Clinical Development of Anticancer Agents-A National Cancer Institute
`Perspective
`
`Silvia Marsoni* and Robert Wittes 1
`
`Since the first report that a chemical could cause sig(cid:173)
`nificant tumor shrinkage (1), the development of clin(cid:173)
`ically useful antineoplastic drugs has grown from the
`preoccupation of a few investigators to a major interna(cid:173)
`tional effort. Over the past 35 years or so, about 30
`drugs have been defined as active in one or more tumor
`types. When used alone in patients with disseminated
`malignancy, these drugs cause reduction in bulk of
`measurable neoplasm in a significant percent of cases;
`for most tumor types, however, ample evidence of re(cid:173)
`sidual cancer usually persists and after a few months,
`tumor regrowth occurs. More striking successes have
`been achieved with combinations of drugs; as is well
`known, for several kinds of disseminated human can(cid:173)
`cers, a high frequency of clinical complete remissions,
`with substantial long-term disease-free survival rates,
`is now possible (2-5). For other cancers which may not
`be curable by chemotherapy once they have disseminat(cid:173)
`ed, combinations of drugs appear to result in a higher
`total remission rate and a greater prolongation of life
`than single drugs (6,7). Perhaps more significant in the
`long run is the apparent effect of chemotherapy when
`it is used as part of a planned multimodality effort
`(8,9).
`By some perverse quirk of fate, chemotherapy seems to
`chiefly exert a major impact in rare tumors, while the
`common epithelial neoplasms of adulthood have
`thus far resisted satisfactory solutions. Therefore, the
`central problem of drug development, the identification
`of effective agents with reasonable therapeutic index,
`is as pertinent for oncology now as at any time in the
`past.
`The idealized outlines of the successive steps in drug
`development are familiar to all oncologists. In phase I
`trials, we define a dose suitable for use in studies of
`the drug's activity across a spectrum of human tumors.
`Increasing awareness of the importance of patient- and
`disease-related parameters has effectively led to the re(cid:173)
`placement of the broad phase II trial with a series of
`disease-oriented activity studies. Having defined set-
`
`tings in which the new drug is active, investigators
`then proceed to compare the new treatment with stand(cid:173)
`ard therapy (phase III) and to further explore the
`drug's therapeutic potential in other ways, such as in
`combination with other agents or by alternate rouies of
`administration.
`Anyone familiar with the actual workings of this
`process over the past two decades knows that despite
`its successes, it has not functioned as systematically or
`efficiently as the above description might imply. In ad(cid:173)
`dition, many of the assumptions on which the process
`was based are in need of re-examination. Since there
`are no
`reliable
`laboratory predictors of efficacy
`for specific human cancers, drug development will con(cid:173)
`tinue to require extensive testing in human subjects, an
`endeavor that is never without ethical dilemmas, how(cid:173)
`ever thoughtfully it is carried out. In addition, because
`human cancers vary widely in sensitivity to anticancer
`drugs, the apparatus required to sustain the clinical
`trials effort is necessarily large and very expensive. For
`these reasons alone, another look at the drug develop(cid:173)
`ment program of the National Cancer Institute (NCI)
`seems to be worthwhile.
`
`Phase I
`
`Phase I trials of antineoplastic compounds are con(cid:173)
`ducted in patients with disseminated malignancies for
`whom standard treatment either does not exist or has
`proved ineffective. Drugs are given in a phase I trial
`with therapeutic intent; the main scientific goal is to
`define the qualitative and quantitative characteristics
`of the drug's acute toxicity, and in so doing, to deter(cid:173)
`mine a biologically active dose which is tolerable for ev(cid:173)
`ery patient. The maximum tolerated dose (MTD) is
`usually higher in children than in adults (10), probably
`because of better organ function and possibly because
`of different pharmacokinetics (11,12). Also, since the
`MTD for patients with acute leukemia is often substan(cid:173)
`tially higher than that for solid tumors, at least four
`
`ICancer Therapy Evaluation Program, Division of Cancer Treatment,
`National Cancer Institute, Bethesda, MD.
