Clinical Development of Anticancer Agents-A National
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`Perspective
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`Canc.~r Institute
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`Silvia Marsoni* and Robert Wittes 1
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`Since the first report that a chemical could cause sig(cid:173)
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`nificant tumor shrinkage (1), the development of clin(cid:173)
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`ically useful antineoplastic drugs has grown from the
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`preoccupation of a few investigators to a major interna(cid:173)
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`tional effort. Over the past 35 years or so, about 30
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`drugs have been defined as active in one or more tumor
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`types. When used alone in patients with disseminated
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`malignancy, these drugs cause reduction in bulk of
`measurable neoplasm in a significant percent of cases;
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`for most tumor types, however, ample evidence of re(cid:173)
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`sidual cancer usually persists and after a few months,
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`tumor regrowth occurs. More striking successes have
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`been achieved with combinations of drugs; as is well
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`known, for several kinds of disseminated human can(cid:173)
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`cers, a high frequency of clinical complete remissions,
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`with substantial long-term disease-free survival rates,
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`is now possible (2-5). For other cancers which may not
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`be curable by chemotherapy once they have disseminat(cid:173)
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`ed, combinations of drugs appear to result in a higher
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`total remission rate and a greater prolongation of life
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`than single drugs (6,7). Perhaps more significant in the
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`long run is the apparent effect of chemotherapy when
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`it is used as part of a planned multimodality effort
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`By some perverse quirk of fate, chemotherapy seems to
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`chiefly exert a major impact in rare tumors, while the
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`common epithelial neoplasms of adulthood have
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`thus far resisted satisfactory solutions. Therefore, the
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`central problem of drug development, the identification
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`of effective agents with reasonable therapeutic index,
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`is as pertinent for oncology now as at any time in the
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`past.
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`The idealized outlines of the successive steps in drug
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`development are familiar to all oncologists. In phase I
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`trials, we define a dose suitable for use in studies of
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`the drug's activity across a spectrum of human tumors.
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`Increasing awareness of the importance of patient- and
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`disease-related parameters has effectively led to the re(cid:173)
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`placement of the broad phase II trial with a series of
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`disease-oriented activity studies. Having defined set-
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`tings in which the new drug is active, investigators
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`then proceed to compare the new treatment with stand(cid:173)
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`ard therapy (phase III) and to further explore the
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`drug's therapeutic potential in other ways, such as in
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`combination with other agents or by alternate rouies of
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`administration.
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`Anyone familiar with the actual workings of this
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`process over the past two decades knows that despite
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`its successes, it has not functioned as systematically or
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`efficiently as the above description might imply. In ad(cid:173)
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`dition, many of the assumptions on which the process
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`was based are in need of re-examination. Since there
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`are no
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`for specific human cancers, drug development will con(cid:173)
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`tinue to require extensive testing in human subjects, an
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`endeavor that is never without ethical dilemmas, how(cid:173)
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`ever thoughtfully it is carried out. In addition, because
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`human cancers vary widely in sensitivity to anticancer
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`drugs, the apparatus required to sustain the clinical
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`trials effort is necessarily large and very expensive. For
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`these reasons alone, another look at the drug develop(cid:173)
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`ment program of the National Cancer Institute (NCI)
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`seems to be worthwhile.
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`Phase I
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`Phase I trials of antineoplastic compounds are con(cid:173)
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`ducted in patients with disseminated malignancies for
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`whom standard treatment either does not exist or has
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`proved ineffective. Drugs are given in a phase I trial
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`with therapeutic intent; the main scientific goal is to
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`define the qualitative and quantitative characteristics
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`of the drug's acute toxicity, and in so doing, to deter(cid:173)
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`mine a biologically active dose which is tolerable for ev(cid:173)
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`ery patient. The maximum tolerated dose (MTD) is
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`usually higher in children than in adults (10), probably
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`because of better organ function and possibly because
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`of different pharmacokinetics (11,12). Also, since the
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`MTD for patients with acute leukemia is often substan(cid:173)
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`tially higher than that for solid tumors, at least four
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`ICancer Therapy Evaluation Program, Division of Cancer Treatment,
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`National Cancer Institute, Bethesda, MD.
