Eligibility and Response Guidelines for Phase II Clinical
`Trials in Androgen-Independent Prostate Cancer:
`Recommendations From the Prostate-Specific Antigen
`Working Group
`
`By Glenn J. Bubley, Michael Carducci, William Dahut, Nancy Dawson, Danai Daliani, Mario Eisenberger,
`William D. Figg, Boris Freidlin, Susan Halabi, Gary Hudes, Maha Hussain, Richard Kaplan, Charles Myers, William Oh,
`Daniel P. Petrylak, Eddie Reed, Bruce Roth, Oliver Sartor, Howard Scher, Jonathan Simons, Vickie Sinibaldi, Eric J. Small,
`Matthew R. Smith, Donald L. Trump, Robin Vollmer, and George Wilding
`
`Purpose: Prostate-specific antigen (PSA) is a glyco-
`protein that is found almost exclusively in normal and
`neoplastic prostate cells. For patients with metastatic
`disease, changes in PSA will often antedate changesin
`bonescan. Furthermore, many butnotall investigators
`have observed an association between a decline in PSA
`levels of 50% or greater and survival. Since the majority
`of phaseII clinical trials for patients with androgen-
`independent prostate cancer (AIPC) have used PSA as a
`marker, we believed it was important for investigators
`fo agree on definitions and values for a minimum set of
`parameters foreligibility and PSA declines and to de-
`velop a common approach to outcome analysis and
`reporting. We held a consensus conference with 26
`leading investigatorsin the field of AIPC to define these
`parameters.
`Result: Wedefined four patient groups: (1) progres-
`sive measurable disease, (2) progressive bone metasta-
`sis, (3) stable metastases and a rising PSA, and (4) rising
`PSA and noother evidence of metastatic disease. The
`
`purpose of determining the numberof patients whose
`PSAlevel drops in a phase II trial of AIPC is to guide the
`selection of agents for further testing and phase Ill
`trials. We propose that investigators report at a mini-
`mum a PSA decline. of at least 50% and this must be
`confirmed by a second PSA value 4 or more weekslater,
`Patients may not demonstrateclinical or radiographic
`evidence of disease progression duringthis time period.
`Someinvestigators may want fo report additional mea-
`sures of PSA changes(ie, 75% decline, 90% decline).
`Response duration and the time to PSA progression may
`also be importantclinical end point.
`Conclusion: Through this consensus conference, we
`believe we have developed practical guidelines for
`using PSA as a measurement of outcome. Furthermore,
`the use of commonstandardsis important as we deter-
`mine which agents should progress to randomizedtrials
`whichwill use survival as an end point.
`J Clin Oncol 17:3461~-3467,
`1999 by American
`Society ofClinical Oncology.
`
`DASESDEDLTSESSESELIEETREBOSPEEDORENEVESSTAREENSESSSTETEESEAREISTELOS
`
`
`
`~
`
`ROSTATE CANCER IS THE most commonly diag-
`nosed malignancy among males in the U.S. and the
`second leading cause of cancer-related mortality.
`It
`is
`estimated that 39,000 men will die of prostate cancer in
`1999.' Androgen ablation has been the cornerstone for the
`treatment of metastatic disease for more than 50 years,” but
`ultimately, almost all patients with distant metastasis will
`develop androgen-independent cancer and succumbtotheir
`disease. In addition, no therapeutic regimen has been shown
`to prolong survival
`in this setting.? The difficulties in
`determining the activity of new agents
`in androgen-
`independent prostate cancer (AIPC) are well documented
`(especially the slow resolution of bone lesions on bone
`scan). Mostpatients have disease limited to the bone, which
`is notoriously difficult to assess for response, with a small
`subset having soft tissue lesions. To limit trials to only
`patients with bidimensionally measurable disease would
`eliminate 70% to 80% of patients who would otherwise be
`eligible. Lack of consensus on responsecriteria further
`complicates the evaluation of new treatments. A review of
`recently completed trials suggest
`that, even within one
`
` i
`
`y&E: Q| B
`
`
`
`there is a wide variation in both the
`cooperative group,
`eligibility and response criteria used (N. Dawson, personal
`communication, February, 1999), These differences can
`impede the development of new agents (or regimens) and
`hinder the comparison between therapies,
`
`From the Beth Israel Deaconess Medical Cenier, Dana Farber
`Cancer Center, and Massachusetts General Hospital, Boston, MA;
`Johns Hopkins University, Baltimore, MD, National Cancer Institute,
`Bethesda, MD, University ofMaryland, Baltimore, MD, MD Anderson
`Cancer Center, Houston, TX, Duke University, Durham, NC, Fox Chase
`Cancer Center, Philadelphia, PA, Wayne State University, Detroit, Ml,
`University of Virginia, Charlottesville, VA, Columbia University, New
`York, NY, Vanderbilt University, Louisiana State Medical Center. New
`Orleans, LA, Memorial Sloan Kettering Cancer Center, New York, NY,
`University of California at San Francisco, San Francisco, CA, Massa-
`chusetts General Hospital, Boston, MA, University of Pittsburgh,
`Pittsburgh, PA, and University of Wisconsin, Madison, WI.
