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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`_______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_______________________
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`AMERIGEN PHARMACEUTICALS LIMITED and
`ARGENTUM PHARMACEUTICALS LLC
`Petitioners,
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`v.
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`JANSSEN ONCOLOGY, INC.
`Patent Owner.
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`_______________________
`Case IPR2016-002861
`Patent 8,822,438 B2
`_______________________
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`DECLARATION OF GERALD WALTER CHODAK, MD
`IN SUPPORT OF JANSSEN ONCOLOGY, INC.’S
`PATENT OWNER RESPONSE
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`1 Case IPR2016-01317 has been joined with this proceeding.
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`JANSSEN EXHIBIT 2042
`Amerigen v. Janssen IPR2016-00286
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`I, Gerald W. Chodak, M.D., hereby declare as follows:
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`I.
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`INTRODUCTION
`1.
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`I have been retained by counsel for Patent Owner Janssen Oncology,
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`Inc. (“Janssen”) to provide expert testimony as background for the panel of
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`Administrative Patent Judges of the Patent Trial and Appeal Board of the United
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`States Patent and Trademark Office (“Panel”) as it considers issues relating to the
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`patentability of U.S. Patent No. 8,822,438 (“the ’438 patent”) (Ex. 1001) in an
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`inter partes review requested by Amerigen Pharmaceuticals Ltd. (“Amerigen”) and
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`Argentum Pharmaceuticals LLC (collectively “Petitioners”) in Case No. IPR2016-
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`00286 and Case No. IPR2016-01317.
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`2.
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`I am being compensated at my customary rate of $325 per hour for
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`work in connection with this proceeding. I am also being reimbursed for
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`reasonable and customary expenses associated with my work in this proceeding.
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`My compensation is in no way contingent upon the outcome of this proceeding or
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`the specifics of my testimony.
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`II. QUALIFICATIONS AND EXPERIENCE
`3.
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`I am a Board Certified physician in Urology and have been in clinical
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`practice since 1982 . I received my M.D. degree from the State University of New
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`York at Buffalo in 1975 and completed my training in Urology at the University of
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`Chicago in 1981. I received my Bachelor’s degree in Chemistry from the
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`University of Rochester in 1969, and my Master’s degree in Chemistry from the
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`State University of New York at Buffalo in 1971. My curriculum vitae can be
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`found at Exhibit 2043.
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`4.
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`From 1982-1999, I was a full time faculty member in the Department
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`of Surgery/Urology at the University of Chicago, reaching the rank of Professor in
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`1989. In 1999, I formed the Midwest Prostate and Urology Health Center in
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`Chicago, and remained its director until 2008 when I closed my clinical practice.
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`Currently, I conduct online consultations for patients with prostate cancer.
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`5.
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`I am credited with performing the first laparoscopic lymph node
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`operation for prostate cancer in Japan, Sweden, Finland and Norway and also the
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`first continent urinary diversion for bladder cancer in Illinois. In addition, I was
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`part of the team that performed the first laparoscopic retroperitoneal lymph node
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`dissection (“RPLND”) for testes cancer and bilateral nephrectomy.
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`6.
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`I am a named author on over 161 original peer-reviewed medical
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`articles, over 40 published abstracts, and 24 book chapters, mostly on prostate
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`cancer. I have been invited to speak in over 120 engagements, throughout the
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`United States and in more than 14 countries to both physicians and the public.
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`7.
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`I have received numerous awards over the course of my career and
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`served on numerous professional committees. I have also served as an expert
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`speaker for a number of pharmaceutical companies, including Johnson and
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`Johnson, and have served on numerous pharmaceutical advisory boards.
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`8. My primary area of research over the last 33 years has been in the
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`field of prostate cancer. I have been a principal or co-investigator on numerous
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`prostate cancer clinical trials sponsored by the NIH, the American Cancer Society,
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`and pharmaceutical companies.
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`9. My opinions are based on my education, research, and medical
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`practice and experience in the field of oncology, including my specific experience
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`studying and treating prostate cancer, as well as my investigation and study of the
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`relevant materials. A list of the documents that I relied on in connection with the
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`development of my opinions set forth in this declaration is attached as Appendix
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`A.
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`III. GERBER (1990)
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`A. BACKGROUND
`10.
