID) and maximum tolerated dose (MTD) based on toxicity. If at the study's end, the MTID and MTD are the same, selection of the dose for further evaluation is simple. If the MTID and MTD are substantially different, it is most appropriate to select the dose with lower toxicity but maximum target effect for further evaluation. If at
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Figure 4. Patterns of anti-tumor effects seen in preclinical experiments. Growth delay may be more commonly seen with novel agents than with traditional cytotoxics.
all possible, however, consideration should be given to comparing these two doses early on for efficacy in a randomized (phase II) study. Only in this way will we develop the database necessary to know which approach is best. After phase I: Screening for efficacy
The goal of phase II trials is to screen agents for their potential for efficacy. Traditionally this has been measured by objective tumor regression described using standard criteria (e.g., World Health Organization). It is important to point out that response per se is not synonymous with efficacy; rather, efficacy means improved cure rates, survival or quality of life. Tumor shrinkage has proved to be useful as a phase II endpoint because it has allowed us to select drugs or regimens which have subsequently been shown to be effective by prolonging survival. Although only randomized trials can unequivocally show a survival impact, non-randomized trials remain important as a means of screening agents for their potential in this regard. If, as shown in Figure 4 (left panel), a new agent produces tumor regression in animal models it is reasonable to expect it will in the clinical situation as well. Under these circumstances, response remains the most useful phase II endpoint. The more common scenario is that of growth delay, rather than tumor regression, as shown in the right panel of Figure 4. The issues raised in
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no inhibition continue or stop?
continue
Table 1. Phase I trials of novel agents: my view.
1050 rate of rise of serum marker; an effect which also seemed to demonstrate a dose-response relationship. On the basis of these data, randomized trials are proceeding. The results of these studies may contribute to validation of this particular endpoint. Finally, if measurement of markers is to be proposed as a surrogate for activity, it must be assured that there is not a direct effect of the investigational agent on marker levels through changes in secretion unrelated to tumor burden as has been shown with some agents [3].
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Figure 5. Survival rates by best response in the combined chemotherapy arms of a trial of best supportive care vs. two regimens of platinum based chemotherapy. Overall survival was improved by chemotherapy and response rate was low. The curve demonstrates that patients with SD or PR enjoyed similar survival experiences. (Abbreviations: PD - progressive disease; SD - stable disease, PR partial response).
screening an agent having this type of profile for clinical efficacy are the following: Is evidence of activity in phase II really necessary, before proceeding to phase III trials? If so, are there alternatives to response as a phase II endpoint if tumor regression is not to be anticipated? In answer to the first question, is evidence of activity in phase II necessary before proceeding to phase III trials?, no, provided the preclinical data is sufficiently compelling. However, there are resource, time and ethical advantages to having positive phase II data in hand before moving to phase III. For this reason, there has been much interest in pursuing the answer to the second question: the identification of alternative endpoints to response which may be used to appropriately select or reject a new drug in a phase II design. Possible candidate endpoints include: changes in tumor markers, measures of target inhibition, PET scanning, time to progression and proportion of patients with early progression. It is important to note that no proposed alternative endpoint has been validated. That is, none have been used alone to select agents later shown to be useful in prolonging survival. Tumor markers Tumor markers have the advantage of being well described and easily measured. Unfortunately, as noted above, no marker used alone has been validated as a phase II endpoint. Although the work done with CA 125 by Rustin in ovarian cancer suggests that this marker may substitute for response rate in phase II trials, these data were generated in studies where the drugs also produced tumor regression [1]. One research group has suggested that a change in the rate of rise in marker may be a useful endpoint for identifying an active agent [2]. In their studies of a metalloproteinase inhibitor, patients were observed to show a decline in the pre-treatment
Measure of target inhibition Measure of target inhibition is appealing from a scientific point of view but since many novel agents target molecules of, as yet, hypothetical importance in human tumor growth, their inhibition has not yet shown relationship to efficacy in the clinical setting. As noted earlier, measures of target inhibition (preferably in tumor tissue) may be a more relevant endpoint for phase I trials where optimal dosing is the goal. Positron emission tomography (PET) Positron emission tomography (PET) scanning is a nuclear medicine technique which uses radiopharmaceuticals such as 2-18flouro-2-deoxy-D-glucose to identify changes in tumor tissue function and metabolism predictive of tumor regression [4]. However, if the major advantage of PET scanning is to anticipate tumor regression (i.e., response), then this costly test is not really an 'alternative' to response. Will effective cytostatic therapy produce changes in tumors assessed by PET scanning when response is not documented? This is certainly possible, but remains to be shown. Median time to progression (TTP) has the advantage of being a well described and standardized endpoint in randomized trials. However, it is difficult is to interpret when there is no control group and patient numbers are limited as is the case in a phase II setting. A related idea that has come from work done by the NCIC Clinical Trials Group is a variation on TTP. We have been interested in using the progression rate (i.e., the proportion of patients who progress in the first eight weeks of therapy and thus have a 'best response' of progression) as a possible endpoint for phase II trials. We have come to this from two different avenues of thinking. The first related to some work on phase II stopping rules of cytotoxic drugs which incorporated both response rate and early progression rate as factors in determining whether a trial of a new drug should stop early [5]. We have shown that certain drugs could be appropriately declared inactive when one considered not only the number of responses but also the number of progressions in the first cohort of patients in a phase II trial [6, and unpublished data]. That is, even if the critical one response was seen in the first 15 patients, a high number of patients with PD in the same group