`• Reprint requests to: Silvia Marsoni, MD, Drug Evaluation and Re-
`
`portingiSection, Investigational Drug Branch, Cancer Therapy Evaluation
`Program, National Cancer Institute, Landow Bldg, Rm 4C09, 7910 Wood·
`mont Ave, National Institutes of Health, Bethesda, MD 20814.
`
`Cancer Treatment Reports Vol. 68, No.1, January 1984
`
`77
`
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`
`phase I trials should be conducted for each drug. In
`practice, of course, three to four phase I trials testing
`different schedules of the drug are usually performed
`in adult patients with solid tumor alone, and trials in
`children do not start until substantial experience is ac(cid:173)
`cumulated from the adult trials.
`The assumption underly~ng all phase I escalation pro(cid:173)
`cedures is that anticancer compounds must be given at
`or near the MTD; therefore, the job of a phase I trial is
`to define the highest dose that can be safely delivered
`to a patient, since this dose will also be the one that
`has the best chance of being active. This approach re(cid:173)
`flects the difficulties in establishing a clear-cut measur(cid:173)
`able endpoint for drug activity against cancel'. Since
`induction of response is not usually an event that is im(cid:173)
`mediately recognizable, attainment of toxicity is the
`only assurance that, if a response is not obtained, at
`least a biologically active dose was delivered. Underly(cid:173)
`ing this assumption is the more fundamental one that
`the dose-response curve for human cancers is monoton(cid:173)
`ically increasing throughout the range of tolerated
`doses and is to the right of the dose-toxicity curve.
`Needless to say, the details of this assumption have not
`been generally verified for antitumor agents, chiefly
`because rigorously defining the shape of a clinical dose(cid:173)
`response curve is a laborious task, requiring a large
`number of patients treated at each of several dose lev(cid:173)
`els. Where the relationship between dose and response
`has been examined, however, most of the data are at
`least consistent with the conclusion that the higher the
`administered dose, the more probable an antitumor ef(cid:173)
`fect (13-17) or the longer the duration of remission
`(18). On the other hand, recent trials in small cell lung
`cancer suggest that the probability of response does
`not continue to increase linearly as the dose approaches
`the MTD (19).
`For most of the clinically useful compounds, the bone
`marrow is dose-limiting. The dose-toxicity curve for
`
`myelosuppression is quite reproducible, and the status
`of marrow reserve is the major source of interpatient
`variabilit.y. Generally, tl'eatment of six to ten patients
`at 01' neal' the MTD is sufficient to establish a safe
`phase II dose when myelosuppression is the dose-limit_
`ing toxicity.
`However, major problems may arise when other toxic
`effects which are less easily quantifiable are dose-limit_
`ing. For example, in a phase I study of escalating doses
`of carmustine with autologous bone marrow support
`(20), major organ toxicity (liver, central nervous system
`and lung) surfaced abruptly at a dose of 1500 mg/mZ:
`Because of
`the sudden appearance of
`these side
`effects in the escalation scheme and the long interval
`from the beginning of treatment to onset of toxicity
`(6-9 weeks), the overall mortality rate for patients en(cid:173)
`tered at a dose of ~ 1500 mg/m2 was approximately
`30%.
`Experience suggests that whenever a drug has dose(cid:173)
`limiting side effects other than myelosuppression, its
`transition into phase II has often been compromised.
`An analysis of 31 drugs entered in phase I evaluation
`by the NCr shows that whenever the drug had myelo(cid:173)
`suppression alone as the dose-limiting toxicity, it had a
`high probability of undergoing full phase II study; how(cid:173)
`ever, when other organ toxicity was dose-limiting, only
`25% of the drugs proceeded to full phase II study (ta(cid:173)
`ble i). Evaluation of the remainder of drugs was re(cid:173)
`stricted by either the NCI or lack of investigator inter(cid:173)
`est. The main reason for these difficulties relates large(cid:173)
`ly to the uncertainty regarding reversibility of acute
`major organ damage. In addition, even if organ damage
`should turn out to be reversible, medical support dur(cid:173)
`ing periods of severe organ failure is either extremely
`intensive and costly (kidney, CNS) or technically unsat(cid:173)
`isfactory (liver), and is not seen as feasible or justifia(cid:173)
`ble by most investigators in the context of a clinical ex(cid:173)
`periment.
