There Are No Bad Anticancer Agents, Only Bad Clinical Trial Designs-Twenty-First Richard and Hinda Rosenthal Foundation Award Lecture1

Vol. 4, 1079 -1086, May 1998 Clinical Cancer Research 1079

Special Lecture

There Are No Bad Anticancer Agents, Only Bad Clinical Trial Designs-Twenty-first Richard and Hinda Rosenthal Foundation Award Lecture1

Daniel D. Von Hoff 2,3 pointingly low. Fig. 1 details the number of new agents brought Institute for Drug Development, Cancer Therapy and Research into clinical trials from 1975 to 1994 and the number of those Center, and Department of Medicine, University of Texas Health agents eventually approved for clinical use. Overall, there were Science Center at San Antonio, San Antonio, Texas 78245 280 new agents brought into Phase I (dose-finding) clinical trials in patients. Only 29 of them (10%) were eventually approved for use in patients. Abstract There are three main reasons that emerge in examining Unfortunately, the vast majority (90%) of new antican- why the other 90% of new agents don’t make it into routine use. cer agents designed in the laboratory never make it into These include: (a) the toxicities of the agent were too great; (b) routine clinical use. The hypothesis of this lecture is that there was a lack of efficacy; and (c) no attention was paid to the many new agents fail in the clinic because the appropriate mechanism of action of the compound when the clinical trials clinical trial(s) that could exploit the attributes of the new were designed and conducted. agent are not performed. An appreciation that both bench In the discussion below, we will explore all three of these and clinical investigations are difficult endeavors should aid major reasons why new agents don’t make it into general in improving clinical trial designs and give the best chance clinical use. In addition, examples will be given of how to for new agents to be added to our therapeutic armamen- bypass these problems so that a greater percentage of agents tarium. brought into clinical trials will actually make it to general use.

Introduction Why Compounds Don’t Make It-Toxicities A very common story is that a basic scientist works for Table 1 gives examples of severe toxicities that halted the years and years to develop a new agent with a unique mecha- development of several new anticancer agents. These toxicities nism of action to treat tumor cells; but that new agent never basically stopped the development of the new agents in their makes it into clinical trials, or if it does, it almost always fails to tracks, in most instances, with a complete suspension of their make an impact on the disease. clinical trials. However, because of the clinical activity of the The hypothesis of today’s lecture is that many new agents agent that had been seen early on, e.g. , responses to the agent fail because the appropriate clinical trials to exploit the at- paclitaxel in patients with a variety of malignancies, clinicians tributes of the new agent have not been performed. This is persisted in trying to find a way to circumvent the toxicity of because of a basic uncoupling or disconnection between the paclitaxel. The thesis is that one can circumvent toxicities of the bench scientist, who has worked long and hard on his or her new agent if the drug has clinical antitumor activity. Table 1 hypothesis but who may not understand the difficulties of and also details the methods that were used to circumvent toxicities creativity required for clinical trials, and the clinical scientist, for each of the agents. who may not understand how difficult the basic discovery has The observation of our drug development team in San been and how careful one must be before abandoning the new Antonio, TX, is that in dealing with the phenomenon of dose- concept or new agent from the bench. limiting toxicities, stopping the drug and then the clinician The magnitude of the disconnection between the bench finding a way to circumvent those toxicities, we have devised scientist and the bedside clinician cannot be assessed solely by the life cycle of a new anticancer drug as shown in Fig. 2 (1). As how many new agents don’t make it into general use in the can be seen in the figure, a drug is discovered and brought into oncology community. The percentage of agents, however, that clinical testing. Almost inevitably, a crisis in the development of do go to clinical trial and are adopted for clinical use is disap- the agent occurs in which either a severe toxicity is noted with the agent or no antitumor activity is noted with the agent. The agent then undergoes programmed drug death, which we like to call “pharmacoptosis.” Fortunately, methods can sometimes be Received 2/3/98; accepted 3/4/98. developed to circumvent the toxicity of the new agent, and the 1 Presented at the 88th Annual Meeting of the American Association for agent then emerges from the state of pharmacoptosis and is Cancer Research, April 15, 1997, San Diego. CA. rediscovered or reborn. As is noted in Table 1, this ability to 2 To whom requests for reprints should be addressed, at Institute for Drug Development, Cancer Therapy and Research Center, 14960 reverse pharmacoptosis is a very common phenomenon. Omicron Drive, San Antonio, TX 78245. Phone: (210) 677-3880; Fax: An Example of Recovery from Pharmacoptosis Because (2 10) 677-0058; E-mail: [email protected]. of Toxicity-Mitoguazone. A recent example of recovery 3 Dr. Von Hoff is a founder and minority owner of ILEX Oncology, from pharmacoptosis is the redevelopment of mitoguazone. which is working on clinical trials with MGBG and DFMO. He is also a member of the Scientific Advisory Board for Eli Lilly, which owns Mitoguazone was synthesized in 1898 by Thiele et a!. (2). It also and markets gemcitabine. has the names MGBG, methylglyoxal bis(guanylhydrazone),