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indicated the drug was unlikely to have meaningful ac- Table 2. Using PD rate to select new agents. tivity and it would be appropriate to stop the trial early. Set maximum PD rate above which agent will be rejected. The other information which was important in getting us to think along these lines was that, at least in PD rate of interest will vary according to tumor type as does response rate now. some studies, partial response and stable disease appear to have same impact on survival. Several years ago the For example: NCIC CTG conducted a trial in non-small cell lung Tumor type Response rate of interest PD rate of interest cancer which demonstrated that two different regimens Breast <20% of platinum based chemotherapy both offered a survival > 30% NSCLC >20% < 30% advantage over best supportive care [7]. However, the Glioma > 10% <40% response rates on the chemotherapy arms were low (15% and 25%) so it was puzzling that the treatment had an impact on overall survival. The analysis of survival by best response category shown in Figure 5 provided the Table 3. Data fromNCIC CTG phase II trials. answer [8]. In fact in this trial, the designation of PR Observed Observed Tumor type Agent had no meaning at all: patients with either PR or SD had response PD rate identical outcomes. Thus the gain in survival was likely rate (%) (%) due to the treatment's ability to stop progression of 55" 11" Docetaxel disease not to cause regression. When we examined Breast (first-line) 10a DPPE/doxorubicin 50" other trials in various tumor types some, but not all, 41 a 19" 10-EDAM showed similar results. 23 23 Menogaril po 26 43 Menogaril IV Perhaps these observations are relevant to novel 23" 27" NSCLC (first-line) MTA agents where it is likely, that at least in advanced disease, 27 a 15 Paclitaxel/ifos they may not exhibit their efficacy by causing tumor 55 6 Acivicin regression but rather by halting early progression. If so, 13-cisRA 50 3 the next logical question is: can PD rate by itself allow us 50 0 DUP937 72 to accept or reject interesting compounds appropriately? 0 Elsamitrucin 87 Tiazofurin 0 If so, this might be a useful tool for evaluation of those 26" 8 Topotecan Glioma (first-line) new drugs which are predicted to cause tumor stability. 28" 0 Docetaxel To pursue this we examined our phase II database to 40 0 Gemcitabine see if by looking at PD rate only we would select the 69 0 Tiazofurin 86 0 Trimetrexate same agents for further study as identified by response rate. The usual phase II trial is designed to stop early if an agent shows no responses, and a minimum response " Results which surpass the selection criteria noted in Table 2. rate (often 20%) is required to make an agent 'interesting' [9]. To evaluate the usefulness of PD rate, a max- and response criteria were used. As can be seen, regardimum PD rate above which the agent would be rejected less of whether response rate alone or PD rate alone is required to declare the agent 'uninteresting' (i.e., would have been used, the same three agents would have would be rejected from further study). We also realized been selected as 'interesting' in breast cancer. In NSCLC, that the PD rate 'of interest' might vary according to the response rate criteria selected only one agent, while tumor type, just as response rate does now. In designing the PD criteria selected two (one of which was a pacliphase II trials, higher response rates must be observed taxel combination regimen). Finally, in glioma although for a new drug to be selected in those diseases in which no agent made it over the response rate hurdle it is numerous agents are already available (e.g., breast or interesting to note the disparity in PD rates with two small-cell lung cancer) as compared to those tumor agents (topotecan and docetaxel) having low PD rates. types with few effective treatments (e.g., melanoma). These results suggest that the proportion of patients The same logic ought to apply in assigning PD rates to progressing early might be useful to select agents of select new agents. In Table 2 minimum response rates interest for further evaluation when those agents are not have been assigned to breast, NSCLC and glioma tu- expected to cause tumor regression. However, like all mors based on the general results of 'active' treatment other alternative endpoints PD rate as a means of selectand the usual phase II stopping rules. In addition, ing new agents for phase III study remains non-valimaximum PD rates have been assigned to the same dated. More work on all of these measures is needed to tumors on the basis of what might be considered intui- determine which, if any, are useful. tively reasonable rates of progression which would make What should we do at the moment to assess novel a new regimen more or less interesting. In Table 3, agents in phase II trials? My views are summarized in results from a series of NCIC CTG phase II trials in Table 4. We should continue to measure response endeach of these tumor types is shown in which the response and PD rate selection criteria have been applied. In all points, follow those alternative endpoints which are trials for each tumor type, the same patient eligibility feasible, and, most importantly, we should have a very clear idea of whether further phase III trials will occur