`
`TABLE l.-Phase II evaluation as a function of the dose-limiting toxicity of 31 cytotoxic compounds (1975-1982)
`
`Phase II
`evaluation
`
`Full
`
`Restricted
`
`Dl'Opped
`Toxicity
`No interest
`No drug supply
`
`Myelosu ppression *
`10
`
`0
`
`0
`1
`1
`
`Dose-limiting toxicity
`
`Myelosuppression
`and organ toxicityt
`
`3
`
`3
`
`0
`
`0
`
`Organ
`toxicity*
`
`3
`
`4
`
`4
`1
`0
`
`Total
`12
`12
`7
`* Bisantrene, diaziquone, aclarubicin (aclacinomycin), mitoxantrone, PCNU, amsacrine, zOl'ubicin, chlorozotocin,
`carboplatin, ICRF 187, 5-methyltetrahydrohomofolate, and 3-deazauridine.
`t Acivicin, maytansine, anguidine, tel'oxirone, dihydl'o-5-azacitidine, indicineN-oxide, and DON.
`*Pyrazofurin, L-alanosine, homoharringtonine, TCN-P, N-methyifol'mamide, pentostatin, hycanthone, dichloroal(cid:173)
`lyllawsone, pyrazole, aminothiadiazole, bruceantin, and spirogermanium.
`
`78
`
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`
`This dilemma appears to have no easy solutions. One
`alternative might be to utilize data from pharmacologic
`studies to define the relationship between dose, plasma
`level, tissue level, and clinical activity. For example, in
`the case of pentostatin, knowledge concerning the
`amount of drug needed to abolish activity of the target
`enzyme adenosine deaminase has helped to establish a
`phase II dose independent of the attainment of clinical
`toxicity. Unfortunately, however, this is an exceptional
`situation and, under most circumstances, specific intra(cid:173)
`cellular targets of drug action either have not been
`identified or are not so susceptible to analysis.
`A somewhat more empiric approach is exemplified by
`the current plans for developing N-methylformamide, a
`drug which had been introduced into the clinic in the
`1950s and was subsequently dropped while in phase I
`because of hepatotoxicity (21). Interest in the drug has
`recently been revived because of its activity against hu(cid:173)
`man tumor xenografts (22) and its capacity to induce
`differentiation in vitro (23). Phase I trials in both the
`United Kingdom and the US confirm that, at a dose of
`1000 mg/m2, the reversible hepatotoxicity of N-methyl(cid:173)
`formamide is dose-limiting and myelosuppression is
`completely absent.2•3 This dose has been defined, as the
`MTD, at which phase II trials have just begun. If activ(cid:173)
`ity is observed in any tumor type, a repeat phase II
`study in one or more susceptible tumors will be per(cid:173)
`formed at a level immediately below the MTD. This
`procedure will define whether the attainment of toxic(cid:173)
`ity is necessary for activity.
`
`Phase II
`
`In a phase II trial, the main goal is to assess the ac(cid:173)
`tivity of the drug in a variety of disseminated malig(cid:173)
`nancies and to further define the patterns of acute
`toxicity in patients who are homogeneous in diagnosis
`and in better general medical condition than patients in
`phase I. Since large numbers of patients are treated
`during phase II, rarer acute toxic effects often surface
`for the first time (24). Also, since cumulative drug
`doses may be appreciable in responding or stable pa(cid:173)
`tients, phase II provides an appropriate setting for ini(cid:173)
`tial assessment of chronic toxic effects.
`Several vexing problems are inherent in this process.
`In the first place, since patient numbers and resources
`are finite, it is impossible to explore the activity of
`each drug in each tumor type. A method must be found
`to focus the effort of drug development in a way that
`will minimize the chance of overlooking active agents.
