V O L U M E 2 2 䡠 N U M B E R 2 2 䡠 N O V E M B E R 1 5 2 0 0 4
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`JOURNAL OF CLINICAL ONCOLOGY
`
`E D I T O R I A L
`
`Phase II Studies of Modern Drugs Directed
`Against New Targets: If You Are Fazed, Too,
`Then Resist RECIST
`
`Mark J. Ratain, University of Chicago, Chicago, IL; and S. Gail Eckhardt, University of Colorado, Denver, CO
`
`There is no question that the treatment of cancer 10
`years from now will be very different from that employed
`10 years ago. Are we at the beginning of a series of rapid
`breakthroughs, or are we making slow progress? Only
`time will tell. We have many new “druggable” targets,
`and maybe the results really will be different from the
`past, with major advances in the treatment of tradition-
`ally refractory malignancies.
`Let us first briefly recapitulate the history of anticancer
`agents, to understand that the more things change, the more
`they stay the same. The pharmacologic management of
`cancer can be traced back to the Manhattan Project (1945),
`with a number of
`laboratories developing alkylating
`agents.1,2 These were clearly targeted agents, directed to-
`ward alkylating DNA, albeit in a diffuse manner.
`The next drugs were the antimetabolites, including the
`antifols, such as methotrexate,3 and the purine and pyrim-
`idine analogs, such as 6-mercaptopurine and fluoroura-
`cil.4,5 Again, these drugs were clearly targeted against specific
`pathways and even specific enzymes, such as dihydrofolate
`reductase for methotrexate. Even then, we implicitly under-
`stood the concept of biomarkers, and myelosuppression was
`considered to be pharmacodynamic evidence of effects on the
`target—DNA.
`Now, approximately a half century (and hundreds of
`drugs) later, we are engrossed in a new era of oncology
`therapeutics, that many call “targeted therapies.” To para-
`phrase one perennially asked question, why are these drugs
`different from all other drugs? They are meant to be differ-
`ent because we believe that we can preferentially target the
`tumor rather than normal tissue. This belief is partially
`supportable, as particularly exemplified by the fantastic
`results achieved in chronic myelogenous leukemia with
`imatinib.6 The drugs are different because we have identi-
`
`fied new signaling pathways and tumor biology, which we
`must learn and understand. They are different because we
`can’t remember or spell the generic names. They are not
`different, however, in that we have always had targets, and
`we have generally known that we have hit a target (which
`may be different from the intended target). As one example,
`estramustine was developed as an estrogen-receptor targe-
`ted–alkylating agent. However, it was subsequently demon-
`strated to be an antimitotic agent with activity in prostate
`cancer independent of the estrogen receptor.7 Furthermore,
`we have demonstrated that targeted agents, both old and
`new, can exhibit mechanism-based effects on normal tissue
`(myelosuppression, skin rash, diarrhea) that may or may
`not be associated with a beneficial effect on the patient.
`With a plethora of new targets, we also have a plethora
`of new drugs and sponsors, some of whom only have one
`drug to develop. There is immense competition among
`companies for patient resources, particularly in the United
`States and Europe, though many investigators in Asia and
`South America are equally inundated with requests for tri-
`als. Thus, many sponsors and investigators have attempted
`to minimize the number of patients treated in early clinical
`trials because of concerns relating to imbalances in patient
`resources, and financial incentives to move quickly toward
`phase III trials.
`Phase I trials have become smaller, in large part because
`of the recognition that newer targeted agents are less toxic,
`and are therefore less likely to result in serious toxic effects.
`This has led to the widespread adaptation of a variety of
`accelerated titration designs, which have in common, ag-
`gressive dose escalations and small patient cohorts, in the ab-
`sence of toxicity.8 Such designs are very efficient for defining
`the maximum-tolerated dose, but are less useful for obtaining
`a full understanding of a new agent’s clinical pharmacology. In
`
`4442
`
`Journal of Clinical Oncology, Vol 22, No 22 (November 15), 2004: pp 4442-4445
`DOI: 10.1200/JCO.2004.07.960
`
`Downloaded from jco.ascopubs.org on April 4, 2016. For personal use only. No other uses without permission.
`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2104
`Par v. Novartis, IPR 2016-01479
`Page 1 of 4
`
`

`

`Editorial
`
`particular, smaller phase I studies do not often permit an
`analysis of pharmacokinetic-pharmacodynamic relationships,
`or the effects of doses well below the maximum-tolerated dose,
`which may have a better therapeutic index than higher doses.
`In our opinion, one of the biggest challenges in modern
`oncology drug development is phase II testing, which
`should be the primary indicator of antitumor efficacy. In
`the past, it was easy to prioritize agents for phase III trials
`based on their ability to induce objective tumor regression.
`However, a drug may be active without consistent achieve-
`ment of high-level tumor regression, as illustrated by the
`development of gefitinib, bevacizumab, and cetuximab—
`all agents that have definitive, but minimal, single-agent
`effects using traditional Response Evaluation Criteria in
`Solid Tumors (RECIST) criteria. This level of activity is
`considered more acceptable with agents that exhibit a rela-
`tively mild toxicity profile, and are administered over pro-
`longed periods. But what is the optimal phase II design for
`such agents? Can we really establish the activity of these
`agents with trial designs developed principally to detect a
`substantial rate of tumor regression?