`SubmittedApril 19, 1999; acceptedAugust3, 1999,
`Address reprint requests to William D. Figg, PharmD, Bldg 10, Room
`SAOI, Medicine Branch, National Cancer Institute, 9000 Rockville
`Pike, Bethesda, MD 20892; email wdfigg@helix.nih.gov.
`1999 by American Society ofClinical Oncology.
`0732-183X/99/1711-3461
`
`Journalof Clinical Oncology, Vol 17, No 11 (November), 1999: pp 3461-3467
`
`346]
`
`Information downloaded from jco.ascopubs.org and provided by at CadmusArticleWorks on August 3, 2016 from 65.196.76.98
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`JANSSEN EXHIBIT 2057
`Mylan v. Janssen IPR2016-01332
`
`JANSSEN EXHIBIT 2057
`Mylan v. Janssen IPR2016-01332
`
`

`

`3462
`
`BUBLEY ET AL
`
`Prostate-specific antigen (PSA) is a 34 kD glycoprotein
`that is found almost exclusively in normal and neoplastic
`prostate cells and seminal fluid.>-8 Changes in PSA will often
`antedate changes on bonescan, andits use could theoreti-
`cally permit new agents to be screened more rapidly for
`activity.2"!! In 1989, Ferro et al'* werethefirst to report PSA
`changesas an indicator of responsein patients enrolled onto
`a trial for AIPC. Since then, the majority of phase II trials
`have used PSA as a marker.!3-!5 However, some of the data
`currently available suggests that serum PSA cannotserve as
`a reliable surrogate end point.!+-!” Indeed, clinical experi-
`ence has provided somesettings in which PSA changes and
`“hard” end points, such as survival, were demonstrated not
`to correspond.!!)!8 The use of PSA as a surrogate for benefit
`would require specific validation for the clinical setting and
`agents underinvestigation.
`Published data lend support to the assumption that, for
`many agents, a decline in serum PSA may be a useful
`indicator of outcome in AIPC. This has been put forward by
`several groups as a potential outcome measure for survival
`in patients with AIPC.'+!7!9 Approximately 95% ofpatients
`with advanced metastatic cancer of the prostate have an
`elevated PSA.* Several
`investigators have attempted to
`correlate a decrease in PSA with clinical benefit and
`survival. !4-!7.1920 Most have noted that a posttherapy decline
`of 50% has been associated with a prolonged survival. Kelly
`et al!® reporteda statistically significant survival advantage
`in 110 patients if they had a posttherapy decline in PSA of
`50% as opposed to those who did not (8.6 months v >25
`months, respectively). Likewise, Smith et al!* reported a
`significant increase in survival if the PSA decreased by 50%
`or greater at 8 weeks (median survival from a landmark
`analysis was 91 weeks in patients with a 50% or greater
`decrease v 38 weeks in those without this decrease), More
`recently, Scher et al!’ reported a multivariate analysis in
`which a posttherapy decline in PSA level of 50% achievedat
`both 8 and 12 weeks was a statistically significant factor
`associated with survival.
`For the purpose of this discussion, we assume that
`guidelines can be established under which serum PSA can
`play a valuable role in pilot studies of new therapeutic
`approachesin androgen-independentdisease purely as a tool
`for determining which approaches warrant selection for
`moredefinitive testing. The only underlying assumptions are
`that observed major decreases in PSA in association with a
`new treatment imply some biologic effect that encourages
`further evaluation and that lack of effect on an increasing
`PSAis likely to indicate an approachoflittle interest (unless
`preclinical testing has suggested the likelihood of a confound-
`ing effect on PSA gene expression, synthesis, or release).