`Accordingly, the NCr decided to evaluate all experi-
`
`2McVie JG, ten Bokkel Huinink WW, Simonetti G, et al. Phase I trial of
`N-methylformamide (NSC 3051) (NMF). Manuscript submitted to Cancel'
`Treatment Reports,
`"Minutes of the Phase I Working Group Meeting, NCl, Bethesda, MD,
`July 1983,
`
`mental drugs in selected types of cancer. The NCT
`Human Tumor Panel was created in 1975 and included
`lung, colon, and breast carcinomas, and lymphoma, leu(cid:173)
`kemia, and melanoma. The original intention was to
`match tumors in the human panel with those in the
`preclinical panel, thereby providing information for the
`validation of the preclinical screening program. In addi(cid:173)
`tion, these classes of human cancel' represent the two
`extremes of chemotherapy sensitivity and might be ex(cid:173)
`pected to exhibit, both high sensitivity and high selec(cid:173)
`tivity. Finally, the inclusion of the most common
`causes of cancer deaths (breast, colon, and lung can(cid:173)
`cers) permits the study of large numbers of patients
`and assures that results will have immediate implica(cid:173)
`tions for the treatment of prevalent cancers. Needless
`to say, evaluation of individual drugs is also carried out
`in tumors other than those in the panel, particularly if
`there is a specific reason to do so. For example, dia(cid:173)
`ziquone was chemically designed to cross the blood(cid:173)
`brain barrier and therefore has been extensively eval(cid:173)
`uated in brain tumors with encouraging results.
`How has activity in the prelinical panel correlated
`with clinical activity? Thus far, we have analyzed the
`results with 13 experimental drugs for which clinical
`and experimental data are available. The correlation of
`activity in each model tumor system with activity in
`the corresponding human cancer is shown in figure 1.
`Prediction of true-negative results (resistance) seems
`fairly reliable across most of the rodent and xenograft
`systems. On the other hand, the probability of predicting
`true-positive results (sensitivity)
`is very
`low. Be(cid:173)
`cause of the small number of active drugs in humans
`for which complete data are available, no definitive
`conclusions can be drawn. However, even if the pre(cid:173)
`clinical panel should not turn out to be an accurate pre(cid:173)
`dictor of response in individual tumor types, overall ac(cid:173)
`tivity in prelinical screening may still serve as a gen(cid:173)
`eral predictor of activity in at least one human cancer.
`The aggregated data are, in fact, consistent with this
`notion. This has obviously been the general premise on
`which antitumor screening programs have operated for
`years. Its validity has been widely assumed but has not
`been subjected to direct test, since drugs are not
`brought to the clinic if screening data are not positive.
`An assessment of the validity of the assumption will be
`afforded by the use of the human tumor stem cell
`assay as a screening tool. The plans are to bring
`selected compounds which are positive in the human
`tumor stem cell assay to clinical trial, even if they are
`negative in the P388 prescreen (26). Obviously, more
`data are needed to determine the ultimate usefulness of
`the panel.
`How has the human panel fared as a predictor of
`clinical efficacy in human tumors other than those of
`the panel? Since 1971, 62 cytotoxic agents have been
`introduced into clinical trials under the sponsorship of
`
`Vol. 68, No.1, January 1984
`
`79
`
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`
`CX-1SC
`Colon xenografts
`
`Colon 38
`
`1
`1 + 1
`c -1-; - -I-----r-
`0+1 0 1 0 1
`1
`1
`1
`1
`o -1- - -I-----r-
`n - 1 018 1
`1
`1
`1
`1
`I,
`1
`Anguidine, Pyrazofurin, Maytansine, Chlorozotocin,
`Deazauridine, Rubidazone, PALA, Amsacrine
`
`816
`melanoma
`
`1
`m 1 + 1
`e -1- - -I-----r-
`1 + 1 0 1 0 1
`a l l 1
`n -1- - -I-----r-
`o - 1 6 1 2 1
`1
`1
`m 1
`1
`1
`1
`a
`Anguidine, Pyrazofurin,