1052 Table 4. Phase II trials of novel agents: my view. 1. 2. 3.
Measure objective response. Follow those alternative endpoints which are feasible. Have a very clear idea of whether phase III trials will take place based on measured outcomes in phase II. 4. Only by selection of agents using alternative endpoints and subjecting them to phase III evaluation will we learn if they are valid.
Table 5. Considerations for phase III trials of novel agent if no phase II trial.
Tumor type • Tumors/settings with rapid time to progression ideally suited (e.g , treated SCLC or ovarian cancer, first-line pancreas). • Animal studies should suggest tumor type will be sensitive. Design • Randomized. • Early stopping rule based on progression/failure should be in place.
References 1. Rustin GJS, Nelstrop AE, Bolis G et al. Use of CA125 to assess activity of topotecan versus paclitaxel in relapsed ovarian carcinoma measured by response and early progression. Proc Am Soc Clin Oncol 1997; 16: 351a (Abstr). 2. Rasmussen H, Rugg T, Brown P et al. A 371 patient meta-analysis of studies of marimastat in patients with advanced cancer. Proc Am Soc Clin Oncol 1997; 16: 429a (Abstr). 3. Thalmann GN, Sikes RA, Chang SM et al. Suramin-induced decrease in prostate specific antigen expression with no effect on tumor growth in the LNCaP model of human prostate cancer. J Natl Cancer Inst 1996, 88: 794-810. 4. Timothy AR, Cook GJR. PET scanning in clinical oncology. Ann Oncol 1998; 9: 353-5. 5. Zee B, Melnychuk D, Dancey J et al. A new design of phase II cancer clinical trials incorporating response and early progression. Controll Clin Trials 1996; 17: 85S (Abstr A80). 6. Dent S, Zee B, Dancey J et al. Design of phase II clinical trials stopping rule using response and early progression. Ann Oncol 1996; 7 (Suppl 1): 134 (Abstr). 7. Rapp E, Pater JL, Willan A et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer report of a Canadian multicenter randomized trial. J Clin Oncol 1988; 6: 633-41. 8. Murray N, Coppin C, Coldman A et al. Drug delivery analysis of the Canadian multicenter trial in non-small-cell lung cancer. J Clin Oncol 1994; 12: 2333-9. 9. Fleming TR. One sample multiple testing procedures for phase II trials. Biometrics 1982; 38: 143-51.
based on measured outcomes in phase II. It will be only if agents are selected on basis of 'positive' findings in one or more of these alternative endpoints and subjected to phase III evaluation that we will learn if any are valid. To return to the first question posed: is evidence of activity in phase II necessary before proceeding to phase HI? This seems to be a reasonable strategy in some circumstances, although it is risky. If pursued it would be most logical with agents where preclinical data is compelling and phase II results will not have an impact on plans to carry out randomized studies. The clinical settings in which such trials are done should be those where time to progression is relatively short and early stopping rules based on progression could interrupt the trial if appropriate (Table 5). Examples could include the 'consolidation' setting for treated SCLC or ovarian cancer. Both of these diseases are, in fact, being studied Received 17 August 1998; accepted 18 August 1998. with metalloproteinase inhibitors. Correspondence to: In summary, this is time of great excitement and Dr. E. A. Eisenhauer. MD, FRCP opportunity for those of us engaged in early clinical Investigational New Drug Program evaluation of anti-cancer therapy. Great strides have NCIC Clinical Trials Group Queen's University been made in identifying potential new therapeutics in Kingston, Ontario K7L 3N6 the very few years since basic scientists have elucidated Canada molecular mechanisms of cancer genesis, growth and E-mail: eisenhae(a ncic.ctg.queensu.ca
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When? • If data is compelling in animals. • If response cannot be anticipated. • If phase III planned regardless of results of phase II trials.
metastases. We cannot be overly complacent in applying the templates of phase I and II studies of tradition to these novel compounds. Nor must we leap into adopting alternative endpoints simply because they are available if they are not validated in either mouse or man. More than anything else this is a time for logic in design, and rigor in our observations and interpretation of results. By striving to evaluate proposed new endpoints in terms of their ability to select drugs and doses that enhance survival, we will assure that any 'meaning' assigned to them is truly earned by their ability to predict real efficacy.