`I am a co-author of Gerber, G.S. et al., “Prostate Specific Antigen for
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`Assessing Response to Ketoconazole and Prednisone in Patients with Hormone
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`Refractory Metastatic Prostate Cancer,” J. of Urology, 144(5):1177-9 (1990)
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`(“Gerber”). My co-author, Dr. Glenn S. Gerber, was then a resident at the
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`University of Chicago, working under my supervision. It is my understanding that
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`a copy of Gerber (1990) has been previously submitted in this proceeding as
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`Amerigen Ex. 1004 (“Ex. 1004”).
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`11.
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`I understand that Petitioners’ expert, Dr. Scott Serels, has stated in his
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`declaration that “[k]etoconazole ... was commonly used off-label in combination
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`with prednisone to treat metastatic refractory prostate cancer.” (Ex. 1002 at ¶23).
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`I also understand that Dr. Serels has stated that “[k]etoconazole ... was known to be
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`effective as a second-line treatment for metastatic hormone-refractory prostate
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`cancer.” (Id. at ¶ 33). In addition, I understand that Dr. Serels has stated that
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`“Gerber teaches that the combination of ketoconazole and prednisone is safe and
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`effective in treating human patients with hormone-refractory advanced prostate
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`cancer.” (Id. at ¶ 48). I disagree with all three of his statements.
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`12. Gerber is a retrospective chart review of clinical observations,
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`including prostate-specific antigen (“PSA”) levels, in 15 men with metastatic
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`hormone refractory prostate cancer who were administered ketoconazole and
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`prednisone. 2 (Ex. 1004 at Abstract). For purposes of our report, Dr. Gerber and I
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`examined ex post facto the charts of a sampling of my patients whom I had
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`previously treated for metastatic hormone refractory prostate cancer that had
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`received ketoconazole and prednisone therapy under my supervision and had PSA
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`measurements taken as part of their clinical care.
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`13. PSA is a glycoprotein found almost exclusively in normal and
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`neoplastic prostate cells and seminal fluids. In 1987, the New England Journal of
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`Medicine published a study examining the potential use of PSA as a biomarker for
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`prostate cancer, which suggested that PSA could be useful in monitoring patient
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`response to prostate cancer therapy. (Ex. 2047 (Stamey) at Abstract). Following
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`the publication of Stamey, researchers began to measure serum PSA levels in
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`patients with prostate cancer with the hope of reliably demonstrating that changes
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`in PSA levels could be useful as an indicator of disease regression or progression
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`and response to treatment.
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`14. At about this time, I also became interested in determining whether
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`PSA measurements could be used as an indicator of disease activity in patients
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`2 “Hormone refractory prostate cancer” can also be referred to “castration resistant
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`prostate cancer” or “androgen independent prostate cancer.”
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`with metastatic hormone refractory prostate cancer. In 1990, PSA was still
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`relatively new, and little was known about what drop in PSA, if any, correlated
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`with clinical benefit. Since PSA was new, and the only other reliable options for
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`determining response to a therapeutic agent were bone scan and CAT scan, we
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`were hoping to find out if PSA could predict whether a patient would show an
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`improved bone scan or CAT scan in response to therapy, which takes much longer
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`to determine. The attempt was to spare patients from continuing on unnecessary
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`and potentially harmful therapy sooner by using PSA rather than having to wait for
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`CAT scan or bone scan results. In the Gerber publication, Dr. Gerber and I sought
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`to share with other researchers our experience using PSA levels as a possible
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`surrogate for disease progression and regression in the context of metastatic
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`hormone refractory prostate cancer. We never believed that our data could prove
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`or disprove whether ketoconazole was safe or effective because it was not a formal
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`study designed to assess those outcomes. If, however, we did find a correlation
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`between the drug and changes in PSA, then the hope would be to do a proper
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`clinical trial to determine if ketoconazole and prednisone were actually safe and
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`effective in this setting.
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`15. By 1990, it was established that medical and surgical castration
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`offered similar clinical benefit to patients. Despite these advances, most castrated
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`patients with metastatic disease eventually relapsed. In 1990, there were no FDA
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`approved treatment options available for patients with hormone refractory
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`metastatic prostate cancer, and no treatment had shown a survival benefit for
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`patients in a controlled clinical trial. As a result, clinicians and researchers,
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`including myself, desperate to offer patients some type of treatment and to find a
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`drug that could control the growth of the cancer and extend survival, were
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`experimenting with off-label uses of available drugs.