`~laytansine, Chlorozotocin, '
`Rubidazone, PALA,
`Amsac ri ne, DON
`
`LX-1SC
`1 ung xenografts
`
`3LL
`Lewis lung carcinoma
`
`MX-l SC
`breast xenografts
`
`L1210
`1 eukemi a
`
`1 + 1 - 1
`1
`e-T---I~
`uti 4
`1 1
`1
`1
`k 1
`1
`e-I---I~
`m - 1 3 1 1 1
`1
`1
`1
`I
`1
`1
`1
`a
`
`Thymidine, Aclacinomycin
`Anguidine, Chlorozotocin'
`Deazauridine, Rubidazone'
`Indicine N-Oxide,
`'
`Amsacrine, pyrazofurin
`
`CDaFl
`mammary carcinoma
`
`Anguidine, Pyrazofurin, Maytansine, Chlorozotocin,
`PALA, Amsacrine, DON
`
`1
`1 + 1
`b -1- - -I-----r-
`r + 1 0 1 1 1
`e l l 1
`a -1- - -I-----r-
`s - 1 1 1 6 1
`1
`1
`1
`t
`1
`1
`1
`Anguidine, Pyrazofurin, Maytansine, Bruceantin, PALA,
`Amsacrine, Mitoxantrone, Chlorolotocin
`
`FIGURE l.-Correlation of activity of 10 antitumor agents in murine model tumor systems with activity in human cancer. Activity in murine tumors was
`judged according to NCI Decision Network 2 criteria (Goldin A, et al. Eur J Cancer 17:129-142,1981). Activity in human tumors is defined as a 20% re(cid:173)
`sponse rate in at least 1 clinical trial with" 14 evaluahle patients.
`
`NCI. Results of an interim analysis of phase II results
`are available for 13 drugs, which were studied in 180
`protocols (table 2). Although these data represent only
`a fraction of the large NCI experieuce, certain trends
`are apparent. First, significant activity of ~ 20% was
`seen only in the lymphomas, leukemia, and breast
`carcinoma (50%, 29%, and 14% of the studies, respec(cid:173)
`tively); most of the results were in the 20%-30% range.
`No drug showed> 20% activity in colon carcinoma and
`melanoma, and only 6% of the lung cancer trials showed
`positive activity. Even with only those drugs which have
`shown activity in at least one tumor type, the overall re(cid:173)
`sponse rate in colon and lung cancers and melanomas is
`still consistently < 10%.
`
`It is well known that colon cancer and melanoma are
`highly resistant diseases, and that these diseases which
`are consistently refractory to all therapies are of no
`value in screening. Although more data are needed, the
`results to date suggest that inclusion of colon cancer
`and melanoma in the panel may not be useful for
`screening. However, it would seem reasonable to con(cid:173)
`tinue testing new agents for activity in those common
`and refractory neoplasms until truly reliable screens
`for activity have been defined. Such screens may
`emerge from further analysis of data for clinical trials
`or from advances in the use of in vitro or in vivo lab(cid:173)
`oratory methods.
`Second, even in intrinsically sensitive diseases like
`
`TABLE 2.-0utcome of phase II studies in human cancer
`
`Total No.
`of studies
`
`30
`
`38
`
`21
`
`47
`
`18
`
`26
`
`180
`
`0%
`
`13(43%)
`
`25(66%)
`
`6(29%)
`
`27(57%)
`
`4(22%)
`
`16(62%)
`
`91 (51%)
`
`Response ra te
`< 20%
`13(43%)
`
`13(34%)
`
`9(48%)
`
`17 (36%)
`
`5(28%)
`
`10(38%)
`
`67(37%)
`
`;;'·20%
`
`4(14%)
`
`0
`
`6(29%)
`
`3(6%)
`
`9(50%)
`
`0
`
`22(12%)
`
`Disease
`
`Breast cancer
`
`Colon cancer
`
`Leukemia
`
`Lung cancer
`
`Lymphoma
`
`Melanoma
`
`Total
`
`80
`
`Cancer Treatment Reports
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`
`breast or small cell lung cancer, the number of drugs
`showing activity turned out to be very small. As seen
`in table 3, of the 11 drugs considered in breast cancer,
`only bisantrene showed an overall response rate of
`> 20%. As has been true throughout the history of
`medical oncology (27), the estimates of activity vary
`widely from trial to trial. For example, with mitoxan(cid:173)
`trone, response rates ranged from 5% to 28%. This ob(cid:173)
`serv~tion suggests the well-known importance of fac(cid:173)
`tors. other than drug dose and schedule as major influ(cid:173)
`ences on estimates of response rate. Again, for mitoxan(cid:173)
`trone, the deleterious effect of prior therapy on response
`seems to be fairly clear (table 4).