.n C.) 30 rI)

I-

Fig. 1 Total number of different agents in Phase I trials per year (#{149}),and number of those agents eventually approved (El).

75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94

Year

methyl-GAG, and NSC-32946. The structure of mitoguazone is Table 1 Agents in which severe toxicities halted their development shown in Fig. 3. One of the intriguing aspects of mitoguazone is and methods used to circumvent those toxicities (and reverse pharmacoptosis) that it has a unique mechanism of action as an inhibitor of S-adenosylmethionine decarboxylase (3, 4). Some investigators Method to have believed that it is also a mitochondrial interactive agent (5). circumvent Agent Toxicity toxicity It should be remembered that compounds with new and unique mechanisms of action have a better chance for non-cross-resis- Doxorubicin/ Congestive heart Dose limitation, Daunomycin failure dexrazoxane tance with the antineoplastics already in clinical use. Vincristine Neurotoxicity Dose limitation Mitoguazone was first given to patients in the early l960s, Cisplatin Renal toxicity, Hydration, usually on a chronic (e.g., daily X 30 days) schedule (6, 7). ototoxicity emesis antiemetics Antitumor activity was noted in patients with leukemia and Paclitaxel Anaphylactic shock Steroids and other premedication lymphoma (6- 8). However, the major toxicity of mucositis (and Docetaxel Fluid retention Steroids other severe toxicities) caused all clinical trials with the agent to CPT-l 1 Diarrhea Antidiarrheals be stopped. Therefore, despite clinical activity, all clinical trials Fludarabine Blindness Dose limitation with mitoguazone were discontinued (the drug underwent phar- phosphate macoptosis). The key to the rebirth of mitoguazone was new scientific knowledge from pharmacokinetic studies performed in the late 1970s and early l980s (and reconfirmed recently) that mitogua- esophageal cancer (12-16). Despite that activity, there was still zone had an extremely long plasma half-life of >5 days (9-1 1). little interest in mitoguazone until the emergence of non- With this new understanding, it was clear that the schedule of Hodgkin’s lymphoma in patients with AIDS. daily administration of mitoguazone was causing an accumula- AIDS-related non-Hodgkin’s lymphoma was first reported tion of mitoguazone that could have been responsible for the in 1982. It is usually a disease with aggressive histologies side-effect profile (severe mucositis and myelosuppression sec- (large-cell immunoblastic and small-cell non-cleaved), has a ondary to toxicity on rapidly turning over cells in the mucous high incidence of central nervous system involvement, accounts membranes). Based on this new knowledge, weekly and every for 12-16% of all AIDS-related deaths, and there is no standard other week schedules of administration were devised (12, 13). treatment for patients who have progressed on first-line therapy Using these dosing schedules, mucositis became an unusual side (17, 18). The average survival for patients who have progressed effect with the agent, and antitumor activity was noted in pa- on first-line therapy is 63 days (19). Polyamines are elevated in tients with Hodgkin’s disease, non-Hodgkin’s lymphoma, head patients with lymphoma 4.0-5.3-fold compared with normal and neck cancer, endometrial cancer, prostate cancer, and volunteers (20, 21); therefore, an agent like mitoguazone, which

Discovery NH2 (Birth)

H2N\,NV \/\IN N /\ I NH2 2HCI . H20

Rediscovery Clinical H2N (Rebirth) testing Fig. 3 Structure of mitoguazone.

llps Crisis 1’

I Ssv#{149}retoxicity 100w ‘ No activity

Programmed g 750- drug death : (pharmacoptosis)

Fig. 2 The life cycle of a new anticancer drug (reprinted with permission from Annals of Oncology).

