there are no bad anticancer agents, only bad clinical trial ......vol. 4, 1079 -1086, may 1998...

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 2,3Institute for Drug Development, Cancer Therapy and ResearchCenter, and Department of Medicine, University of Texas HealthScience Center at San Antonio, San Antonio, Texas 78245

Abstract

Unfortunately, the vast majority (90%) of new antican-

cer agents designed in the laboratory never make it into

routine clinical use. The hypothesis of this lecture is that

many new agents fail in the clinic because the appropriate

clinical trial(s) that could exploit the attributes of the new

agent are not performed. An appreciation that both bench

and clinical investigations are difficult endeavors should aid

in improving clinical trial designs and give the best chance

for new agents to be added to our therapeutic armamen-

tarium.

IntroductionA very common story is that a basic scientist works for

years and years to develop a new agent with a unique mecha-

nism of action to treat tumor cells; but that new agent never

makes it into clinical trials, or if it does, it almost always fails to

make an impact on the disease.

The hypothesis of today’s lecture is that many new agents

fail because the appropriate clinical trials to exploit the at-

tributes of the new agent have not been performed. This is

because of a basic uncoupling or disconnection between the

bench scientist, who has worked long and hard on his or her

hypothesis but who may not understand the difficulties of and

creativity required for clinical trials, and the clinical scientist,

who may not understand how difficult the basic discovery has

been and how careful one must be before abandoning the new

concept or new agent from the bench.

The magnitude of the disconnection between the bench

scientist and the bedside clinician cannot be assessed solely by

how many new agents don’t make it into general use in the

oncology community. The percentage of agents, however, that

do go to clinical trial and are adopted for clinical use is disap-

Received 2/3/98; accepted 3/4/98.1 Presented at the 88th Annual Meeting of the American Association for

Cancer Research, April 15, 1997, San Diego. CA.

2 To whom requests for reprints should be addressed, at Institute forDrug Development, Cancer Therapy and Research Center, 14960Omicron Drive, San Antonio, TX 78245. Phone: (210) 677-3880; Fax:(2 10) 677-0058; E-mail: [email protected] Dr. Von Hoff is a founder and minority owner of ILEX Oncology,

which is working on clinical trials with MGBG and DFMO. He is alsoa member of the Scientific Advisory Board for Eli Lilly, which owns

and markets gemcitabine.

pointingly low. Fig. 1 details the number of new agents brought

into clinical trials from 1975 to 1994 and the number of those

agents eventually approved for clinical use. Overall, there were

280 new agents brought into Phase I (dose-finding) clinical

trials in patients. Only 29 of them (10%) were eventually ap-

proved for use in patients.

There are three main reasons that emerge in examining

why the other 90% of new agents don’t make it into routine use.

These include: (a) the toxicities of the agent were too great; (b)

there was a lack of efficacy; and (c) no attention was paid to the

mechanism of action of the compound when the clinical trials

were designed and conducted.

In the discussion below, we will explore all three of these

major reasons why new agents don’t make it into general

clinical use. In addition, examples will be given of how to

bypass these problems so that a greater percentage of agents

brought into clinical trials will actually make it to general use.

Why Compounds Don’t Make It-ToxicitiesTable 1 gives examples of severe toxicities that halted the

development of several new anticancer agents. These toxicities

basically stopped the development of the new agents in their

tracks, in most instances, with a complete suspension of their

clinical trials. However, because of the clinical activity of the

agent that had been seen early on, e.g. , responses to the agent

paclitaxel in patients with a variety of malignancies, clinicians

persisted in trying to find a way to circumvent the toxicity of

paclitaxel. The thesis is that one can circumvent toxicities of the

new agent if the drug has clinical antitumor activity. Table 1

also details the methods that were used to circumvent toxicities

for each of the agents.

The observation of our drug development team in San

Antonio, TX, is that in dealing with the phenomenon of dose-

limiting toxicities, stopping the drug and then the clinician

finding a way to circumvent those toxicities, we have devised

the life cycle of a new anticancer drug as shown in Fig. 2 (1). As

can be seen in the figure, a drug is discovered and brought into

clinical testing. Almost inevitably, a crisis in the development of

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

developed to circumvent the toxicity of the new agent, and the

agent then emerges from the state of pharmacoptosis and is

rediscovered or reborn. As is noted in Table 1, this ability to

reverse pharmacoptosis is a very common phenomenon.