`In fact, the success of the human tumor panel in pre(cid:173)
`dicting (or ruling out) general patterns of efficacy for
`other human cancers will depend to a large extent on
`what kinds of patients with "panel cancers" are chosen
`for entry in the study. A negative trial of a new drug
`in 20 patients with breast cancer who have failed mul(cid:173)
`tiple prior regimens tells us nothing about either the
`potential of this drug in a more favorable breast cancer
`population or drug activity in other tumors. Moreover,
`data from earlier eras of cancer chemotherapy cannot
`be used reliably to decide which tumors may be use(cid:173)
`fully included in a panel without extensive consider(cid:173)
`ation of how shifting patterns of practice may have al(cid:173)
`tered important patient characteristics.
`The phase II effort also needs certain administrative
`refinements. Table 5 shows a breakdown by disease of
`patient accrual patterns for negative phase II studies,
`ie, trials yielding a < 10% response rate. Even allowing
`for the histologic heterogeneity of certain primary sites
`such as lung, the extent of over accrual in some of these
`categories suggests the need for much earlier review of
`the data by investigators and a tighter system of con(cid:173)
`trol by the statistical offices of cooperative groups. In(cid:173)
`deed, several groups have already implemented proce-
`
`TABLE 3.-Activity of 11 NCr drugs in patients with breast cancel'
`(1975-1980)
`
`Drug
`
`Aclaru bicin
`
`Amsacrine
`
`Anguidine
`
`Acivicin
`
`Bisantrene
`
`Bruceantin
`
`Diaziquone
`
`Mitoguazone
`
`Mitoxantrone
`
`PCNU
`
`Piperazinedione
`
`No. of responding patientsl
`total evaluable
`
`Response
`rate (%)
`
`1148
`
`12/173
`
`1/37
`
`0115
`
`13/50
`
`0/15
`
`2/63
`
`41104
`
`16/182
`
`0/45
`
`3/47
`
`2
`
`7
`
`3
`
`0
`
`26
`
`0
`
`3
`
`4
`
`9
`
`0
`
`6
`
`TABLE 4.-Responses to mit.oxantrone in carcinoma of the breast trials
`according to previous treatment
`
`Response
`rate(%)
`
`No. of previous
`regimens
`
`3
`
`3
`
`2.6
`
`3
`
`3
`
`10
`
`5
`
`22
`
`21
`
`19
`
`Institution *
`SWOG
`
`SECSG
`
`ECOG
`
`M. D. Anderson Hospital
`and Tumor Institute
`
`Ohio State
`University
`
`EORTC
`
`o
`
`28
`
`The Royal Marsden
`Hospital
`* SWOG = Southwest Oncology Group; SECSG = Southeastern Cancer
`Study Group; ECOG = Eastern Cooperative Oncology Group; and EORTC
`= European Organization for Research on Treatment of Cancer.
`
`dures which should minimize the chances that patients
`will be entered in treatments already shown to be inac(cid:173)
`tive.
`
`Phase III
`
`Once the activity of a compound is established in one
`or more diseases, subsequent development of the drug
`proceeds along two separate lines. One of these lines is
`to establish the role of the drug in the disease for
`which activity was demonstrated. The endpoints of
`such studies, which are designed to compare the drug
`alone or in combination against standard treatment in
`a randomized fashion, are not only relative activity (eg,
`response rate), but also response duration, survival, and
`toxicity; the ultimate goal is to define the specific con(cid:173)
`tribution of the drug in the treatment of a particular
`cancer. The data from such trials may be used by
`pharmaceutic firms seeking New Drug Application
`(NDA) approval from the Food and Drug Administra(cid:173)
`tion (FDA) for marketing purposes.