Special article Phase I and II trials of novel anti-cancer agents: Endpoints, efficacy and existentialism
E. A. Eisenhauer Invesligational New Drug Program, NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada
Key words: phase I, phase II, response, toxicity
Introduction
Decades of work in the laboratory aimed at uncovering genetic and other causes of malignant disease have yielded a tremendous amount of knowledge. Thus this is a time of unprecedented opportunity with many novel targets to pursue in cancer therapeutics. At the level of the cell, targets in cytoplasmic and cell surface signaling molecules, processes of cell cycle control, and mutations or lack of expression of suppressor genes have all yielded multiple new agents for evaluation. Similarly, at the extra cellular level, there are large numbers of novel drugs designed to limit tumor penetration and metastasis and agents which directly inhibit angiogenesis. Finally, vaccines to overcome immune tolerance of cancer are being developed. This unprecedented volume of new agents presents us with numerous challenges. The first, very practical, challenge is to efficiently organize ourselves to quickly investigate the long list of drugs coming into the clinic, so that those that are without potential are discarded and those that have potential in improving outcome are accurately identified for further study. The second major challenge relates to a need to reevaluate the conceptual framework we have used for cancer treatment. Although the ultimate goal of cancer therapy, to prolong survival or cure this disease, will not change, our understanding of the mechanism of action of the some of these new agents will cause us to shift our treatment approach. If certain novel agents are not expected to cause tumor regression, the familiar paradigm of giving as high a dose as possible in rounds of cyclical therapy will need to be shifted to one of repeated smaller doses adequate to inhibit the target, but not sufficient to produce serious toxic effects (Figure 1). This paradigm shift leads us to challenges at the phase I and II level of drug development with respect to how we select dose and how to detect efficacy if it truly exists. Thus it is timely to reflect on several issues with respect to phase I and II trial
design. What measures in these clinical trials are possible? Which measures are plausible in providing surrogate assessments of efficacy? Will any be meaningful in terms of the ultimate survival of the patient? As the title suggests, this paper will review some of the challenges of cancer drug development today reflecting on elements of endpoints, efficacy and existentialism. An endpoint is that which can be measured to assist in reaching the stated trial goal; efficacy must reflect meaningful benefit at the level of the patient with the disease. Existentialism is a philosophic theory which emphasizes the existence of an individual as a free agent in determining his or her own development, purpose and meaning. In some ways, the clinical evaluation of many novel agents will require us to engage in new thinking, making use of some of the elements of existentialist thought with respect to assigning purpose and meaning to the design, measurement and interpretation of data.
Goals of phase I and II trials
Despite the fact that novel agents present new challenges in trial design, in reality, the goals of phase I and II clinical trials of these agents will remain the same: phase I trials will determine an appropriate dose and schedule for further evaluation, will describe the pharmacologic behaviour of the drug and its toxic effects. The goal of phase II trials will be to screen agents for evidence of anti-tumor activity. The area that has been generating a great deal of discussion is not the goals of these trials but rather what endpoints are available to assess them. Alternatives to toxicity as endpoints for phase I trials The tradition of utilizing toxicity as the phase I endpoint was born from the observation that for most cytotoxics there is a direct relationship between the dose of a drug
Downloaded from https://academic.oup.com/annonc/article-abstract/9/10/1047/292346 by guest on 07 September 2018
The Michel Clavel lecture, held at the 10th NCI-EORTC Conference on New Drugs in Cancer Therapy, Amsterdam, 16-19 June 1998
1048 urements of surrogates for activity, and assessment of drug levels in plasma. Toxicity is still relevant of course because it may limit dosing on its own, so it cannot be excluded as an endpoint.
Drug Dosing
M
old paradigm
Figure I. Shifting paradigm for cancer drug delivery which may be relevant in the design and endpoints for early clinical studies.
toxicity-/
£ LJJ
LJJ
target^ f
, / - antitumor ''/
/ - antityfnor
Dose
Dose
Panel A
Panel B
Figure 2. Preclinical data (idealized) which may exist for some novel agents. See text for explanation of panels A and B.