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`• Reprint requests to: Silvia Marsoni, MD, Drug Evaluation and Re-
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`portingiSection, Investigational Drug Branch, Cancer Therapy Evaluation
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`Program, National Cancer Institute, Landow Bldg, Rm 4C09, 7910 Wood·
`mont Ave, National Institutes of Health, Bethesda, MD 20814.
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`Cancer Treatment Reports Vol. 68, No.1, January 1984
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`77
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`NOVARTIS EXHIBIT 2047
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 9
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`phase I trials should be conducted for each drug. In
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`practice, of course, three to four phase I trials testing
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`different schedules of the drug are usually performed
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`in adult patients with solid tumor alone, and trials in
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`children do not start until substantial experience is ac(cid:173)
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`cumulated from the adult trials.
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`The assumption underly~ng all phase I escalation pro(cid:173)
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`cedures is that anticancer compounds must be given at
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`or near the MTD; therefore, the job of a phase I trial is
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`to define the highest dose that can be safely delivered
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`to a patient, since this dose will also be the one that
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`has the best chance of being active. This approach re(cid:173)
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`flects the difficulties in establishing a clear-cut measur(cid:173)
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`able endpoint for drug activity against cancel'. Since
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`induction of response is not usually an event that is im(cid:173)
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`mediately recognizable, attainment of toxicity is the
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`only assurance that, if a response is not obtained, at
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`least a biologically active dose was delivered. Underly(cid:173)
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`ing this assumption is the more fundamental one that
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`the dose-response curve for human cancers is monoton(cid:173)
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`ically increasing throughout the range of tolerated
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`doses and is to the right of the dose-toxicity curve.
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`Needless to say, the details of this assumption have not
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`been generally verified for antitumor agents, chiefly
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`because rigorously defining the shape of a clinical dose(cid:173)
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`response curve is a laborious task, requiring a large
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`number of patients treated at each of several dose lev(cid:173)
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`els. Where the relationship between dose and response
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`has been examined, however, most of the data are at
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`least consistent with the conclusion that the higher the
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`administered dose, the more probable an antitumor ef(cid:173)
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`fect (13-17) or the longer the duration of remission
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`(18). On the other hand, recent trials in small cell lung
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`cancer suggest that the probability of response does
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`not continue to increase linearly as the dose approaches
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`the MTD (19).
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`For most of the clinically useful compounds, the bone
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`marrow is dose-limiting. The dose-toxicity curve for
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`myelosuppression is quite reproducible, and the status
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`of marrow reserve is the major source of interpatient
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`variabilit.y. Generally, tl'eatment of six to ten patients
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`at 01' neal' the MTD is sufficient to establish a safe
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`phase II dose when myelosuppression is the dose-limit_
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`ing toxicity.
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`However, major problems may arise when other toxic
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`ing. For example, in a phase I study of escalating doses
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`of carmustine with autologous bone marrow support
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`(20), major organ toxicity (liver, central nervous system
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`and lung) surfaced abruptly at a dose of 1500 mg/mZ:
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`Because of
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`effects in the escalation scheme and the long interval
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`from. the beginning of treatment to onset of toxicity
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`(6-9 weeks), the overall mortality rate for patients en(cid:173)
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`tered at a dose of ~ 1500 mg/m2 was approximately
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`30%.
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`Experience suggests that whenever a drug has dose(cid:173)
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`limiting side effects other than myelosuppression, its
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`transition into phase II has often been compromised.