250- inhibits the synthesis of polyamines, was an attractive agent to try against the disease. In addition, mitoguazone was interesting to try because: (a) the agent already had documented activity in 0 5 10 15 20 25 30 35 40 45 patients with non-AIDS-related non-Hodgkin’s lymphoma (12, Days 13); (b) the agent causes minimal myelosuppression and other toxicities on the new schedule (12, 13); and (c) mitoguazone Fig. 4 Antitumor activity of the hypothetical new agent difungomuc- crosses the blood brain barrier, as evidenced by high concen- tane ( #{149}) in an in vivo tumor growth system compared with control growth (0) of the tumor. trations in brain tumors (22). Recently, Levine et a!. (23) reported the results of a Phase II trial of mitoguazone given at a dose of 600 mg/m2 on days I, 8, and then every 2 weeks, in patients with AIDS-related lym- investigators would argue that the reason we have so many phoma. In that study, she treated 35 patients with AIDS-related compounds that make it into clinical trials that have poor to no lymphoma, all of whom had failed on prior regimen and 17 of activity in the clinic is the poor (nonpredictive) preclinical whom had failed 2-6 prior regimens. Twenty-four (80%) of the systems we have for selecting those agents (25, 26). Our thesis patients had a CD4 count of < lOO/dl. There were three patients in San Antonio is that in our clinical trial designs, we are asking who attained a complete response, plus three who attained a the drug to do more clinically than it did preclinically. For partial response for an overall response rate of 6 of 35 or 17% example, take the hypothetical new drug “difungomuctane” (not (95% confidence interval, 4.7-29.6%; Ref. 23). A second study a real drug), which inhibits tumor growth to the degree noted in in a similar population has confirmed that response rate (24). Fig. 4. As can be seen in Fig. 4, difungomuctane clearly causes The toxicities associated with the use of mitoguazone on the tumor growth delay. However, can we really expect this drug to days 1 , 8, and then every 2 weeks schedule were minimal, with shrink tumors in patients when all it does in animal systems is only an 8% incidence of grades 3 and 4 mucositis. The lesson slow down tumor growth? Again, the theory is that with our learned from the further development of mitoguazone is that current clinical trial designs, we are asking our drugs to do more new knowledge regarding the basis for toxicity with a corn- clinically than they do in preclinical systems. Perhaps new pound (in this case, its clinical pharmacology) can lead to a clinical trial end points besides shrinkage of patients’ tumors are different way of using that compound that avoids the toxicities needed to assess the antitumor activity of some new agents. and allows its antitumor activities to be exploited. An Example of Recovery from Pharmacoptosis Because After the presentation of this lectureship, the Phase II data of Supposed Lack of Antitumor Activity. Gemcitabine (LY on the activity of mitoguazone in patients with AIDS-related 18801 1, difluorodeoxycytidine; dFdC) is a nucleoside with the non-Hodgkin’s lymphorna was presented to the Food and Drug structure shown in Fig. 5. The compound was synthesized by Administration Advisory Committee, and the Committee rec- Hertel et a!. (27) with tumor growth delay documented in ommended against its approval based only on Phase II data. A several animal models and human tumor xenograft models randomized Phase HI trial to further support its efficacy was including X5563 myeloma; 6C3HED lymphosarcoma; Ll 210, recommended by the Food and Drug Administration, and plans P388, and P1543J leukemia; and the CX-l and LX-1 xenografts are being made to conduct that study. The drug has not yet (28 -30). In addition, the agent had a broad spectrum of antitu- emerged from pharmacoptosis. mor activity against human tumor colony-forming units taken directly from patients and growing in soft agar (31). Activity Why Compounds Don’t Make It-Lack of Efficacy was particularly impressive against breast, non-small cell lung, A second reason new agents don’t make it into routine ovarian, and pancreatic cancer colony-forming units. clinical use is no efficacy (or a supposed lack of efficacy). Many Phase I trials were conducted with gemcitabine beginning