`Usedin this way, no assumption or claimsof clinical benefit
`
`can or should be made; however, screening of new therapies
`could proceed much more quickly, and a larger number of
`patients would have the opportunity to participate in clinical
`research.
`
`To use PSA mosteffectively, investigators must agree on
`definitions and values for a minimal set of parameters such
`as eligibility criteria, criteria for PSA response, and ap-
`proach to outcomeanalysis and reporting. For manyof these
`criteria, existing data does not permit an unequivocal determi-
`nationof the “right” approach, but use of serum PSAforthe
`limited purpose does not require that we begin with vali-
`dated surrogacy data. All that is requiredis that investigators
`agree to use somestandardizedcriteria, which can and should be
`updated as better data becomeavailable. In addition, these
`criteria for PSA response may require future validation.
`
`Standardization of Terms
`
`Unfortunately, even among investigators who have re-
`ported a decline in serum PSA as an end point, there is no
`consistency in how a PSA decline is measured and reported.
`Moreover, divergent criteria for treatment eligibility have
`been used. Trials have required different minimum PSA
`values and different criteria for biochemical progression
`after a previous treatment. In fact, a survey published in
`1998 reported that among 35 leading investigators in the
`field, the response duration for a hypothetical patient varied
`by as much as 77 days (range, 49 to 126 days) because of
`differences in the calculation of response.?! These data
`emphasize the need to standardize eligibility and response
`criteria to advancethe field and develop new therapies.
`
`EFFECT OF DRUGS ON PSA EXPRESSION
`
`to recognize that some agents may
`important
`is
`It
`modulate PSA (either up- or downregulation) independent
`of their effect on cell growth.?? The majority of those agents
`identified to date are not conventional cytotoxic agents. It is
`also important to emphasize that the models currently used
`to evaluate these changes have not been validated. Nonethe-
`less, we would recommend that attempts be made to
`prospectively evaluate the effects of novel anticancer agents
`on PSA as an aid to interpreting clinical studies using PSA as
`an end point. For example, a phaseII clinicaltrial in patients
`with AIPC was conducted using carboxyamido-triazole
`inhibitor, an agent that had been shown to downregulate the
`expression of PSA,'8?3 Therefore, the trial was limited to
`those with measurable soft tissue lesions. A large percent of
`patients were found to have decreases in their PSA,but their
`soft tissue lesions continued to grow, as demonstrated by
`serial
`radiographic studies.!® These data emphasize the
`importance of understanding the effect of new agents on
`PSAexpression.
`
`Information downloaded from jco.ascopubs.org and provided by at Cadmus ArticleWorks on August 3, 2016 from 65.196.76.98
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`|ii
`
`
`
`OTITIS
`
`

`

`PSA IN ANDROGEN INDEPENDENT PROSTATE CANCER
`
`3463
`
`RECOMMENDATIONSFORELIGIBILITY CRITERIA
`
`For the purpose of this discussion, we have defined four
`groups of patients: 1) progressive measurable disease, 2)
`progressive bone metastasis, 3) stable metastases and an
`increasing PSA, and 4)
`increasing PSA and no other
`evidence of metastatic disease. Although performancesta-
`tus, weight change, and pain may be valid eligibility and
`response criteria for some clinical studies,
`they are not
`addressed in this manuscript.
`
`Progressive Disease
`
`
`
`e
`
`°
`
`°
`
`e
`
`#2
`
`A
`‘
`#1
`reference
`value
`
`L__]]
`2 1 week
`
`PSA progression. An increasing PSA, in some patients,
`may be the only evidence of progressive disease. Investiga-
`tors have defined PSA progression in a variety of different
`ways, with variability concerning the amount of increase,
`number of required consecutive increasing values, and the
`time interval between the values. There is a theoretical
`conflict between easing requirements to allow morepatients
`on phaseIJ trials and using morestringent criteria for better
`accuracy in selecting which drug will undergo phase III
`testing. There are no randomized data that one can use to
`define PSA progression, so all criteria are somewhat arbi-
`trary.
`Patients who are entered onto clinical trials of AIPC must
`In those patients entering ontoaclinical trial and having
`PSA progression as the only evidence of progressive dis-
`have demonstrated evidence of progressive disease. Patients
`may have progressive measurable disease, worsening dis-
`ease, we suggest that two consecutive increases in PSA be
`documented over a previous reference value (see Fig 1). The
`ease on bone scan, or an increasing PSA (as defined below).