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`An analysis of 31 drugs entered in phase I evaluation
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`by the NCr shows that whenever the drug had myelo(cid:173)
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`suppression alone as the dose-limiting toxicity, it had a
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`high probability of undergoing full phase II study; how(cid:173)
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`ever, when other organ toxicity was dose-limiting, only
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`25% of the drugs proceeded to full phase II study (ta(cid:173)
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`ble i). Evaluation of the remainder of drugs was re(cid:173)
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`stricted by either the NCI or lack of investigator inter(cid:173)
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`est. The main reason for these difficulties relates large(cid:173)
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`ly to the uncertainty regarding reversibility of acute
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`major organ damage. In addition, even if organ damage
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`should turn out to be reversible, medical support dur(cid:173)
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`ing periods of severe organ failure is either extremely
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`intensive and costly (kidney, CNS) or technically unsat(cid:173)
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`isfactory (liver), and is not seen as feasible or justifia(cid:173)
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`ble by most investigators in the context of a clinical ex(cid:173)
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`periment.
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`TABLE l.-Phase II evaluation as a function of the dose-limiting toxicity of 31 cytotoxic compounds (1975-1982)
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`Phase II
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`evaluation
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`Full
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`Restricted
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`Dl'Opped
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`Toxicity
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`No interest
`No drug supply
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`Myelosu ppression *
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`10
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`0
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`0
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`Dose-limiting toxicity
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`Myelosuppression
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`and organ toxicityt
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`0
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`Organ
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`toxicity*
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`3
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`4
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`Total
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`12
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`12
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`* Bisantrene, diaziquone, aclarubicin (aclacinomycin), mitoxantrone, PCNU, amsacrine, zOl'ubicin, chlorozotocin,
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`carboplatin, ICRF 187, 5-methyltetrahydrohomofolate, and 3-deazauridine.
`t Acivicin, maytansine, anguidine, tel'oxirone, dihydl'o-5-azacitidine, indicineN-oxide, and DON.
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`*Pyrazofurin, L-alanosine, homoharringtonine, TCN-P, N-methyifol'mamide, pentostatin, hycanthone, dichloroal(cid:173)
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`lyllawsone, pyrazole, aminothiadiazole, bruceantin, and spirogermanium.
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`78
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`Cancer Treatment Reports
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`NOVARTIS EXHIBIT 2047
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 9
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`This dilemma appears to have no easy solutions. One
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`alternative might be to utilize data from pharmacologic
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`studies to define the relationship between dose, plasma
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`level, tissue level, and clinical activity. For example, in
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`the case of pentostatin, knowledge concerning the
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`amount of drug needed to abolish activity of the target
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`enzyme adenosine deaminase has helped to establish a
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`phase II dose independent of the attainment of clinical
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`toxicity. Unfortunately, however, this is an exceptional
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`situation and, under most circumstances, specific intra(cid:173)
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`cellular targets of drug action either have not been
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`identified or are not so susceptible to analysis.
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`A somewhat more empiric approach is exemplified by
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`the current plans for developing N-methylformamide, a
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`drug which had been introduced into the clinic in the
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`1950s and was subsequently dropped while in phase I
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`because of hepatotoxicity (21). Interest in the drug has
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`recently been revived because of its activity against hu(cid:173)
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`man tumor xenografts (22) and its capacity to induce
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`differentiation in vitro (23). Phase I trials in both the
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`United Kingdom and the US confirm that, at a dose of
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`1000 mg/m2, the reversible hepatotoxicity of N-methyl(cid:173)
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`formamide is dose-limiting and myelosuppression is
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`completely absent.2•3 This dose has been defined, as the
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`ity is observed in any tumor type, a repeat phase II
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`study in one or more susceptible tumors will be per(cid:173)
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`procedure will define whether the attainment of toxic(cid:173)
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`ity is necessary for activity.
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`Phase II
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`tivity of the drug in a variety of disseminated malig(cid:173)
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`nancies and to further define the patterns of acute
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`toxicity in patients who are homogeneous in diagnosis
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`and in better general medical condition than patients in
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`during phase II, rarer acute toxic effects often surface
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`tients, phase II provides an appropriate setting for ini(cid:173)
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`tial assessment of chronic toxic effects.