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`16. The drug combination used in Gerber, ketoconazole and prednisone,
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`was one such off-label use. As Gerber explains, ketoconazole was originally
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`developed as an antifungal agent. (Ex. 1004 at 1177). However, it was also
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`observed that ketoconazole is a potent inhibitor of gonadal and adrenocortical
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`steroid synthesis and that it had an in vitro cytotoxic effect on prostate cancer cells.
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`(Id.). In men with hormone-refractory prostate cancer, however, results with
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`ketoconazole had not been promising. (Id.). For example, Gerber describes
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`Jubelirer et al. as concluding that ketoconazole “has limited use in patients who
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`have failed prior hormonal therapy for advanced prostate cancer.” (Id. at 1179).
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`At the same time, however, there were rare reports in the literature suggesting that
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`a small subset of patients with hormone refractory prostate cancer experienced
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`some signs of brief disease regression using measurements of tumor mass or bone
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`scan. (Id. at 1179). In light of these disparate results, Dr. Gerber and I sought to
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`determine whether ketoconazole should be continued in a patient where there is no
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`other option, based on changes in the PSA level, without having to wait for
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`changes in bone scan or CAT scan which take longer to observe. There was never
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`any expectation that our paper would prove “safety and efficacy” of the
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`combination of ketoconazole and prednisone. We selected ketoconazole and
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`prednisone because, as I have noted above, there were some rare reports in the
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`literature that suggested short-term responses in some patients with hormone
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`refractory disease. No other approved options were available for hormone-
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`refractory prostate cancer patients that increased survival. However, ketoconazole
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`was not “commonly used” for treating hormone refractory prostate cancer patients.
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`17.
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`In order to properly evaluate whether a new therapy is safe or
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`effective, the safety or efficacy (or both) of the therapy should be evaluated using a
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`well-controlled randomized clinical trial. In particular, a study protocol is required
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`that prospectively defines the purpose of the study, the selection criteria for study
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`participants, the duration of treatment and evaluation periods, and response criteria
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`(including describing reliable methods for observing and quantifying the response
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`criteria). Also, side effects must be carefully monitored and documented.
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`Adherence to the protocol is required and any modifications should not only be
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`documented, but also analyzed to determine their potential impact on the results.
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`Any report of the findings should describe the results and the analytic methods
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`used to evaluate them, including the statistical methods used. (See Ex. 2048
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`(Altman) at Table 2).
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`18. Gerber does not satisfy any of these requirements, and does not report
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`the results of an actual prospective clinical trial. The report was not designed to
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`measure whether treatment with ketoconazole and prednisone was “safe and
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`effective.” The patients included in the reported results in Gerber were self-
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`selected from among the many patients I had treated for metastatic hormone
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`refractory prostate cancer after discussing ketoconazole and prednisone therapy as
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`a potential option for them. These men were willing to try an unproven and
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`incompletely tested therapy because no other approved therapy was available that
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`increased survival. Thus, there was an obvious selection bias because men were
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`not randomly selected to receive this treatment.
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`19. Gerber does not describe that any clinical trial protocol was followed
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`for purposes of our report, and the paper does not define the selection criteria for
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`study participants, the duration of treatment and evaluation periods, the response
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`criteria (including describing reliable methods for observing and quantifying the
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`response criteria), the measurement of adverse effects, nor the analytical methods
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`used to analyze any results. By way of example, no patient selection criteria (i.e.
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`inclusion and exclusion criteria) were specified for the patients included in the
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`Gerber report. Rather, we retrospectively described the commonalities and
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`differences between the patients whose results were being reported. Fourteen out
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`of the fifteen patients had undergone orchiectomy at least 5 months before
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`participation, but one had been treated with injections of a luteinizing hormone-
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`releasing hormone agonist for 17 months before participation. (Ex. 1004 (Gerber)
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`at 1177). In addition, 10 of the 15 patients previously received radiotherapy.
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`Twelve “had bone pain and/or other symptoms of widespread malignancy,” and
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`the remaining three were asymptomatic. (Id.). The prior treatment histories of the
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`patients reported in Gerber could have influenced their response to ketoconazole
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`and prednisone.