`first increase in PSA (no. 2) should occur a minimum of1
`Progressive measurable disease. Progressive measurable
`week from the reference value. This increase in PSA should
`disease (changes in size of lymph nodes or parenchymal
`be confirmed (no. 3A). It is recognized that PSA fluctuations
`masses on physical examination or x-rays), regardless of
`changes in PSA, bone scan, or performance status,
`is
`are such that the confirmatory PSA value (no. 3B) might be
`adequate for protocol eligibility using conventional solid
`less than the previous value. In these cases, the patient would
`tumorcriteria. Approximately 20% of patients with radio-
`still be eligible provided the next PSA (no. 4) was found to
`graphic evidence of disease will have measurable soft tissue
`be greater than the second PSA (no. 2 in the above
`disease. In addition to PSA criteria, these patients may be
`sequence). We believe that a patient whose only evidence of
`evaluated using more traditional phaseII criteria. For agents
`progressive disease is an increasing PSA should have a value
`that seem to be promising based on PSAcriteria, it may
`of at least 5 ng/mL before entering onto a clinicaltrial.
`make sense to accrue additional patients with measurable
`disease to increase the understandingofthe drug’s activity.
`Bone scan progression. Most investigators believe that a
`worsening bone scan is adequate evidence of progressive
`disease, regardless of changes in PSA. However,it is well
`known that bone scans may worsen (‘‘flare’’) with the
`initiation of hormonal ablation and even chemotherapy.”4
`This is manifested by dramatic serologic and clinical
`improvement at the same time a bone scan shows more
`intense lesions and occasionally even new lesions. Bone
`scans that worsen because of hormonal ablation or chemo-
`therapy generally occur at the commencementoftreatment
`and have not been difficult to detect clinically.
`Patients who donotfit into this clinical scenario may have
`bone scans that demonstrate larger lesions, new lesions, or a
`combination of larger lesions and new lesions. Changes in
`the intensity or the size of a lesion may be difficult to
`interpret. Thus, we would suggest that at least one new
`lesion be evident before placing a patient onto a clinicaltrial
`based on progression in bone scan alone. In those patients
`entered onto clinical trials on the basis of nonmeasurable but
`assessable disease progression and whowill subsequently be
`observed with PSA as an end point, the PSA levelat trial
`entry should be greater than or equal to 5 ng/mL.
`
`#3A
`
`e
`
`®
`aA
`
`t
`# 3B
`
`e
`
`t
`#4
`
`
`
`Fig 1. For definingeligibility, the reference value (no. 1) is the last PSA
`level before a sequence of increases. The interval between the reference
`value and timepoint no. 2 must be a minimum of 1 week.If the PSA at time
`point no. 3 (value no. 3A) is greater than at time point no. 2, then the
`requirementfor a sequenceofthree increases has been met.If the third value
`is not greater than value no. 2, but value no.4 is, then increasing PSA has
`been confirmed, and the patientcan be eligible. In all cases, value no. 3A or
`no. 4 mustbe greater than or equalto 5 ng/mL,
`
`Information downloaded from jco.ascopubs.org and provided by at Cadmus ArticleWorks on August 3, 2016 from 65.196.76.98
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`::e
`:
`
`

`

` SADEAETETSENSSSRENOIR
`
` Q
`
`Qi
`
`3464
`
`BUBLEY ET AL
`
`Unfortunately, at lower values it is much more difficult to
`interpret changes in PSA. Webelieve this is problematic
`and, thus, a minimum PSAlevel is required.
`Antiandrogen withdrawal. There is evidencethat at least
`20% of AIPC patients will have clinical and PSA responses
`by stopping their antiandrogen treatment.? Therefore,
`to
`standardize results, all patients need to demonstrate contin-
`ued elevation of their PSA 4 to 6 weeksafter the cessation of
`their antiandrogen treatment. The length of time is depen-
`dent on the half-life of the agent used. Four weeks is
`sufficient after flutamide withdrawal, and 6 weeks is re-
`quired for other agents commercially available atthis time.
`Testosteronelevels/suppression. To standardize this popu-
`lation as much as possible, all patients without surgical
`castration should have a serum testosterone level less than
`
`50 ng/dL. There is no need to document a serum testoster-
`one in patients having a priorsurgical castration. In addition,
`patients should continue primary androgen suppression if
`they have not undergone surgical castration. The data for
`continuing androgen suppression are not definitive, but
`again, the intention is to make the patient populations from
`eachtrial as comparableas possible.