Patients with advanced, symptomatic pancreatic cancer

- No prior chemotherapy Gemcitabine - Pain, intensity score of 20 < (1000 mg/m2/week) (out of 100 on MPAC*)

. Analgesic consumption 10 morphine sulfate equivalents 5.Fluorouracil

. Karnofsky Performance (600 mg/m2/week) Status SO but 80

*MPAC = Memorial Pain Assessment Card

Fig. 6 Design for definitive trial of gemcitabine in patients with advanced symptomatic pancreatic cancer.

tumor-induced problems that bother the patient. In the case of pancreatic cancer, the things that bother the patient include pain, weakness, and a declining performance status and weight loss (36, 37). If a new treatment could improve those symptoms for F a patient, we postulated that the new treatment would give them Fig. 5 Structure of gemcitabine. clinical benefit and should be made available to them. To determine whether gemcitabine gave clinical benefit to patients with advanced pancreatic cancer, the clinical trial outlined in Fig. 6 was designed. As can be seen in that figure, to be in 1987 (32, 33). The daily X 5, 30-mm infusion schedule gave eligible for the study, patients had to have advanced pancreatic a maximally tolerated dose of only 9 mg/rn2, with hypertension cancer which was symptomatic (e.g., patients with pain of >20 and flu-like symptoms being the dose-limiting toxicities. On the of 100 on the Memorial Pain Assessment Card (38); patients every 2 weeks schedule, over 0.5-4 h, the maximally tolerated required more than 10 mg of morphine sulfate or equivalent to dose was 3600 mg/rn2. Dose-limiting toxicities included neu- control their pain; and patients had to have a Karnofsky Per- tropenia and flu-like symptoms. In that study, we noted one formance Status of >50 but <80). Patients were randomized to patient with pancreatic cancer with clinical improvements in- receive either weekly treatment with 1000 mg/rn2 of gemcitab- cluding less pain, an improved performance status, and weight me or weekly treatment with 600 mg/rn2 of 5-fluorouracil. The gain. Based on that observation as well as observations from study was single blinded, e.g., the patients did not know which other groups, a Phase II trial of gemcitabine was conducted by of the two agents they were receiving. The end points of the Casper et a!. (34, 35). In that study, 43 patients with advanced study included: (a) clinical benefit (improvement in pain, per- pancreatic cancer with no prior chemotherapy received doses of formance status, or weight gain measured with a rigorous algo- gemcitabine ranging from 800-1250 mg/m2 weekly X 3 re- rithm using the Memorial Pain Assessment Card scored by the peated every 28 days. Five partial responses were noted for an patient), analgesic consumption recorded by the patient, and overall response rate of 13%. Toxicities were mild. What was performance status and weight measured by the research nurse striking was that, despite the overall low incidence of partial (39); (b) response rate (conventional partial or complete re- response (only 13%), there was a far greater percentage of sponses; Ref. 40); (c) TTP” (which should correspond to the end patients who reported improvements in their pancreatic cancer- point of tumor growth delay noted with gemcitabine in animals); related symptoms, i.e., pain, weakness, and weight loss. Because (d) overall survival; and (e) 1-year survival (to allow detection virtually no chemotherapy has been shown to impact the symp- of the minor percentage of patients whose tumors were sensitive torns of pancreatic cancer, it was decided to design a clinical just like in a human tumor cloning assay), which corresponds to trial with gemcitabine to determine, in a controlled setting, the tail of the survival curve. whether that agent decreased the symptoms associated with As reported recently, the study included 126 patients (63 advanced pancreatic cancer. This thinking was a departure from per arm; Refs. 41 and 42). Table 2 summarizes the findings. It the usual oncology clinical trial designs, where typical end is noteworthy that the response rates for both arms were low. points are either tumor shrinkage (complete or partial responses) Pancreatic cancer is a difficult disease to evaluate because of the or survival. However, in other areas of drug development, other effects of prior surgery or prior radiation therapy to the tumor end points are always used in clinical trials. For example, the bed and pancreatitis/phlegmon associated with the tumors. end point for a clinical trial for a new antiarrhythmic agent is Twenty-four % of the patients who received gemcitabine control of arrhythmias, not survival. The end point for the clinical trials of a new antihypertensive is control of blood pressure, not survival. New end points in clinical trials in

patients with advanced cancer may also be in order. One of ‘ The abbreviations used are: ‘fl’P, time to tumor progression; DFMO, those end points could be whether the new therapy improves the difluoromethylornithine (eflornithine); ODC, ornithine decarboxylase.