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`Several vexing problems are inherent in this process.
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`In the first place, since patient numbers and resources
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`are finite, it is impossible to explore the activity of
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`each drug in each tumor type. A method must be found
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`to focus the effort of drug development in a way that
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`will minimize the chance of overlooking active agents.
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`Accordingly, the NCr decided to evaluate all experi-
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`2McVie JG, ten Bokkel Huinink WW, Simonetti G, et al. Phase I trial of
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`N-methylformamide (NSC 3051) (NMF). Manuscript submitted to Cancel'
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`Treatment Reports,
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`"Minutes of the Phase I Working Group Meeting, NCl, Bethesda, MD,
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`July 1983,
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`mental drugs in selected types of cancer. The NCT
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`Human Tumor Panel was created in 1975 and included
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`lung, colon, and breast carcinomas, and lymphoma, leu(cid:173)
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`kemia, and melanoma. The original intention was to
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`match tumors in the human panel with those in the
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`preclinical panel, thereby providing information for the
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`validation of the preclinical screening program. In addi(cid:173)
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`tion, these classes of human cancel' represent the two
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`extremes of chemotherapy sensitivity and might be ex(cid:173)
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`pected to exhibit, both high sensitivity and high selec(cid:173)
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`tivity. Finally, the inclusion of the most common
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`causes of cancer deaths (breast, colon, and lung can(cid:173)
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`cers) permits the study of large numbers of patients
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`and assures that results will have immediate implica(cid:173)
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`tions for the treatment of prevalent cancers. Needless
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`to say, evaluation of individual drugs is also carried out
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`in tumors other than those in the panel, particularly if
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`there is a specific reason to do so. For example, dia(cid:173)
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`ziquone was chemically designed to cross the blood(cid:173)
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`brain barrier and therefore has been extensively eval(cid:173)
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`uated in brain tumors with encouraging results.
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`How has activity in the prelinical panel correlated
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`with clinical activity? Thus far, we have analyzed the
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`results with 13 experimental drugs for which clinical
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`and experimental data are available. The correlation of
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`activity in each model tumor system with activity in
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`the corresponding human cancer is shown in figure 1.
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`Prediction of true-negative results (resistance) seems
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`fairly reliable across most of the rodent and xenograft
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`systems. On the other hand, the probability of predicting
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`true-positive results (sensitivity)
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`low. Be(cid:173)
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`cause of the small number of active drugs in humans
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`for which complete data are available, no definitive
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`conclusions can be drawn. However, even if the pre(cid:173)
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`clinical panel should not turn out to be an accurate pre(cid:173)
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`dictor of response in individual tumor types, overall ac(cid:173)
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`tivity in prelinical screening may still serve as a gen(cid:173)
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`eral predictor of activity in at least one human cancer.
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`The aggregated data are, in fact, consistent with this
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`notion. This has obviously been the general premise on
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`which antitumor screening programs have operated for
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`years. Its validity has been widely assumed but has not
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`been subjected to direct test, since drugs are not
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`brought to the clinic if screening data are not positive.