and its effects on both tumor and toxicity. Thus, toxicity has been seen as a surrogate for doses that might be effective. However, some novel agents may exhibit different relationships between dose and other outcomes as is shown in Figure 2. Although these are 'idealized'curves, they serve to highlight some of the dose-effect relationships which may be seen. In both panels, the effect on the drug target parallels and anticipates the anti-tumor effect, both showing a plateau at a certain dose. These are quite plausible dose-effect relationships for many agents targeting specific molecules or receptors for which there is expected to be a finite number within a tumor cell population. In panel A toxic effects are shown initially to move with the other two parameters but at the point of the plateau in drug targeting effect, toxicity continues to increase. In panel B, toxic effects appear late... well above effective doses. This type of relationship between efficacy and toxicity might be expected if toxic effects are mediated by a different mechanism than the targeted anti-tumor effect. In the setting of the second example, it is clear that increasing doses to toxic levels is not necessary to achieve efficacy. There are several endpoints which may be alternatives to toxicity for agents showing these relationships. These include measurement of target inhibition, meas-
Measurement of effect on the molecular target is particularly appealing because of its rational basis, but the challenges to its use as an endpoint for phase I evaluation are many. The relevant tissue in which to measure target inhibition is tumor and this is seldom available in repeated patient samples. Available tissue, which is usually blood, may not be relevant. At the very least, if blood cells are to be used to evaluate the magnitude of target inhibition, there ought to be evidence from preclinical models that target inhibition in blood cells is a valid marker for efficacy. This is often not the case; furthermore species specificity of molecular inhibitors may make this type of assessment impossible. How one measures the effect on the target is also a subject for debate. Should the target inhibition be measured directly (e.g., decreased production of a specific targeted protein) or indirectly (e.g., measurement of proteins or products 'downstream' from the target itself)? Either approach requires intensive laboratory back-up, and if the measure selected is to be a phase I endpoint, these assays must be done in 'real-time' fashion to allow decisions about subsequent dose escalation. The major weakness of this approach may relate to the target itself. While the preclinical data may suggest that an agent's efficacy is due to it's interaction with a specific target, it is certainly plausible that it may have other, as yet unknown, effects at the cellular level responsible for its anti-tumor activity. Thus the target that we believe is relevant (and may strive to measure) may not be the target that is responsible for anti-tumor effect. The proof of the relevance of many molecular targets, in fact, may only come once they are assessed clinically. Measurement of other surrogates for activity Measurement of other surrogates for activity is another possible endpoint for phase I evaluation. This is of particular interest for immune based treatments where measures of immune response may relate to achievement of effective doses. The major challenge in this context is to define which measures are really related to anti-tumor effect. Preclinical models may help, but immune therapies may have species specific attributes making laboratory determination of the appropriate surrogate difficult. Furthermore, multiple measurements of immune function may generate discordant results leading to confusion about which is the most 'relevant' one for dose and scheduling decisions. Simpler phase I endpoints are those which have been accessible for standardized measurement for many years: blood levels of drug and toxic effects. Although the hypothetical dose effect curves shown in Figure 2
Downloaded from https://academic.oup.com/annonc/article-abstract/9/10/1047/292346 by guest on 07 September 2018
?new paradigm
Measurement of effect on the molecular target
1049
After phase I: Continue Development? Target Effect:
inhibition
Significant Toxicity: seen not seen continue
1.
Measure toxicity, blood levels and if available, target effect.
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Figure 3. Possible outcomes of phase I trials with new endpoints. How to integrate findings of toxicity and target effects in decisions regarding continued development?
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suggest that giving a toxic dose may not be necessary, it would be almost certain that a dose high enough to produce toxic effects will not be too low for efficacy. Furthermore it is reasonable to suppose that blood levels correlating with target inhibition and with efficacy in animal models could be extrapolated to the clinical situation. Even if measures of target inhibition are possible, toxicity and pharmacologic data must still be collected. Provided that some measure of target inhibition as well as usual blood level and toxicity information can be obtained, how will these results be integrated into decisions about the future development of a new agent? Figure 3 illustrates the various outcome scenarios possible following completion of phase I trials. In the presence of dose limiting toxicity plus evidence of target inhibition in relevant tissue, further drug development ought to proceed. The same decision would likely be made if dose-related target inhibition were achieved without severe toxicity. The observation of neither toxic effects nor evidence of inhibition would undoubtedly lead to concern about the continued evaluation of the compound. The most difficult of all scenarios, I believe, is when dose limiting toxicity is seen but no inhibition at the target level has been noted. Here, given the fact that we can sometimes be wrong in our assessment of the true target, the decision to go forward with the drug into phase II or III evaluation should depend upon the strength of the preclinical efficacy data and whether there are unique features to the agent. So what should be done today in designing phase I trials? My views are simple and summarized in Table 1. We should measure toxicity, blood levels and if possible target effect. Ideally the trial should be designed with two MTD's: maximum target inhibiting dose (MTID) and maximum tolerated dose (MTD) based on toxicity. If at the study's end, the MTID and MTD are the same, selection of the dose for further evaluation is simple. If the MTID and MTD are substantially different, it is most appropriate to select the dose with lower toxicity but maximum target effect for further evaluation. If at
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Figure 4. Patterns of anti-tumor effects seen in preclinical experiments. Growth delay may be more commonly seen with novel agents than with traditional cytotoxics.