An Example of Recovery from Pharmacoptosis Because

of Toxicity-Mitoguazone. A recent example of recovery

from pharmacoptosis is the redevelopment of mitoguazone.

Mitoguazone was synthesized in 1898 by Thiele et a!. (2). It also

has the names MGBG, methylglyoxal bis(guanylhydrazone),

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

Year

1080 There Are No Bad Anticancer Drugs

Fig. 1 Total number of differ-ent agents in Phase I trials per

year (#{149}),and number of thoseagents eventually approved (El).

methyl-GAG, and NSC-32946. The structure of mitoguazone is

shown in Fig. 3. One of the intriguing aspects of mitoguazone is

that it has a unique mechanism of action as an inhibitor of

S-adenosylmethionine decarboxylase (3, 4). Some investigators

have believed that it is also a mitochondrial interactive agent (5).

It should be remembered that compounds with new and uniquemechanisms of action have a better chance for non-cross-resis-

tance with the antineoplastics already in clinical use.

Mitoguazone was first given to patients in the early l960s,

usually on a chronic (e.g., daily X 30 days) schedule (6, 7).

Antitumor activity was noted in patients with leukemia and

lymphoma (6- 8). However, the major toxicity of mucositis (and

other severe toxicities) caused all clinical trials with the agent tobe stopped. Therefore, despite clinical activity, all clinical trials

with mitoguazone were discontinued (the drug underwent phar-

macoptosis).

The key to the rebirth of mitoguazone was new scientificknowledge from pharmacokinetic studies performed in the late

1970s and early l980s (and reconfirmed recently) that mitogua-

zone had an extremely long plasma half-life of >5 days (9-1 1).With this new understanding, it was clear that the schedule of

daily administration of mitoguazone was causing an accumula-

tion of mitoguazone that could have been responsible for the

side-effect profile (severe mucositis and myelosuppression sec-

ondary to toxicity on rapidly turning over cells in the mucous

membranes). Based on this new knowledge, weekly and every

other week schedules of administration were devised (12, 13).

Using these dosing schedules, mucositis became an unusual side

effect with the agent, and antitumor activity was noted in pa-

tients with Hodgkin’s disease, non-Hodgkin’s lymphoma, head

and neck cancer, endometrial cancer, prostate cancer, and

Table 1 Agents in which severe toxicities halted their developmentand methods used to circumvent those toxicities (and reverse

pharmacoptosis)

Agent Toxicity

Method tocircumvent

toxicity

Doxorubicin/ Congestive heart Dose limitation,Daunomycin failure dexrazoxane

Vincristine Neurotoxicity Dose limitationCisplatin Renal toxicity,

ototoxicity emesisHydration,

antiemeticsPaclitaxel Anaphylactic shock Steroids and other

premedicationDocetaxel Fluid retention SteroidsCPT-l 1 Diarrhea AntidiarrhealsFludarabine Blindness Dose limitation

phosphate

esophageal cancer (12-16). Despite that activity, there was still

little interest in mitoguazone until the emergence of non-Hodgkin’s lymphoma in patients with AIDS.

AIDS-related non-Hodgkin’s lymphoma was first reportedin 1982. It is usually a disease with aggressive histologies

(large-cell immunoblastic and small-cell non-cleaved), has a

high incidence of central nervous system involvement, accounts

for 12-16% of all AIDS-related deaths, and there is no standard

treatment for patients who have progressed on first-line therapy

(17, 18). The average survival for patients who have progressed

on first-line therapy is 63 days (19). Polyamines are elevated in

patients with lymphoma 4.0-5.3-fold compared with normal

volunteers (20, 21); therefore, an agent like mitoguazone, which



Discovery(Birth)

Rediscovery(Rebirth)

Fig. 3 Structure of mitoguazone.

Fig. 2 The life cycle of a new anticancer drug (reprinted with permis-

sion from Annals of Oncology).

100w

�g 750-�:

250-

25 30 35 40 45

Fig. 4 Antitumor activity of the hypothetical new agent difungomuc-

tane ( #{149}) in an in vivo tumor growth system compared with controlgrowth (0) of the tumor.