`In this connection, the intense interest in chemical
`analogs of existing active agents poses special chal(cid:173)
`lenges to clinical drug development. Of 31 drugs devel(cid:173)
`oped by NCI since 1975, eight have been analogs of
`commercially available or experimental drugs. Until
`very recently, the development of analogs proceeded
`along essentially the same lines as that of novel struc(cid:173)
`tures. Formal prospective comparisons of analog versus
`parent were rarely carried out (28). As a result, little
`direct comparative data exist on the relative merits of
`the various bifunctional alkylating agents, nitrosoureas,
`anthracyclines, or epipodophyllotoxins.
`Surely, if parent and analog have borderline activity
`in a certain cancer, such direct comparisons are prob(cid:173)
`ably not worth undertaking. Moreover, when such com(cid:173)
`parison~ are worth doing, the trials need to be quite
`
`Vol. 68, No.1, January 1984
`
`81
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`NOVARTIS EXHIBIT 2050
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`

`
`TABLE 5.-Patient accrual onto negat.ive phase II st.udies using 13 compounds *
`
`Disease
`
`Breast cancel'
`
`Colon cancer
`
`Leukemia
`
`Lung cancel' (non-small cell)
`
`Lymphoma
`
`Total
`
`10
`
`9
`
`5
`
`15
`
`No. of studies
`
`< 25
`patients
`
`1(10%)
`
`2(22%)
`
`2(40%)
`
`2(13%)
`
`0
`
`25-50
`patients
`
`7(70%)
`
`6(66%)
`
`2(40%)
`
`6(40%)
`
`~ 50
`patients
`
`2 (20'Yc)
`
`1(11%)
`
`1(20%)
`
`7(47%)
`
`0
`
`Median
`No. of
`patients
`
`32
`
`31
`
`35
`
`45
`
`(31)
`
`8
`Melanoma
`* Aclarubicin, bisantrene, amsacrine, anguidine, acivicin, diaziquone, bruceantin, mitoxantrone, DON, mitoguazone, peNU,
`piperazinedione, and zinostatin.
`
`2(25%)
`
`5(62%)
`
`1(12%)
`
`35
`
`large, because multiple endpoints are involved. Also,
`since current analog programs, especially for platinum
`compounds and anthracyclines, are undertaken to ob(cid:173)
`viate major organ toxic effects, design of comparative
`trials must permit the simultaneous assessment of rela(cid:173)
`tive toxicity and efficacy. This task may be particularly
`difficult if one is dealing with equivalent degrees of
`efficacy in the presence of decreased toxicity. In such a
`case, the existence of reduced toxicity is medically im(cid:173)
`portant only if no material loss of efficacy has oc(cid:173)
`curred. Clearly, accrual should be large enough that
`such a conclusion can be drawn with reasonable power.
`Another significant problem with orderly analog de(cid:173)
`velopment is the current embarrassment of riches: ana(cid:173)
`logs are much easier to synthesize than to test compre(cid:173)
`hensively in the clinic. Accordingly, we now have a sit(cid:173)
`uation in which the number of worthy platinum com(cid:173)
`pounds, anthracyclines, and antifols may actually exceed
`our capacity for rigorous and comprehensive comparative
`trials.
`An example of the NCI's current strategy is the de(cid:173)
`velopment program for twq analogs of cisplatin, CHIP
`and carboplatin. The focus of their development is in
`cancers for which the parent compound is active, but
`not curative, such as carcinomas of the head and neck,
`uterine cervix, and bladder. In these disorders, random(cid:173)
`ized trials to compare the two analogs are initiated im(cid:173)
`mediately upon completion of phase I; the superior ana(cid:173)
`log is then to be compared to the parent compound. The
`trial design
`includes provisions for early stopping
`based on absence of efficacy. Nonrandomized phase II
`trials are implemented in diseases which are less sensi(cid:173)
`tive to cisplatin, such as non-small cell lung or colorec(cid:173)
`tal cancel'. The results of these trials will show whether
`the spectrum of activity with the analogs is extended
`significantly compared to the parent.