all possible, however, consideration should be given to comparing these two doses early on for efficacy in a randomized (phase II) study. Only in this way will we develop the database necessary to know which approach is best. After phase I: Screening for efficacy
The goal of phase II trials is to screen agents for their potential for efficacy. Traditionally this has been measured by objective tumor regression described using standard criteria (e.g., World Health Organization). It is important to point out that response per se is not synonymous with efficacy; rather, efficacy means improved cure rates, survival or quality of life. Tumor shrinkage has proved to be useful as a phase II endpoint because it has allowed us to select drugs or regimens which have subsequently been shown to be effective by prolonging survival. Although only randomized trials can unequivocally show a survival impact, non-randomized trials remain important as a means of screening agents for their potential in this regard. If, as shown in Figure 4 (left panel), a new agent produces tumor regression in animal models it is reasonable to expect it will in the clinical situation as well. Under these circumstances, response remains the most useful phase II endpoint. The more common scenario is that of growth delay, rather than tumor regression, as shown in the right panel of Figure 4. The issues raised in
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no inhibition continue or stop?
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Table 1. Phase I trials of novel agents: my view.
1050 rate of rise of serum marker; an effect which also seemed to demonstrate a dose-response relationship. On the basis of these data, randomized trials are proceeding. The results of these studies may contribute to validation of this particular endpoint. Finally, if measurement of markers is to be proposed as a surrogate for activity, it must be assured that there is not a direct effect of the investigational agent on marker levels through changes in secretion unrelated to tumor burden as has been shown with some agents [3].
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Figure 5. Survival rates by best response in the combined chemotherapy arms of a trial of best supportive care vs. two regimens of platinum based chemotherapy. Overall survival was improved by chemotherapy and response rate was low. The curve demonstrates that patients with SD or PR enjoyed similar survival experiences. (Abbreviations: PD - progressive disease; SD - stable disease, PR partial response).
screening an agent having this type of profile for clinical efficacy are the following: Is evidence of activity in phase II really necessary, before proceeding to phase III trials? If so, are there alternatives to response as a phase II endpoint if tumor regression is not to be anticipated? In answer to the first question, is evidence of activity in phase II necessary before proceeding to phase III trials?, no, provided the preclinical data is sufficiently compelling. However, there are resource, time and ethical advantages to having positive phase II data in hand before moving to phase III. For this reason, there has been much interest in pursuing the answer to the second question: the identification of alternative endpoints to response which may be used to appropriately select or reject a new drug in a phase II design. Possible candidate endpoints include: changes in tumor markers, measures of target inhibition, PET scanning, time to progression and proportion of patients with early progression. It is important to note that no proposed alternative endpoint has been validated. That is, none have been used alone to select agents later shown to be useful in prolonging survival. Tumor markers Tumor markers have the advantage of being well described and easily measured. Unfortunately, as noted above, no marker used alone has been validated as a phase II endpoint. Although the work done with CA 125 by Rustin in ovarian cancer suggests that this marker may substitute for response rate in phase II trials, these data were generated in studies where the drugs also produced tumor regression [1]. One research group has suggested that a change in the rate of rise in marker may be a useful endpoint for identifying an active agent [2]. In their studies of a metalloproteinase inhibitor, patients were observed to show a decline in the pre-treatment
Measure of target inhibition Measure of target inhibition is appealing from a scientific point of view but since many novel agents target molecules of, as yet, hypothetical importance in human tumor growth, their inhibition has not yet shown relationship to efficacy in the clinical setting. As noted earlier, measures of target inhibition (preferably in tumor tissue) may be a more relevant endpoint for phase I trials where optimal dosing is the goal. Positron emission tomography (PET) Positron emission tomography (PET) scanning is a nuclear medicine technique which uses radiopharmaceuticals such as 2-18flouro-2-deoxy-D-glucose to identify changes in tumor tissue function and metabolism predictive of tumor regression [4]. However, if the major advantage of PET scanning is to anticipate tumor regression (i.e., response), then this costly test is not really an 'alternative' to response. Will effective cytostatic therapy produce changes in tumors assessed by PET scanning when response is not documented? This is certainly possible, but remains to be shown. Median time to progression (TTP) has the advantage of being a well described and standardized endpoint in randomized trials. However, it is difficult is to interpret when there is no control group and patient numbers are limited as is the case in a phase II setting. A related idea that has come from work done by the NCIC Clinical Trials Group is a variation on TTP. We have been interested in using the progression rate (i.e., the proportion of patients who progress in the first eight weeks of therapy and thus have a 'best response' of progression) as a possible endpoint for phase II trials. We have come to this from two different avenues of thinking. The first related to some work on phase II stopping rules of cytotoxic drugs which incorporated both response rate and early progression rate as factors in determining whether a trial of a new drug should stop early [5]. We have shown that certain drugs could be appropriately declared inactive when one considered not only the number of responses but also the number of progressions in the first cohort of patients in a phase II trial [6, and unpublished data]. That is, even if the critical one response was seen in the first 15 patients, a high number of patients with PD in the same group