`
`For the purpose of defining duration of biochemical
`decline in PSA, we suggest defining two points on a time
`course, time to 50% increase from PSA nadir (PSA response
`duration) and time tofirst consistent PSA increase (ie, time
`to inflection or time to positive slope; see Fig 2). The PSA
`response duration should commenceonthe date of the first
`50% decline in PSA. The response duration ends when the
`PSA value increases by 50% above the nadir, provided that
`the increase is at least 5 ng/mL(or back to the baseline). All
`PSAresponses and progressions should be confirmed by a
`second determination.
`The time from initial 50% decline until the time at which
`the PSA beginsto consistently increase (the inflection point)
`is also of interest to investigators. For an individual patient,
`this inflection point would be defined retrospectively. We
`emphasize that clear radiographic or clinical evidence of
`disease progression would constitute evidence of progres-
`sion regardless of changes in PSA.
`
`Objective Response
`
`Patients with measurable soft tissue disease may also
`meet traditional guidelines for tumor response. We believe
`that this should also be noted and included in any description
`of a clinicaltrial.
`
`REPORTING TRIAL OUTCOMES
`
`PSA Normalization
`
`We strongly discourage the term “PSA complete re-
`sponse.” There is no compelling evidence that patients
`
`®
`
`) t
`
`on
`
`100
`
`study
`
`e
`
`|
`
`50 pom ocomm ro te Qn ee ee ee ee ae eo
`!
`e
`inflection
`t
`:
`@
`v
`66
`
`Posttherapy PSA Changes
`
`The purpose of determining the numberof patients whose
`PSA decreases in a phase IJ trial of AIPC is to guide the
`selection of agents for further testing and phase III trials.
`There have been attempts to determine if a posttherapy
`decline in PSA is of prognostic significance.!4!7!9 Many,
`but not all
`investigators have observed an association in
`uncontrolled trials between a decline in PSA levels of 50%
`or greater and survival.!! There is also considerable contro-
`versy aboutthe timing of the determination of the PSA level
`and the determination ofthe length of the response. The goal
`of the criteria herein proposed is quite focused to not use
`decline in PSA as a surrogate marker for survival but,
`instead,
`to use it as an outcome measure to guide the
`developmentoffurthertrials, generally randomized. Thus,it
`is acceptable that these criteria are necessarily arbitrary. We
`proposethat investigators should report, at minimum, a PSA
`decline of at least 50%, which must be confirmed by a
`second PSAvalue 4 or more weekslater. The reference PSA
`for these declines should be a PSA measured within 2 weeks
`before starting therapy. Patients may not demonstrate clini-
`cal or radiographic evidence of disease progression during
`this time period. Some investigators may want to report
`additional measures of PSA changes (ie, 75% decline and
`90% decline).
`
`
`
`e
`
`e
`
`e
`e
`°
`duration of PSA ‘control’
`
`+
`>
`
`>
`+
`Time to PSA progression
`
`duration of PSA ‘response’
`
`Fig 2. The duration of both PSA-based reporting end points are mea-
`sured from thefirst time point at which the PSA has declined by at least 50%
`{which must eventually be confirmed by a second value). The duration of PSA
`responseis the time until PSA has increased back to 50% of the original
`on-study value. However, in many cases,it will be possible (in retrospect) to
`identify an inflection point, the point at which PSA began what became a
`continuous increase. Someinvestigators feel that this may be considered the
`point at which disease control could be assumed to be lost. Thus, the duration
`of PSA control may be also be reported. Others prefer the time to PSA
`progression, whichis defined as the time at which therapy started and ends
`when the PSA increases by 50% above the nadir.
`
`Information downloaded from jco.ascopubs.org and provided by at Cadmus ArticleWorks on August 3, 2016 from 65.196.76.98
`Copyright © 1999 American Society of Clinical Oncology.All rights reserved.
`
`

`

` | |: a‘:: ‘ : |ie
`
`12808PODERESOLOERSERSELEIISISOONII
`
`
`
`
`
`PSA IN ANDROGEN INDEPENDENT PROSTATE CANCER
`
`3465
`
`long-term
`whose PSA has normalized have a different
`outcome than patients whose PSAs have declined by 50%,
`However, investigators may wish to report the number of
`patients achieving a PSA ofless than 0.2 ng/mL.