Clinical Cancer Research 1081

Clinicaltesting

�ll�p�s� Crisis 1’� I Ssv#{149}retoxicity

‘ No activity

Programmeddrug death

(pharmacoptosis)

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

patients with non-AIDS-related non-Hodgkin’s lymphoma (12,

13); (b) the agent causes minimal myelosuppression and other

toxicities on the new schedule (12, 13); and (c) mitoguazone

crosses the blood brain barrier, as evidenced by high concen-

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-phoma. In that study, she treated 35 patients with AIDS-related

lymphoma, all of whom had failed on prior regimen and 17 of

whom had failed 2-6 prior regimens. Twenty-four (80%) of the

patients had a CD4 count of < lOO/dl. There were three patients

who attained a complete response, plus three who attained a

partial response for an overall response rate of 6 of 35 or 17%

(95% confidence interval, 4.7-29.6%; Ref. 23). A second study

in a similar population has confirmed that response rate (24).

The toxicities associated with the use of mitoguazone on the

days 1 , 8, and then every 2 weeks schedule were minimal, with

only an 8% incidence of grades 3 and 4 mucositis. The lesson

learned from the further development of mitoguazone is that

new knowledge regarding the basis for toxicity with a corn-

pound (in this case, its clinical pharmacology) can lead to adifferent way of using that compound that avoids the toxicities

and allows its antitumor activities to be exploited.

After the presentation of this lectureship, the Phase II dataon the activity of mitoguazone in patients with AIDS-related

non-Hodgkin’s lymphorna was presented to the Food and Drug

Administration Advisory Committee, and the Committee rec-

ommended against its approval based only on Phase II data. Arandomized Phase HI trial to further support its efficacy wasrecommended by the Food and Drug Administration, and plans

are being made to conduct that study. The drug has not yet

emerged from pharmacoptosis.

Why Compounds Don’t Make It-Lack of Efficacy

A second reason new agents don’t make it into routine

clinical use is no efficacy (or a supposed lack of efficacy). Many

NH2

\/\ /\H2N\,NV N II N NH2 2HCI . H20

H2N

0 5 10 15 20

Days

investigators would argue that the reason we have so many

compounds that make it into clinical trials that have poor to no

activity in the clinic is the poor (nonpredictive) preclinical

systems we have for selecting those agents (25, 26). Our thesis

in San Antonio is that in our clinical trial designs, we are asking

the drug to do more clinically than it did preclinically. For

example, take the hypothetical new drug “difungomuctane” (nota real drug), which inhibits tumor growth to the degree noted in

Fig. 4. As can be seen in Fig. 4, difungomuctane clearly causes

tumor growth delay. However, can we really expect this drug to

shrink tumors in patients when all it does in animal systems is

slow down tumor growth? Again, the theory is that with our

current clinical trial designs, we are asking our drugs to do more

clinically than they do in preclinical systems. Perhaps new

clinical trial end points besides shrinkage of patients’ tumors are

needed to assess the antitumor activity of some new agents.

An Example of Recovery from Pharmacoptosis Becauseof Supposed Lack of Antitumor Activity. Gemcitabine (LY

18801 1, difluorodeoxycytidine; dFdC) is a nucleoside with the

structure shown in Fig. 5. The compound was synthesized by

Hertel et a!. (27) with tumor growth delay documented in

several animal models and human tumor xenograft models

including X5563 myeloma; 6C3HED lymphosarcoma; Ll 210,

P388, and P1543J leukemia; and the CX-l and LX-1 xenografts

(28 -30). In addition, the agent had a broad spectrum of antitu-

mor activity against human tumor colony-forming units taken

directly from patients and growing in soft agar (31). Activity

was particularly impressive against breast, non-small cell lung,

ovarian, and pancreatic cancer colony-forming units.

Phase I trials were conducted with gemcitabine beginning



< Gemcitabine(1000 mg/m2/week)

5.Fluorouracil(600 mg/m2/week)

F

Fig. 5 Structure of gemcitabine.