`One approach that many companies have taken to
`avoid this problem is to rapidly proceed into phase III trials.
`Unfortunately, most that have utilized this approach have
`been disappointed, resulting in high profile failures, includ-
`ing matrix metalloproteinase inhibitors, farnesyl trans-
`ferase inhibitors, tyrosine kinase inhibitors, and antisense
`oligonucleotides. Interestingly, phase III trials in other ther-
`apeutic areas fail infrequently and are intended to confirm
`phase II findings rather than to refute activity altogether.
`These areas also routinely use randomized phase II trials,
`often evaluating a range of doses, including a placebo.9 Such
`trials can be designed to test readily ascertainable end
`points, such as time to progression, and can utilize cross-
`over or randomized discontinuation designs to enhance the
`attractiveness of the trial to patients and physicians. Ran-
`domized phase II studies can also address questions other
`than activity, such as biomarkers and pharmacokinetic-
`pharmacodynamic relationships.
`Will we find another imatinib anytime soon, or will we
`have to settle for drugs that have a more subtle effect, but are
`clearly active, such as the epidermal growth factor tyrosine
`kinase inhibitors (gefitinib and erlotinib) or the multiple
`new agents targeting the vascular endothelial growth factor
`pathway (eg, bevacizumab, SU11248, PTK787, sorafenib)?
`The key point is to understand the pharmacology of the
`agent and the expected effect of treatment so that the trial
`can be designed to detect that effect. If the anticipated
`outcome is significant tumor regression, then our stan-
`dard phase II designs are fine, though randomization
`across dose levels may be desirable, as was utilized for
`gefitinib and bevacizumab.10-12
`Overall, we need to be more flexible in our end points
`and our definitions of antitumor activity, as long as the
`
`effect is distinguishable from no treatment or a placebo.
`This is really an issue to be addressed in phase II, as a
`mechanism to avoid failures in phase III. The RECIST cri-
`teria for response (and its predecessors) were designed pri-
`marily for cytotoxic agents and are not applicable to all new
`agents.13 For example, these criteria do not consider dura-
`ble modest regressions or prolonged disease stability as
`activity, which we now know is an effect of several agents
`such as gefitinib, erlotinib, and bevacizumab. On the other
`hand, we should not rush to falsely define drugs as active on
`the basis of stable disease, since stable disease is a composite
`outcome consisting of inherent tumor growth kinetics and
`potential drug effect.
`This was the rationale for the randomized discontinu-
`ation trial design, which sought to differentiate drug effects
`from intrinsic growth patterns in patients with stable dis-
`ease, which has now been utilized for two new agents in
`patients with metastatic renal cell cancer.14,15 Another im-
`portant study was the randomized placebo-controlled
`dose-ranging study of bevacizumab in metastatic renal cell
`cancer, with cross-over at progression.12 The latter trial
`resulted in a very low response rate by RECIST criteria, but
`clearly demonstrated the potential activity of bevacizumab
`in this disease. The key point is that all of the above trials are
`much larger than the traditional single-arm phase II oncol-
`ogy trial, as larger sample sizes are necessary to obtain a
`more robust answer on which decisions about phase III
`trials may be based. Lastly, as has been recently illus-
`trated by the discovery of the association of somatic
`mutations in epidermal growth factor receptor (EGFR)
`with response to gefitinib, a clearer understanding of the
`target of agents may eventually lead to better patient
`selection and the ability to enhance clinical benefit, even
`when using traditional measures.16,17
`So, how do we manage this dilemma? As noted above,
`the clinical trial system is already stretched to its limit,
`particularly in the United States and Europe. If we are going
`to perform larger phase II trials, one approach is to do fewer
`of them, as illustrated by the study of CI-1040 by Rinehart et
`al18 in this issue.
`This study is novel because it does not follow the en-
`trenched dogma of phase II oncology trials of one protocol
`per disease site. This seems appropriate given the broad
`relevance of the MEK pathway to aberrant signaling in
`many cancers. The investigators could also have considered
`a waiver of restrictions on prior therapy, given that the
`investigational drug bears little resemblance to any mar-
`keted agent, with the exception of gefitinib.
`Although this study included patients with carcino-
`mas of four different organ sites, each was analyzed
`separately. Is organ site the most important determinant
`of response, or might it be a particular molecular lesion,
`such as EGFR-activating mutations? In trying to identify
`an active drug, is it most efficient to have broad or
`
`www.jco.org
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`4443
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`Downloaded from jco.ascopubs.org on April 4, 2016. For personal use only. No other uses without permission.
`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2104
`Par v. Novartis, IPR 2016-01479
`Page 2 of 4
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`

`

`Ratain and Eckhardt
`
`narrow eligibility criteria? The answer clearly depends on
`the hypothesized effect, leading to the specific design of
`the trial. But, if the hypothesized effect is a partial re-
`sponse, one could argue that the net should be tossed far
`and wide to demonstrate proof of activity.