`DEFINING PROGRESSIVE DISEASE
`
`Progressive Measurable Disease
`
`Progressive measurable disease (changesin size of lymph
`nodes or parenchymal masses on physical examination or
`x-rays) is evidence of disease progression, regardless of
`changes in PSA, bonescan, or performancestatus.
`
`Bone Scan Progression
`
`Mostinvestigators believe that a worsening bone scanis
`adequate evidence of progressive disease, regardless of
`changes in PSA.Ifthere is strong evidence that a bone scan
`change is not indicative of progressive disease, then this
`should be noted and the patient continued ontrial. Changes
`in the intensity or the size of a lesion may be difficult to
`interpret. Thus, we suggest that, if there is no evidence of
`flare, one or more new lesions are required to identify
`disease progression.”
`
`PSA Progression
`
`An increasing PSA maybe the only marker of presumed
`progressive disease. In patients whose PSA has not de-
`creased, progressive disease is a 25% increase over the
`baseline (on-study) and an increase in the absolute-value
`PSA level by at least 5 ng/mL, which is confirmed by a
`second value. In patients whose PSA has decreased but has
`not reached response criteria, progressive disease would be
`considered to have occurred when PSA increases 25% over
`the nadir, provided that the increase is a minimum of 5
`ng/mL andis confirmed.
`There are sometrials in which investigators may wish to
`administer at least two cycles of therapy before removing
`patients from the study because of PSA progression. Thisis
`especially true for cytostatic agents that may require a period
`of time before treatmenteffect.
`
`Time to PSA Progression
`
`In the absence of evidence of clinical progression, the
`time to PSA progression is an appropriate outcometo report
`(especially for noncytotoxic agents). PSA progression may
`occur before clinical progression. The start of the time to
`PSA progression is the day treatmentis initiated (time to
`progression as shownin Fig 2). If at least a 50% decline in
`PSAhasbeen achieved, the end date is the time the PSA has
`increased 50% above the nadir at a minimum of 5 ng/mL
`(this is the same as the parameter for PSA response). For
`patients without a PSA decrease of this magnitude (or no
`decrease in PSA),
`the end point for progression will be
`
`the time a 25% increase in PSA has been
`calculated at
`achieved (see above). All end dates require a confirmatory
`PSA.
`
`Stable Disease
`
`The category of“stable disease” is controversial. There is
`no need to define or report stable disease as a category
`because the same information is contained in a more robust
`way within the definitions of time to PSA progression. The
`term stable disease may be usedin the clinical situation as an
`interim classification of patients on an ongoingtrial; how-
`ever, this term should not be used when reporting an analysis
`of the data.
`
`DESIGN, ANALYSIS, AND REPORTING
`
`In general, multi-institutional phase I]trials are preferred
`and encouraged because they tend to be less prone to
`extremes of patient selection bias andalsoserve better to test
`the ‘real world” feasibility of the therapy (facilitating the
`transition to phaseIII trials). For all phaseII trials, primary
`analysis and reporting should be donein a fashion consistent
`with an intent-to-treat approach, treated patients should not
`be excluded from the analysis for disease progression or
`toxicity before an arbitrary time point, such as one or two
`cycles of therapy. The only exclusions should be patients
`whoneverstarted therapy or who died of an unrelated cause
`before initial evaluation. However, it is acknowledged that
`some investigators feel
`that adequate trials of cytostatic
`agents may require considerable periods of exposure before
`treatment effects may be observed.
`In such cases,
`the
`treatment protocol should include a prospective definition of
`an adequate trial, and a secondary analysis may be reported
`that is based on a denominator of adequately treated patients.
`For all phase II trials,
`there should be a prospective
`identified, explicit, response rate ofinterest (or a time to PSA
`progression of interest, or both) and a (one- or two-stage)
`statistical design that explains the alpha and beta errors of
`the design. If the study includes different cohorts of patients
`(PSA only, PSA plus assessable disease or symptoms, or
`PSAplus measurable disease), it may be appropriate to have
`separate outcome parameters for these cohorts. Some pa-
`tients will have AIPC yet have no evidence of disease on
`physical exam, bone scan, or computed tomography scan.
`These patients, when included in these trials, should be
`distinguished separately in the report from patients who
`have measurable or assessable evidenceof disease.It is also
`recognized that prior treatment for patients with AIPC may
`influence subsequent
`response. For that
`reason,
`in the
`reporting of data, patients should be categorized by the
`number and type of hormonal and nonhormonaltreatments
`previously administered.