‘ The abbreviations used are: ‘fl’P, time to tumor progression; DFMO,difluoromethylornithine (eflornithine); ODC, ornithine decarboxylase.

in 1987 (32, 33). The daily X 5, 30-mm infusion schedule gave

a maximally tolerated dose of only 9 mg/rn2, with hypertension

and flu-like symptoms being the dose-limiting toxicities. On the

every 2 weeks schedule, over 0.5-4 h, the maximally tolerated

dose was 3600 mg/rn2. Dose-limiting toxicities included neu-

tropenia and flu-like symptoms. In that study, we noted one

patient with pancreatic cancer with clinical improvements in-

cluding less pain, an improved performance status, and weight

gain. Based on that observation as well as observations from

other groups, a Phase II trial of gemcitabine was conducted by

Casper et a!. (34, 35). In that study, 43 patients with advanced

pancreatic cancer with no prior chemotherapy received doses of

gemcitabine ranging from 800-1250 mg/m2 weekly X 3 re-

peated every 28 days. Five partial responses were noted for an

overall response rate of 13%. Toxicities were mild. What was

striking was that, despite the overall low incidence of partial

response (only 13%), there was a far greater percentage of

patients who reported improvements in their pancreatic cancer-

related symptoms, i.e., pain, weakness, and weight loss. Because

virtually no chemotherapy has been shown to impact the symp-

torns of pancreatic cancer, it was decided to design a clinical

trial with gemcitabine to determine, in a controlled setting,

whether that agent decreased the symptoms associated with

advanced pancreatic cancer. This thinking was a departure from

the usual oncology clinical trial designs, where typical end

points are either tumor shrinkage (complete or partial responses)

or survival. However, in other areas of drug development, other

end points are always used in clinical trials. For example, the

end point for a clinical trial for a new antiarrhythmic agent is

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

those end points could be whether the new therapy improves the

Patients with advanced,symptomatic pancreaticcancer

- No prior chemotherapy

- Pain, intensity score of � 20

(out of 100 on MPAC*). Analgesic consumption

� 10 morphine sulfateequivalents

. Karnofsky PerformanceStatus � SO but � 80

*MPAC = Memorial Pain Assessment Card

Fig. 6 Design for definitive trial of gemcitabine in patients with ad-

vanced 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

a patient, we postulated that the new treatment would give them

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 out-

lined in Fig. 6 was designed. As can be seen in that figure, to be

eligible for the study, patients had to have advanced pancreatic

cancer which was symptomatic (e.g., patients with pain of >20

of 100 on the Memorial Pain Assessment Card (38); patients

required more than 10 mg of morphine sulfate or equivalent to

control their pain; and patients had to have a Karnofsky Per-

formance Status of >50 but

Table 2 Summary of results of randomized trial of gemcitabineversus 5-fluorouracil (5-FU) for treatment of patients with advanced

pancreatic cancer”

Fig. 7 Preclinical-clinical uncoupling in drug development.


Parameter 5-FU arm Gemcitabine arm P

Clinical benefit 4.8% 23.8% 0.0022Response rate 0% 5.4% 0.077TTP (mo) 1.0 3.2 0.0002Survival

Median (mo) 4.41 5.65 0.0025One year 2%

“Bums et al. (42).

18%

had clinical benefit versus 5% of the patients who received

5-fluorouracil (P 0.0022). This has now been reported in

other trials (43, 44). The TTP (which corresponds best to the

tumor growth delay in animals) was also significantly better. Of

additional note and importance is that median survival and

1-year survival were significantly better for the gemcitabine-

treated patients. This finding helped validate the use of our

clinical benefit parameter as a clinically meaningful end point.

Also importantly, the side-effects profile of gemcitabine was not

significantly different from the profile of 5-fluorouracil, except

that more transfusions were required in the patients receiving

gemcitabine, and neutropenia was also more common. How-

ever, the gemcitabine patients also lived longer to obtain those

transfusions or to develop neutropenia.

The gemcitabine example is provided to document that if a

new agent produces tumor growth delay in a preclinical model,

we should strive to use a tumor growth delay end point (e.g.,

‘FTP) in our clinical trials. Above all, we should strive to match

our clinical trial end points to what has been found in preclinical

models. Only then will there be a true and fair clinical test for

that new agent. This will be particularly important as our new

molecular biology gives us new agents that are growth-modu-

lating agents rather than cytotoxic agents that shrink established

tumors (see below).