`It is also useful to consider within phase III the mul(cid:173)
`titude of exploratory studies that go on with a new
`agent after conclusion of phase II. These studies in(cid:173)
`clude: incorporation of the new drug into combina-
`
`tions, exploration of alternate routes of administration,
`and use of the agent in high doses accompanied by "res(cid:173)
`cue" procedures. Such studies, particularly the combina(cid:173)
`tion trials, constitute a large proportion of clinical
`research in cancer. It would certainly be churlish not to
`acknowledge the many advances that have come from
`such studies, including many of the crucial advances in
`medical oncology (2,3,5). Protec~ion of the kidneys
`from platinum-induced damage (13) and current efforts
`with intracavitary chemotherapy (29) and intra-arterial
`chemotherapy (30) are other examples of "post-phase
`II" drug development that either have been proved val(cid:173)
`uable already or appear particularly promising.
`However, it is equally clear that much of the work in
`phase III, particularly studies with drug combinations,
`has been disappointing in concept, design, or execution.
`Perhaps influenced by the success in certain leukemias
`and lymphomas, investigators have all too often at(cid:173)
`tempted to hit the home run against tumors which
`have repeatedly proven refractory to easy solutions.
`The vast clinical literature in most solid tumors bears
`witness to the inefficacy of this approach, at least with
`combinations of drugs having individually low complete
`response rates. At the end of such uncontrolled "pilot"
`studies, one is almost always left with efficacy and
`toxicity data having no clear point of reference. The
`true pilot study does exist, of course, and is an inval(cid:173)
`uable tool for testing the feasibility of an approach.
`Beyond the question of feasibility, however, a clinical
`trial is always comparative in intent, simply because
`there is always another way to treat the patient. There(cid:173)
`fore, the issue of a suitable control group will never go
`away, no matter how difficult or inconvenient it is to
`deal with. Whether the control group should always (ie,
`wherever possible) be selected by a random process or
`whether under certain circumstances nonrandomized
`controls can serve nearly as well is, in a sense, less im(cid:173)
`portant than the somewhat more basic notion that the
`use of an explicit control group must be much more
`pervasive and sophisticated than is now common prac(cid:173)
`tice.
`
`82
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`Cancer Treatment Reports
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`NOVARTIS EXHIBIT 2050
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`
`Coordination of the Process
`
`For many years, the NCI has been the single largest
`. contributor to all aspects of anticancer drug develop(cid:173)
`ment. Because of its multifaceted involvement (from
`organic
`synthesis and natural product screening
`through phase III clinical trials) and the sheer volume
`of its support for the total effort toward drug develop(cid:173)
`ment, the NCr has functioned, in effect, as the national
`coordinator of drug development in the US. In the
`past, the pharmaceutic industry has been less heavily
`involved in the development of antineoplastics than in
`other areas. Recently, however, with the growth of
`clinical oncology as a specialty and the far wider appli(cid:173)
`cation of chemotherapy in the treatment of cancer, the
`industry has dramatically increased its interest in
`cancer.
`At the outset, one must recognize that the goals of
`the NCI and pharmaceutic industry share an important
`common feature: to define the activity of a new agent
`and make it available to patients as expeditiously as
`possible. It is only in this way that the population at
`large will benefit maximally
`from
`the fruits of
`research. However, one must also recognize the consid(cid:173)
`erable differences
`in emphasis that the NCI and
`pharmaceutic industry often bring to this task. In its
`capacity as a financially disinterested supporter of
`basic and clinical research, the NCI wishes to see all
`reasonable steps taken to ensure that the therapeutic
`potential of a new agent is explored fully. By contrast,
`a pharmaceutic firm may be somewhat less inclined to
`support exploratory trials that have no direct role in
`securing an NDA for a new drug, and will strive to get
`a drug to market by the most direct and least costly
`route possible. Once a drug has been approved by the
`the company can deal with the question of
`FDA,
`whether to expand the indications in the postmarketing
`period or, as has been more often the case with anti(cid:173)
`neoplastic agents, whether to let the evolution of subse(cid:173)
`quent results work its own effects on the market.
`Obviously, the multiplicity of drug sponsors creates
`both opportunities and problems. The opportunities are
`clear enough: at a time when federal funds for re(cid:173)
`search are increasingly difficult to obtain, support from
`private sources is sorely needed. In addition, many
`pharmaceutic firms now have, in both basic and clinical
`areas, excellent professional staff with the competence
`to formulate and supervise comprehensive drug devel(cid:173)
`opment programs in cancel'.