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indicated the drug was unlikely to have meaningful ac- Table 2. Using PD rate to select new agents. tivity and it would be appropriate to stop the trial early. Set maximum PD rate above which agent will be rejected. The other information which was important in getting us to think along these lines was that, at least in PD rate of interest will vary according to tumor type as does response rate now. some studies, partial response and stable disease appear to have same impact on survival. Several years ago the For example: NCIC CTG conducted a trial in non-small cell lung Tumor type Response rate of interest PD rate of interest cancer which demonstrated that two different regimens Breast <20% of platinum based chemotherapy both offered a survival > 30% NSCLC >20% < 30% advantage over best supportive care [7]. However, the Glioma > 10% <40% response rates on the chemotherapy arms were low (15% and 25%) so it was puzzling that the treatment had an impact on overall survival. The analysis of survival by best response category shown in Figure 5 provided the Table 3. Data fromNCIC CTG phase II trials. answer [8]. In fact in this trial, the designation of PR Observed Observed Tumor type Agent had no meaning at all: patients with either PR or SD had response PD rate identical outcomes. Thus the gain in survival was likely rate (%) (%) due to the treatment's ability to stop progression of 55" 11" Docetaxel disease not to cause regression. When we examined Breast (first-line) 10a DPPE/doxorubicin 50" other trials in various tumor types some, but not all, 41 a 19" 10-EDAM showed similar results. 23 23 Menogaril po 26 43 Menogaril IV Perhaps these observations are relevant to novel 23" 27" NSCLC (first-line) MTA agents where it is likely, that at least in advanced disease, 27 a 15 Paclitaxel/ifos they may not exhibit their efficacy by causing tumor 55 6 Acivicin regression but rather by halting early progression. If so, 13-cisRA 50 3 the next logical question is: can PD rate by itself allow us 50 0 DUP937 72 to accept or reject interesting compounds appropriately? 0 Elsamitrucin 87 Tiazofurin 0 If so, this might be a useful tool for evaluation of those 26" 8 Topotecan Glioma (first-line) new drugs which are predicted to cause tumor stability. 28" 0 Docetaxel To pursue this we examined our phase II database to 40 0 Gemcitabine see if by looking at PD rate only we would select the 69 0 Tiazofurin 86 0 Trimetrexate same agents for further study as identified by response rate. The usual phase II trial is designed to stop early if an agent shows no responses, and a minimum response " Results which surpass the selection criteria noted in Table 2. rate (often 20%) is required to make an agent 'interesting' [9]. To evaluate the usefulness of PD rate, a max- and response criteria were used. As can be seen, regardimum PD rate above which the agent would be rejected less of whether response rate alone or PD rate alone is required to declare the agent 'uninteresting' (i.e., would have been used, the same three agents would have would be rejected from further study). We also realized been selected as 'interesting' in breast cancer. In NSCLC, that the PD rate 'of interest' might vary according to the response rate criteria selected only one agent, while tumor type, just as response rate does now. In designing the PD criteria selected two (one of which was a pacliphase II trials, higher response rates must be observed taxel combination regimen). Finally, in glioma although for a new drug to be selected in those diseases in which no agent made it over the response rate hurdle it is numerous agents are already available (e.g., breast or interesting to note the disparity in PD rates with two small-cell lung cancer) as compared to those tumor agents (topotecan and docetaxel) having low PD rates. types with few effective treatments (e.g., melanoma). These results suggest that the proportion of patients The same logic ought to apply in assigning PD rates to progressing early might be useful to select agents of select new agents. In Table 2 minimum response rates interest for further evaluation when those agents are not have been assigned to breast, NSCLC and glioma tu- expected to cause tumor regression. However, like all mors based on the general results of 'active' treatment other alternative endpoints PD rate as a means of selectand the usual phase II stopping rules. In addition, ing new agents for phase III study remains non-valimaximum PD rates have been assigned to the same dated. More work on all of these measures is needed to tumors on the basis of what might be considered intui- determine which, if any, are useful. tively reasonable rates of progression which would make What should we do at the moment to assess novel a new regimen more or less interesting. In Table 3, agents in phase II trials? My views are summarized in results from a series of NCIC CTG phase II trials in Table 4. We should continue to measure response endeach of these tumor types is shown in which the response and PD rate selection criteria have been applied. In all points, follow those alternative endpoints which are trials for each tumor type, the same patient eligibility feasible, and, most importantly, we should have a very clear idea of whether further phase III trials will occur