Table 2 Summary of results of randomized trial of gemcitabine versus 5-fluorouracil (5-FU) for treatment of patients with advanced pancreatic cancer”

Parameter 5-FU arm Gemcitabine arm P

Clinical benefit 4.8% 23.8% 0.0022 Response rate 0% 5.4% 0.077 TTP (mo) 1.0 3.2 0.0002 Survival Median (mo) 4.41 5.65 0.0025 Fig. 7 Preclinical-clinical uncoupling in drug development. One year 2% 18%

“Bums et al. (42).

DFMO has the structure shown in Fig. 8. The compound has a had clinical benefit versus 5% of the patients who received unique mechanism of action, i.e., the irreversible inhibition of 5-fluorouracil (P 0.0022). This has now been reported in ODC (45, 46). ODC is becoming a more interesting target in other trials (43, 44). The TTP (which corresponds best to the both the areas of cancer treatment and in cancer etiology and, tumor growth delay in animals) was also significantly better. Of hence, in cancer prevention. More specifically, ODC has been additional note and importance is that median survival and found to be up-regulated in the tissues of several premalignant 1-year survival were significantly better for the gemcitabine- conditions, including cervical intraepithelial neoplasia (47), co- treated patients. This finding helped validate the use of our lon polyps (48), and others (49). Manni et a!. (50) have found clinical benefit parameter as a clinically meaningful end point. that ODC is up-regulated in patient breast cancer tissue, and Also importantly, the side-effects profile of gemcitabine was not elevation of the expression of ODC in that tissue is of greater significantly different from the profile of 5-fluorouracil, except significance for a poor prognosis than is the estrogen receptor that more transfusions were required in the patients receiving status or the number of positive lymph nodes. Finally, of great gemcitabine, and neutropenia was also more common. How- interest, is that Auvinen et al. (51) have reported that ODC is an ever, the gemcitabine patients also lived longer to obtain those oncogene. Transfection of the ODC gene into NIH 3T3 cells transfusions or to develop neutropenia. causes transformation of the cells. The gemcitabine example is provided to document that if a As noted above, DFMO is an irreversible inhibitor of ODC. new agent produces tumor growth delay in a preclinical model, DFMO blocks the promotion step of carcinogenesis in several we should strive to use a tumor growth delay end point (e.g., animal models including breast, colon, bladder, skin, and pros- ‘FTP) in our clinical trials. Above all, we should strive to match tate models (52-55). Unfortunately, the initial clinical trials with our clinical trial end points to what has been found in preclinical DFMO developed the agent as a standard anticancer agent with models. Only then will there be a true and fair clinical test for escalation to the maximally tolerated dose of the agent. Toxic- that new agent. This will be particularly important as our new ities noted with doses of 20 g/m2/day of DFMO included molecular biology gives us new agents that are growth-modu- thrombocytopenia, nausea and vomiting, leukopenia, anemia, lating agents rather than cytotoxic agents that shrink established diarrhea, high frequency hearing loss, and in some cases, met- tumors (see below). abolic acidosis (56, 57). After those studies, DFMO was aban- doned (underwent pharmacoptosis) by most investigators. Why Compounds Don’t Make It-Attention Is Not A breakthrough in the use of DFMO was a study by Love Paid to the Mechanisms of Action of the Compound et al. (58) who performed a clinical trial to attempt to exploit the When attention is not paid to the mechanism of action of a mechanism of action of DFMO, the inhibition of ornithine new compound, our clinical trials often do not exploit that decarboxylase. They conducted a study to determine the small- mechanism of action, which usually leads to failure of the est dose of DFMO that could be used to inhibit ornithine compound in the clinic. As noted in Fig. 7, I refer to this as decarboxylase by carefully performing skin biopsies on the “preclinical-clinical uncoupling.” Table 3 gives some examples patients. They found that a dose of 0.5 g/m2/day (one-twentieth of preclinical-clinical uncoupling. As can be seen in that table, the daily dose used in prior cytotoxic approach studies) inhibited regardless of the mechanism of action of the agent, the only ornithine decarboxylase. Also, importantly, they noted that no parameter we have used to determine whether to continue de- toxicity was seen at that dose level. This finding fostered addi- velopment of a new agent has been to assess whether the tional clinical trials because DFMO could now be used as a compound causes complete tumor shrinkage (100% disappear- chemoprevention agent. ance of the tumor lasting at least 1 month) or a partial response The field of chemoprevention has changed substantially (50% disappearance of tumor lasting at least 1 month). This over the past few years because there are now histological nearly total neglect of the mechanism of action probably has led changes that are regarded as premalignant. These premalignant to discontinuing the development of many new agents that, had changes include cervical intraepithelial neoplasia (CIN III), their mechanism of action been remembered and our trials actimc keratosis, colon adenoma, ductal carcinoma in situ of the designed to measure that mechanism, may have been successful breast, previously resected superficial bladder cancer, atypical in the clinic. squamous metaplasia/dysplasia in the lung, oral dysplastic leu- An Example of an Agent Recovering from Pharmacop- koplakia, and prostatic intraepithelial neoplasia. The goal in tosis Because of Attention Paid to Its Mechanism of Action. chemoprevention now is to reverse those premalignant changes