Why Compounds Don’t Make It-Attention Is Not

Paid to the Mechanisms of Action of the Compound

When attention is not paid to the mechanism of action of a

new compound, our clinical trials often do not exploit that

mechanism of action, which usually leads to failure of the

compound in the clinic. As noted in Fig. 7, I refer to this as

“preclinical-clinical uncoupling.” Table 3 gives some examples

of preclinical-clinical uncoupling. As can be seen in that table,

regardless of the mechanism of action of the agent, the only

parameter we have used to determine whether to continue de-

velopment of a new agent has been to assess whether the

compound causes complete tumor shrinkage (100% disappear-

ance of the tumor lasting at least 1 month) or a partial response

(�50% disappearance of tumor lasting at least 1 month). This

nearly total neglect of the mechanism of action probably has led

to discontinuing the development of many new agents that, had

their mechanism of action been remembered and our trials

designed to measure that mechanism, may have been successful

in the clinic.

An Example of an Agent Recovering from Pharmacop-tosis Because of Attention Paid to Its Mechanism of Action.

DFMO has the structure shown in Fig. 8. The compound has a

unique mechanism of action, i.e., the irreversible inhibition of

ODC (45, 46). ODC is becoming a more interesting target in

both the areas of cancer treatment and in cancer etiology and,

hence, in cancer prevention. More specifically, ODC has been

found to be up-regulated in the tissues of several premalignant

conditions, including cervical intraepithelial neoplasia (47), co-

lon polyps (48), and others (49). Manni et a!. (50) have found

that ODC is up-regulated in patient breast cancer tissue, and

elevation of the expression of ODC in that tissue is of greater

significance for a poor prognosis than is the estrogen receptor

status or the number of positive lymph nodes. Finally, of great

interest, is that Auvinen et al. (51) have reported that ODC is an

oncogene. Transfection of the ODC gene into NIH 3T3 cells

causes transformation of the cells.

As noted above, DFMO is an irreversible inhibitor of ODC.

DFMO blocks the promotion step of carcinogenesis in several

animal models including breast, colon, bladder, skin, and pros-

tate models (52-55). Unfortunately, the initial clinical trials with

DFMO developed the agent as a standard anticancer agent with

escalation to the maximally tolerated dose of the agent. Toxic-

ities noted with doses of �20 g/m2/day of DFMO included

thrombocytopenia, nausea and vomiting, leukopenia, anemia,

diarrhea, high frequency hearing loss, and in some cases, met-

abolic acidosis (56, 57). After those studies, DFMO was aban-

doned (underwent pharmacoptosis) by most investigators.

A breakthrough in the use of DFMO was a study by Love

et al. (58) who performed a clinical trial to attempt to exploit the

mechanism of action of DFMO, the inhibition of ornithine

decarboxylase. They conducted a study to determine the small-

est dose of DFMO that could be used to inhibit ornithine

decarboxylase by carefully performing skin biopsies on the

patients. They found that a dose of 0.5 g/m2/day (one-twentieth

the daily dose used in prior cytotoxic approach studies) inhibited

ornithine decarboxylase. Also, importantly, they noted that no

toxicity was seen at that dose level. This finding fostered addi-

tional clinical trials because DFMO could now be used as a

chemoprevention agent.

The field of chemoprevention has changed substantially

over the past few years because there are now histological

changes that are regarded as premalignant. These premalignant

changes include cervical intraepithelial neoplasia (CIN III),

actimc keratosis, colon adenoma, ductal carcinoma in situ of the

breast, previously resected superficial bladder cancer, atypical

squamous metaplasia/dysplasia in the lung, oral dysplastic leu-

koplakia, and prostatic intraepithelial neoplasia. The goal in

chemoprevention now is to reverse those premalignant changes



CHF2

H2N - CH2 - CH2 - CH2- C - COOH

NH2

Fig. 8 Structure of DFMO.

Period A

I (Standard �Therapy)

Period B

(New Agent) �1

- Ratio Period B = Growth Modulation IndexPeriod A-Anything > 1.33 (33% improvement) is

considered excellent (and is unexpected forsecond-line therapy)

Fig. 9 A method for early determination as to whether a new agent ishaving a modulating effect on tumor growth.

/7� Standard agent + Placebo

Standard agent + new agent


with end points of ‘FTP and 1-year survival.

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.

3

The agent prevents metastases

The agent induces apoptosis

Partial or complete tumor shrinkage

Partial or complete tumor shrinkage

(use them as an intermediate marker for an effect of the agent

being studied; Ref. 59).

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 substan-

tially reduce (in 52% of patients) cervical intraepithelial neo-

plasia (CIN-Ill, a substantial risk factor for the development of

cervical cancer) after only one month of use. Meyskens et al.