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`An assessment of the validity of the assumption will be
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`afforded by the use of the human tumor stem cell
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`assay as a screening tool. The plans are to bring
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`selected compounds which are positive in the human
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`tumor stem cell assay to clinical trial, even if they are
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`negative in the P388 prescreen (26). Obviously, more
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`data are needed to determine the ultimate usefulness of
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`How has the human panel fared as a predictor of
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`clinical efficacy in human tumors other than those of
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`the panel? Since 1971, 62 cytotoxic agents have been
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`introduced into clinical trials under the sponsorship of
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`Vol. 68, No.1, January 1984
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`79
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`NOVARTIS EXHIBIT 2047
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 9
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`CX-1sc
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`Colon xenogra fts
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`Colon 38
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`1
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`Anguidine, Pyrazofurin, Maytansine, Chlorozotocin,
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`Deazauridine, Rubidazone, PALA, Amsacrine
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`LX-1SC
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`1 ung xenografts
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`3LL
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`Lewi slung carei noma
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`Anguidine, Pyrazofurin, Maytansine, Chlorozotocin,
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`PALA, Amsacri ne, DON
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`816
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`melanoma
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`L1210
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`1 eukemi a
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`Angui di ne, Pyrazofuri n,
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`Rubi dazone, PALA,
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`Amsac ri ne, DON
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`Thymidine, Aclacinomycin
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`Anguidine, Chlorozotocin'
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`Deazauri di ne, Rubi dazone'
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`Indicine N-Oxide,
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`Amsacri ne, Pyrazofuri n
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`MX-l SC
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`breast xenografts
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`CDaFl
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`mammary carci noma
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`1
`1 + 1
`b -1- - -I-----r-
`r + 1 0 1 1 1
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`1
`1
`t
`1
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`Anguidine, Pyrazofurin, Maytansine, Bruceantin, PALA,
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`Amsacri ne, Mitoxantrone, Chlorolotocin
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`FIGURE l.-Correlation of activity of 10 antitumor agents in murine model tumor systems with activity in human cancer. Activity in murine tumors was
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`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)
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`sponse rate in at least 1 clinical trial with" 14 evaluahle patients.
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`NCI. Results of an interim analysis of phase II results
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`are available for 13 drugs, which were studied in 180
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`protocols (table 2). Although these data represent only
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`a fraction of the large NCI experieuce, certain trends
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`are apparent. First, significant activity of ~ 20% was
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`seen only in the lymphomas, leukemia, and breast
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`carcinoma (50%, 29%, and 14% of the studies, respec(cid:173)
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`tively); most of the results were in the 20%-30% range.
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`No drug showed> 20% activity in colon carcinoma and
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`melanoma, and only 6% of the lung cancer trials showed
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`positive activity. Even with only those drugs which have
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`shown activity in at least one tumor type, the overall re(cid:173)
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`sponse rate in colon and lung cancers and melanomas is
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`still consistently < 10%.
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`It is well known that colon cancer and melanoma are
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`highly resistant diseases, and that these diseases which
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`are consistently refractory to all therapies are of no
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`value in screening. Although more data are needed, the
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`results to date suggest that inclusion of colon cancer
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`and melanoma in the panel may not be useful for
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`screening. However, it would seem reasonable to con(cid:173)
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`tinue testing new agents for activity in those common
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`and refractory neoplasms until truly reliable screens
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`for activity have been defined. Such screens may
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`emerge from further analysis of data for clinical trials
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`or from advances in the use of in vitro or in vivo lab(cid:173)
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`oratory methods.
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`Second, even in intrinsically sensitive diseases like
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`TABLE 2.-0utcome of phase II studies in human cancer
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`Total No.
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`of studies
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`30
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`38
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`21
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`47
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`18
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`26
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`180
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`0%
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`13(43%)
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`25(66%)
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`6(29%)
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`27(57%)
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`4(22%)
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`16(62%)
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`91 (51%)
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`Response ra te
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`< 20%
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`13(43%)
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`13(34%)
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`9(48%)
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`17 (36%)
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`5(28%)
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`10(38%)
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`67(37%)
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`;;'·20%
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`4(14%)
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`0
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`6(29%)
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`3(6%)
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`9(50%)
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`0
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`22(12%)
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`Disease
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`Breast cancer
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`Colon cancer
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`Leukemia
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`Lung cancer
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`Lymphoma
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`Melanoma
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`Total
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`80
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`Cancer Treatment Reports
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`NOVARTIS EXHIBIT 2047
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 9
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`

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`breast or small cell lung cancer, the number of drugs
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`showing activity turned out to be very small. As seen
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`in table 3, of the 11 drugs considered in breast cancer,
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`only bisantrene showed an overall response rate of
`> 20%. As has been true throughout the history of
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`medical oncology (27), the estimates of activity vary
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`widely from trial to trial. For example, with mitoxan(cid:173)
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`trone, response rates ranged from 5% to 28%. This ob(cid:173)
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`serv~tion suggests the well-known importance of fac(cid:173)
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`tors. other than drug dose and schedule as major influ(cid:173)
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`ences on estimates of response rate. Again, for mitoxan(cid:173)
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`trone, the deleterious effect of prior therapy on response
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`seems to be fairly clear (table 4).