Table 3 Examples of preclinical-clinical uncoupling What is seen preclinically What we are measuring clinically

1. The agent inhibits angiogenesis Partial or complete tumor shrinkage 2. The agent prevents metastases Partial or complete tumor shrinkage 3 The agent induces apoptosis Partial or complete tumor shrinkage

CHF2 Period A Period B I (Standard (New Agent) 1 H2N - CH2 - CH2 - CH2- C - COOH Therapy)

NH2 - Ratio Period B = Growth Modulation Index Period A Fig. 8 Structure of DFMO.

Anything > 1.33 (33% improvement) is -considered excellent (and is unexpected for second-line therapy)

(use them as an intermediate marker for an effect of the agent Fig. 9 A method for early determination as to whether a new agent is being studied; Ref. 59). having a modulating effect on tumor growth. To date, three clinical trials have correctly used low doses of DFMO to inhibit ODC. Mitchell et a!. (47) have recently published their work demonstrating that DFMO could substantially reduce (in 52% of patients) cervical intraepithelial neo- trial)? One way that might be used to obtain an early lead as plasia (CIN-Ill, a substantial risk factor for the development of to whether a growth-modulating agent is having an effect is cervical cancer) after only one month of use. Meyskens et al. outlined in Fig. 9. Our hypothesis is that if the new agent has (60) have clearly documented that low doses of DFMO can an antitumor effect, it will change the natural history of the suppress polyamine content in colorectal biopsy specimens as disease. Therefore, we will use the patient as his/her own preparation for their randomized trial of a nonsteroidal, anti- control. As can be seen in Fig. 9, period B is the TTP on the inflammatory agent plus DFMO versus the nonsteroidal agent new agent. Period A is the TTP on the treatment the patients alone in patients with a history of recurrent colorectal polyps. received just before the new agent was started. Given the The end point for this study will be the number of polyps that natural history of cancer, it would be shorter that the TTP on recur per unit of time. the new agent would be shorter than the TTP on a prior Last, but not least, is a trial published by Alberts et a!. (61), regimen. Therefore, if the TTP on the new agent (period B) who randomized 44 patients with actinic keratoses (a premalig- is greater than the TTP on the prior therapy (period A) it is nant skin condition) to receive either DFMO cream or a placebo likely the new agent is having an effect on the natural history cream. This randomized, double-blinded trial showed a signif- of that patient’s tumor. In Fig. 9, we suggested a 33% icant decrease in actinic keratoses with three months of use of improvement; however, that value is arbitrary. Although not the DFMO cream, whereas there was no decrease with the yet tested prospectively, the use of a patient as his/her control placebo cream (61). There was a reduced spermidine:spermine may be a way to determine whether a growth-modulating ratio in the skin biopsies from the patients receiving DFMO, agent is having a clinical effect before the randomized Phase indicating that DFMO was inhibiting the ODC. This is a proof III trial is launched. of principle that inhibition of the ODC by DFMO resulted in a clinically measurable decrease in the number of actinic kerato- Summary of Lessons Learned ses after only a short period of application. What lessons have we learned to increase the percentage of our agents that make it in the clinic? The first lesson is to avoid How Can We Measure a Clinical Effect of a New pharmacoptosis (programmed drug death). If the new agent Compound That Is Not a Cytotoxic Agent? shows toxicities in the clinic but has hints of antitumor activity, The developments in molecular biology and the identi- be persistent and find a way to circumvent that toxicity. fication of new targets provide challenges to both the bench The second lesson is for the correct clinical trial design to and the clinical investigator (62). There are new antisense mimic the preclinical activity of the agent. For a growth-mod- molecules, farnesyl transferase inhibitors, telomerase inhib- ulatory agent, a suggested clinical trial design would be: itors, kinase inhibitors, angiogenesis inhibitors, and many other molecules that are likely to be growth-modulating and that will not cause immediate tumor shrinkage. One way to /7 Standard agent + Placebo test a growth-modulating agent is to conduct a randomized trial, as was done for gemcitabine, with end points of time- Standard agent + new agent to-tumor progression and 1-year survival. However, is there a way we can tell early in its development whether an agent has any promise (before conducting the randomized Phase III with end points of ‘FTP and 1-year survival.