(60) have clearly documented that low doses of DFMO can

suppress polyamine content in colorectal biopsy specimens as

preparation for their randomized trial of a nonsteroidal, anti-

inflammatory agent plus DFMO versus the nonsteroidal agent

alone in patients with a history of recurrent colorectal polyps.

The end point for this study will be the number of polyps that

recur per unit of time.

Last, but not least, is a trial published by Alberts et a!. (61),

who randomized 44 patients with actinic keratoses (a premalig-

nant skin condition) to receive either DFMO cream or a placebo

cream. This randomized, double-blinded trial showed a signif-

icant decrease in actinic keratoses with three months of use of

the DFMO cream, whereas there was no decrease with the

placebo cream (61). There was a reduced spermidine:spermine

ratio in the skin biopsies from the patients receiving DFMO,

indicating that DFMO was inhibiting the ODC. This is a proof

of principle that inhibition of the ODC by DFMO resulted in a

clinically measurable decrease in the number of actinic kerato-

ses after only a short period of application.

How Can We Measure a Clinical Effect of a New

Compound That Is Not a Cytotoxic Agent?

The developments in molecular biology and the identi-

fication of new targets provide challenges to both the bench

and the clinical investigator (62). There are new antisense

molecules, farnesyl transferase inhibitors, telomerase inhib-

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

test a growth-modulating agent is to conduct a randomized

trial, as was done for gemcitabine, with end points of time-

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

trial)? One way that might be used to obtain an early lead as

to whether a growth-modulating agent is having an effect is

outlined in Fig. 9. Our hypothesis is that if the new agent has

an antitumor effect, it will change the natural history of the

disease. Therefore, we will use the patient as his/her own

control. As can be seen in Fig. 9, period B is the TTP on the

new agent. Period A is the TTP on the treatment the patients

received just before the new agent was started. Given the

natural history of cancer, it would be shorter that the TTP on

the new agent would be shorter than the TTP on a prior

regimen. Therefore, if the TTP on the new agent (period B)

is greater than the TTP on the prior therapy (period A) it is

likely the new agent is having an effect on the natural history

of that patient’s tumor. In Fig. 9, we suggested a 33%

improvement; however, that value is arbitrary. Although not

yet tested prospectively, the use of a patient as his/her control

may be a way to determine whether a growth-modulating

agent is having a clinical effect before the randomized Phase

III trial is launched.

Summary of Lessons Learned

What lessons have we learned to increase the percentage of

our agents that make it in the clinic? The first lesson is to avoid

pharmacoptosis (programmed drug death). If the new agent

shows toxicities in the clinic but has hints of antitumor activity,

be persistent and find a way to circumvent that toxicity.

The second lesson is for the correct clinical trial design to

mimic the preclinical activity of the agent. For a growth-mod-

ulatory agent, a suggested clinical trial design would be:




The third lesson is to take advantage of the mechanism of

action of the new agent when designing a clinical trial. For an

angiogenesis inhibitor, use a minimal residual disease model

such as:

. . Angiogenesis inhibitor

put patient in bestremission (minimal

residual disease) Placebo

with end points of ‘FTP or recurrence-free survival.

The fourth lesson (for the preclinical scientist) is to demand

better trial designs for your molecule! The fifth lesson for my

clinical colleagues and myself is to take it upon ourselves to

personally give new agents the best mechanism-of-action-based

trial design we possibly can.

Conclusion

In conclusion, I would like to thank all of the patients,

mentors, and colleagues who have made this work possible. San

Antonio is the birthplace of Texas freedom, and we always say,

“Remember the Alamo!” From this lectureship, I would like you

to remember that both bench investigations and clinical inves-

tigations are difficult endeavors and that we need to appreciate

both of them as important sciences. Remembering that will keep

our clinical trial designs optimal and provide the best clinical

development of a new idea or a new agent from the bench.

Acknowledgments

I gratefully acknowledge the expert assistance of Laida Garcia,Meredith Sterling, and Judy Turner in preparing the manuscript for

publication.

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1998;4:1079-1086. Clin Cancer Res D D Von Hoff Award Lecture.designs--twenty-first Richard and Hinda Rosenthal Foundation There are no bad anticancer agents, only bad clinical trial

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