`In the study by Rinehart et al,18 the hypothesized effect
`was either a partial response, or stable disease of at least 3
`months duration. No partial responses were observed,
`but stable disease was observed in eight patients. How-
`ever, it is not possible to ascertain from this uncontrolled
`trial whether the stable disease was the result of a drug
`effect or was due to the inherent growth characteristics of
`the disease.
`A significant concern regarding this study is the au-
`thors’ use of a modified Simon design, incorporating stable
`disease as a measurement of activity, when stable disease in
`a patient does not imply that the drug has activity.19 Specif-
`ically, the drug would be considered of no interest if there
`were five objective responses in 43 patients with a particular
`“disease,” even though that frequency of objective re-
`sponses would suggest that this agent was as active as other
`recently approved EGFR- and vascular endothelial growth
`factor–targeted agents, and worthy of phase III study. Con-
`versely, would we really believe the drug is active if there
`were 13 of 43 patients with stable disease, but no objective
`responses? We also would challenge the authors’ analysis
`relating pERK expression to stable disease. If we don’t know
`whether stable disease represents drug effect, why perform
`such a correlation? Clearly, the clinical benchmarking of
`gefitinib, cetuximab, and bevacizumab has indicated that,
`at some level, tumor regression continues to be a predictor
`of successful clinical development. As newer agents come
`along that may be of interest without anticipation of disease
`regression, we will certainly require well-controlled ran-
`domized phase II studies to minimize failure in phase III.
`What can we conclude? The authors have certainly
`demonstrated that multidisease phase II trials are feasible
`and efficient. They have also demonstrated that CI-1040 has
`an objective response rate of less than 5%, whereas any
`conclusions regarding whether or not the drug induces
`stable disease are suspect, due to the diverse diseases repre-
`sented in the eight patients and the lack of a control group.
`We also cannot draw any conclusions regarding pERK as a
`predictive marker for this or other MEK-targeted drugs,
`though this should be investigated in larger studies, but only
`when there is clear evidence of activity.
`What is the future of this agent? The authors imply
`that its development is being discontinued in favor
`of a more potent second-generation compound with
`the potential advantage of a decreased likelihood of
`mechanism-independent toxicities and drug interac-
`tions. It may also exhibit more favorable pharmacody-
`namics such as a longer duration of target inhibition.
`
`Thus, we would like to provide some advice to the
`sponsor, as well as to other sponsors and investigators who
`might read this editorial. First of all, carefully define your
`expectations for your compound. Do you expect objective
`responses (by RECIST criteria), minor responses, disease
`stabilization, or combinations of these? Then use a design
`appropriate to detect the expected effect in early clinical
`trials. This may mean that randomized phase II studies are
`required, which may provide substantive evidence of activ-
`ity, as well as information regarding optimal dose and
`schedule. Incorporation of readily obtainable biomarkers
`may also be useful. Most importantly, a well-conducted
`phase II trial should minimize the risk of failure in phase III.
`Incorporating expensive studies of predictive markers will
`probably not enhance your likelihood of detecting activity
`unless you are lucky enough to have both an active agent
`and an accurate assessment of the population most likely to
`respond. Alternatively, these studies can be deferred until
`after demonstration of activity, as was done for gefitinib.
`Reducing the risk of phase III oncology trials needs to
`be a goal of all concerned parties. In theory, a reduced risk in
`phase III should eventually lead to a greater incentive to
`develop oncology drugs, as well as a reduction in costs. In
`particular, sponsors with drugs in phase III trials without
`substantive proof of activity should be openly criticized, as
`they are ultimately increasing the long-term societal costs of
`oncology drugs.
`
`■ ■ ■
`
`Authors’ Disclosures of Potential
`Conflicts of Interest
`The following authors or their immediate family mem-
`bers have indicated a financial interest. No conflict exists for
`drugs or devices used in a study if they are not being evalu-
`ated as part of the investigation. Leadership Position: S. Gail
`Eckhardt, Pfizer, AstraZeneca. Consultant/Advisory Role:
`Mark J. Ratain, Genentech, Bristol-Myers Squibb, Novartis;
`S. Gail Eckhardt, Pfizer, AstraZeneca. Honoraria: Mark J.
`Ratain, Onyx Pharmaceuticals; S. Gail Eckhardt, Pfizer,
`AstraZeneca. Research Funding: Mark J. Ratain, OSI Phar-
`maceuticals, Bayer; S. Gail Eckhardt, Pfizer, AstraZeneca.
`Other Remuneration: Mark J. Ratain, Bayer. For a detailed
`description of these categories, or for more information
`about ASCO’s conflict of interest policy, please refer to the
`Author Disclosure Declaration form and the “Disclosures
`of Potential Conflicts of Interest” section of Information for
`Contributors found in the front of every issue.
`
`© 2004 by American Society of Clinical Oncology
`
`REFERENCES
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`Downloaded from jco.ascopubs.org on April 4, 2016. For personal use only. No other uses without permission.
`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2104
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`Downloaded from jco.ascopubs.org on April 4, 2016. For personal use only. No other uses without permission.
`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2104
`Par v. Novartis, IPR 2016-01479
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