The third lesson is to take advantage of the mechanism of 10. Hart, R. D., Roboz, J., Wu, K., Bruckner, T., Ohnuma, T., and action of the new agent when designing a clinical trial. For an Holland, J. F. Clinical and pharmacologic studies with weekly and angiogenesis inhibitor, use a minimal residual disease model biweekly methylglyoxal bis-guanylhydrazone (methyl-G). Proc. Am. Assoc. Cancer Res., 21: 181, 1980. such as: 11. Rizzo, J., Levine, A. M., Weiss, G. R., Pearce, T., Kraynak, M.,

. . Angiogenesis inhibitor Mueck, R., Smith, S., Von Hoff, D. D., and Kuhn, J. G. Pharmacoki- put patient in best netics profile of mitoguazone (MGBG) in patients with AIDS-related remission (minimal non-Hodgkin’s lymphoma. Invest. New Drugs, 14: 227-234, 1996. residual disease) Placebo 12. Knight, W. A., III, Fabian, C., Costanzi, J. J., Jones, S. E., and Coltman, C. A., Jr. Methylglyoxal bis-guanylhydrazone (methyl GAG, with end points of ‘FTP or recurrence-free survival. MGBG) in lymphoma and Hodgkin’s disease. Invest. New Drugs, 1: The fourth lesson (for the preclinical scientist) is to demand 225-237, 1983. better trial designs for your molecule! The fifth lesson for my 13. Warrell, R. P., Lee, B. J., Kempin, S. J., Lacher, M. J., Straus, D. J., and Young, C. W. Effectiveness of methyl-GAG (methylglyoxal-bis- clinical colleagues and myself is to take it upon ourselves to [guanylhydrazone]) in patients with advanced malignant lymphoma. personally give new agents the best mechanism-of-action-based Blood,57: 1011-1014, 1981. trial design we possibly can. 14. Warrell, R. P., and Burchenal, J. H. Methylglyoxal- bis(guanylhydrazone) (methyl GAG): current studies and future prospects. J. Clin. Conclusion Oncol., 1: 52-65, 1983. In conclusion, I would like to thank all of the patients, 15. Luedke, D. W., Maddox, W., Birch, R., Velez-Garcia, E., and mentors, and colleagues who have made this work possible. San Schleuter, J. Mitoguazone in advanced squamous cell carcinoma of head and neck origin: a Phase II trial of the Southeastern Cancer Study Group. Antonio is the birthplace of Texas freedom, and we always say, Cancer Treat. Rep., 70: 529-530, 1986. “Remember the Alamo!” From this lectureship, I would like you 16. Scher, H. 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