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`In fact, the success of the human tumor panel in pre(cid:173)
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`dicting (or ruling out) general patterns of efficacy for
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`other human cancers will depend to a large extent on
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`what kinds of patients with "panel cancers" are chosen
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`for entry in the study. A negative trial of a new drug
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`in 20 patients with breast cancer who have failed mul(cid:173)
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`tiple prior regimens tells us nothing about either the
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`potential of this drug in a more favorable breast cancer
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`population or drug activity in other tumors. Moreover,
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`data from earlier eras of cancer chemotherapy cannot
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`be used reliably to decide which tumors may be use(cid:173)
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`fully included in a panel without extensive consider(cid:173)
`ation of how shifting patterns of practice may have al(cid:173)
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`tered important patient characteristics.
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`The phase II effort also needs certain administrative
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`refinements. Table 5 shows a breakdown by disease of
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`patient accrual patterns for negative phase II studies,
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`ie, trials yielding a < 10% response rate. Even allowing
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`for the histologic heterogeneity of certain primary sites
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`such as lung, the extent of over accrual in some of these
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`categories suggests the need for much earlier review of
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`the data by investigators and a tighter system of con(cid:173)
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`
`
`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
`
`
`1137
`
`
`0115
`
`
`13/50
`
`
`0115
`
`
`2/63
`
`
`41104
`
`
`16/182
`
`
`0145
`
`
`3/47
`
`
`2
`
`
`
`
`
`
`
`
`26
`o
`
`
`
`
`
`
`9
`o
`
`
`6
`
`
`
`
`
`
`
`
`
`
`
`TABLE 4.-Responses to mit.oxantrone in carcinoma of the breast trials
`according to previous treatment
`
`
`
`
`
`Response
`
`
`rate(%)
`
`No. of previous
`
`
`
`regimens
`
`
`
`
`
`
`
`2.6
`
`
`
`
`
`10
`
`
`
`
`
`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
`
`
`NOVARTIS EXHIBIT 2047
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 9
`
`

`

`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
`
`Melanoma
`
`
`
`
`
`No. of studies
`
`
`< 25
`
`
`patients
`
`
`1(10%)
`
`
`2(22%)
`
`
`2(40%)
`
`
`2(13%)
`
`
`
`
`25-50
`
`patients
`
`
`7(70%)
`
`
`6(66%)
`
`
`2(40%)
`
`
`6(40%)
`
`
`
`
`2(25%)
`
`
`5(62%)
`
`
`
`~ 50
`
`patients
`
`
`2 (20'Yc)
`
`
`1(11%)
`
`
`1(20%)
`
`
`7(47%)
`
`
`0
`
`
`
`1(12%)
`
`
`Median
`
`No. of
`
`patients
`
`
`32
`
`31
`
`
`
`35
`
`
`45
`
`
`(31)
`
`
`35
`
`
`Total
`
`
`10
`
`
`9
`
`
`15
`
`
`
`
`
`
`* Aclarubicin, bisantrene, amsacrine, anguidine, acivicin, diaziquone, bruceantin, mitoxantrone, DON, mitoguazone, peNU,
`
`
`
`
`
`
`
`
`
`
`
`
`
`piperazinedione, and zinostatin.
`
`
`
`
`
`
`
`
`
`
`
`
`large, because multiple endpoints are involved. Also,
`
`
`
`
`
`
`
`since current analog programs, especiall