`
`Information downloaded from jco.ascopubs.org and provided by at Cadmus ArticleWorks on August 3, 2016 from 65.196.76.98
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`

`

` Ia : : i:§
`
`' g
`
`|g
`
`'
`
`sonestoare
`
`3466
`
`BUBLEY ET AL
`
`If time to PSA progression will be a planned primary end
`point, the time of interest should be chosen to be sufficiently
`long, so as to be of likely clinical
`importance, and the
`intervals for PSA testing should be appropriate to the time
`frame. We recommendthat PSA be monitored at a minimum
`of once a month.
`
`DISCUSSION
`
`A serum PSA is much simpler to obtain than traditional
`measurements of treatment outcome and can also be ob-
`
`tained more frequently. In addition, patients often become
`quite focused on their PSA value andits sense of seemingly
`mathematical objectivity, and they desire to have it tested
`frequently. Trials have used weekly, biweekly, and monthly
`measurements of PSA to assess response. The time for
`which the decline must be maintained to be considered a
`relevant end point and the numberof values required have
`also varied.
`Surrogate end points have been defined as response
`variables that can substitute for a true end point for the
`purpose of comparing specific interventions or treatments in
`a clinicaltrial. It is generally agreed that PSA changes alone
`do not currently meet the criteria for surrogacy. But changes
`in PSA canstill be of use as an aid in determining which
`agents should be tested in phase III trials using more
`traditional end points.
`A standardized set of eligibility and responsecriteria is
`needed as new agents undergoclinical testing. The defini-
`tions described in this paper have not been validated;
`nonetheless,the guidelines outlined in this article attempt to
`allow clinical investigators who are evaluating new regi-
`mens in AIPC to speak the same language. There is not
`necessarily a correct set of guidelines, but we believe our
`definitions are reasonable to incorporate into most trials for
`patients with AIPC. Obviously, there may be times when
`these criteria may not seem tofit the clinical question posed.
`In thatsituation, the investigators may modify these criteria,
`clearly document the reason why they have done so, and
`clarify how their reporting differs from that used in this
`
`document. It is recognized that new validation data may
`come forward that advances the field,
`rendering these
`criteria obsolete.
`Response duration and the time to PSA progression may
`also be important clinical end points. A short dramatic
`decrease in PSA may not be as important as a sustained
`decrease, even if it is not of the same magnitude. The date of
`the confirmatory PSA values should have no impact on the
`response duration and time to disease progression. Clearly,
`there may not be any clinical or radiographic evidence of
`progressive disease in responding patients.
`We believe that these are practical guidelines for using
`PSA as a measurement of outcome, The use of common
`standards is important as we determine which agents should
`progress to randomizedtrials that will use survival as an end
`point. These guidelines may need to be updated as moreis
`learned about the use of PSAin this population.
`
`METHODS FOR CONFERENCE
`
`This conference was organized by investigators from the Medicine
`Branch [and Cancer Treatment Evaluation program] of the National
`Cancer Institute, Bethesda, MD, and paid for through the Office of
`Special Populations, National Cancer Institute, Bethesda, MD,and the
`Office of Research on Minority Health, National Institutes of Health,
`Bethesda, MD. The objective was to standardize eligibility and response
`criteria for phase II clinical trials of patients with androgen-independent
`prostate cancer. The participants were recognized as expert clinical
`investigators in the field of metastatic prostate cancer and included a
`broad representation from the different cooperative groups. The confer-
`ence washeld over 2 days (March 10-11, 1999) in McLean, VA.
`
`ACKNOWLEDGMENT
`
`Wethank Hank Porterfield of U.S. TOO, Hinsdale, IL; John Willie of
`National Prostate Cancer Coalition, Washington, DC; Howard Soule,
`PhD, the Association for the Cure of Cancer of the Prostate (CaP
`CURE), Santa Monica, CA; Barry Kramer, MD, National Cancer
`Institute, Bethesda, MD; and Steve Hirschfeld, MD, Food and Drug
`Administration, Rockville, MD for assisting with the development of
`these guidelines. The following investigators were invited but unable to
`participate: Philip Kantoff, MD; William K. Kelly, MD; David Smith,
`MD; Ken Pienta, MD; Nick Vogelzang, MD; Ian Tannock, MD; Otis
`Brawley, MD; and Chris Logothetis, MD.
`
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