1052 Table 4. Phase II trials of novel agents: my view. 1. 2. 3.
Measure objective response. Follow those alternative endpoints which are feasible. Have a very clear idea of whether phase III trials will take place based on measured outcomes in phase II. 4. Only by selection of agents using alternative endpoints and subjecting them to phase III evaluation will we learn if they are valid.
Table 5. Considerations for phase III trials of novel agent if no phase II trial.
Tumor type • Tumors/settings with rapid time to progression ideally suited (e.g , treated SCLC or ovarian cancer, first-line pancreas). • Animal studies should suggest tumor type will be sensitive. Design • Randomized. • Early stopping rule based on progression/failure should be in place.
References 1. Rustin GJS, Nelstrop AE, Bolis G et al. Use of CA125 to assess activity of topotecan versus paclitaxel in relapsed ovarian carcinoma measured by response and early progression. Proc Am Soc Clin Oncol 1997; 16: 351a (Abstr). 2. Rasmussen H, Rugg T, Brown P et al. A 371 patient meta-analysis of studies of marimastat in patients with advanced cancer. Proc Am Soc Clin Oncol 1997; 16: 429a (Abstr). 3. Thalmann GN, Sikes RA, Chang SM et al. Suramin-induced decrease in prostate specific antigen expression with no effect on tumor growth in the LNCaP model of human prostate cancer. J Natl Cancer Inst 1996, 88: 794-810. 4. Timothy AR, Cook GJR. PET scanning in clinical oncology. Ann Oncol 1998; 9: 353-5. 5. Zee B, Melnychuk D, Dancey J et al. A new design of phase II cancer clinical trials incorporating response and early progression. Controll Clin Trials 1996; 17: 85S (Abstr A80). 6. Dent S, Zee B, Dancey J et al. Design of phase II clinical trials stopping rule using response and early progression. Ann Oncol 1996; 7 (Suppl 1): 134 (Abstr). 7. Rapp E, Pater JL, Willan A et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer report of a Canadian multicenter randomized trial. J Clin Oncol 1988; 6: 633-41. 8. Murray N, Coppin C, Coldman A et al. Drug delivery analysis of the Canadian multicenter trial in non-small-cell lung cancer. J Clin Oncol 1994; 12: 2333-9. 9. Fleming TR. One sample multiple testing procedures for phase II trials. Biometrics 1982; 38: 143-51.
based on measured outcomes in phase II. It will be only if agents are selected on basis of 'positive' findings in one or more of these alternative endpoints and subjected to phase III evaluation that we will learn if any are valid. To return to the first question posed: is evidence of activity in phase II necessary before proceeding to phase HI? This seems to be a reasonable strategy in some circumstances, although it is risky. If pursued it would be most logical with agents where preclinical data is compelling and phase II results will not have an impact on plans to carry out randomized studies. The clinical settings in which such trials are done should be those where time to progression is relatively short and early stopping rules based on progression could interrupt the trial if appropriate (Table 5). Examples could include the 'consolidation' setting for treated SCLC or ovarian cancer. Both of these diseases are, in fact, being studied Received 17 August 1998; accepted 18 August 1998. with metalloproteinase inhibitors. Correspondence to: In summary, this is time of great excitement and Dr. E. A. Eisenhauer. MD, FRCP opportunity for those of us engaged in early clinical Investigational New Drug Program evaluation of anti-cancer therapy. Great strides have NCIC Clinical Trials Group Queen's University been made in identifying potential new therapeutics in Kingston, Ontario K7L 3N6 the very few years since basic scientists have elucidated Canada molecular mechanisms of cancer genesis, growth and E-mail: eisenhae(a ncic.ctg.queensu.ca
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When? • If data is compelling in animals. • If response cannot be anticipated. • If phase III planned regardless of results of phase II trials.
metastases. We cannot be overly complacent in applying the templates of phase I and II studies of tradition to these novel compounds. Nor must we leap into adopting alternative endpoints simply because they are available if they are not validated in either mouse or man. More than anything else this is a time for logic in design, and rigor in our observations and interpretation of results. By striving to evaluate proposed new endpoints in terms of their ability to select drugs and doses that enhance survival, we will assure that any 'meaning' assigned to them is truly earned by their ability to predict real efficacy.