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`20. Gerber states that patients were initially administered “600 mg to 900
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`mg. ketoconazole daily in 3 divided doses and 5 mg. prednisone twice per day,”
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`and that “the ketoconazole dosage was increased to 1,200 mg. daily in 3 divided
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`doses if the PSA did not decrease.” (Id. at 1178). However, the paper does not
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`describe how often the higher dose was administered. Gerber also explains that at
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`each visit, the patients underwent history and physical examination, and were
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`asked about any treatment-related side effects. (Id.). However, we made no
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`attempt to monitor patients’ compliance to the dosage schedule or report the use of
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`other medications, including analgesics. This in turn may have affected the
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`patients’ response to ketoconazole and prednisone, or the side effects they
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`experienced. We also made no effort to objectively measure symptomatic side
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`effects.
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`21. Gerber also does not describe the actual interval between
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`measurement of PSA levels, stating only that “PSA levels were recommended
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`monthly.” (Id.) (emphasis added). As shown in Figures 1-3, this recommendation
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`was not always followed. Figures 1-3 show that PSA measurements were
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`performed at a variety of different time periods. (See, e.g., id. Figs. 1-3).
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`22. We also did not specify a minimum change in PSA level that was to
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`be considered a “response” to ketoconazole and prednisone for purposes of the
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`Gerber (1990) report. Rather, we included as a “responder” any patient who
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`experienced any measurable decline in PSA. (See, e.g., id. at 1178, in which one
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`“‘responding patient[]’… had a 7% decrease in PSA”).
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`23. We also did not use any objective criteria, such as reduction in
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`measurable tumor size or improvements in bone scan abnormalities, to evaluate the
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`regression of the patient’s prostate cancer. Furthermore, although the patients were
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`asked about any perceived improvements in their bone pain, there was no
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`standardized survey or objective measures used to evaluate patients’ bone pain
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`while on ketoconazole and prednisone. As a result, the bone pain data reported
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`was highly subjective and subject to a great degree of variability.
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`24.
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`In addition, all of the patients reported in Gerber received both
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`ketoconazole and prednisone. Thus, there was no control for a placebo effect of
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`either drug in any patient.
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`B. RESULTS
`25. Gerber reports that 12 of the 15 patients (80%) with hormone
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`refractory prostate cancer “showed a decrease in PSA in response to ketoconazole
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`and prednisone.” (Id. at 1178, 1179). As explained above, this “response”
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`included any amount of decrease in PSA. Gerber also reports that the mean
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`decrease in PSA in the 12 “responding” patients was 49% of the pre-treatment
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`level. (Id. at 1178). Thus, in Gerber, there were patients included in the
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`“responding” group who had a PSA decline of greater than 50%, but also included
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`individuals who had a PSA decline of less than 50%. However, no information is
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`provided in Gerber as to the number of patients that had a PSA decline of greater
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`than 50% versus the number of patients that had a PSA decline of less than 50%.
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`26. Gerber reports that of the 15 patients, 12 (80%) had a decrease in PSA
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`with a median duration of response of 3 months. (Id. at Abstract, 1178). Gerber
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`also reports that in 9 of 12 men, the improvement in PSA was “short-lived (i.e. less
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`than or equal to four months)”) and “occasionally of small magnitude,” but it did
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`correlate with subjective improvement in symptomatic patients in all but 1
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`instance. (Id. at 1179). More specifically, of the 12 patients who had bone pain
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`and/or other symptoms of advancing malignancy prior to administration of
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`ketoconazole and prednisone, nine (75%) reported subjective improvement,
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`however these were not validated either by documenting patients’ use of analgesics
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`or by documenting in an objective fashion what kind of subjective improvement
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`occurred.3 (Id.). One patient had a 7% decrease in PSA during four months of
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`treatment but he had no improvement in bone pain. (Id. at 1178). However, 1 of
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`the 3 patients who had no decrease in PSA levels also reported a transient decrease
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`in bone pain. (Id. at 1178). We concluded that “[s]hort-term decreases in PSA are
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`of unclear importance but probably do not reflect significant disease regression”
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`and “it is unlikely that significant impact on survival will be seen in these cases.”
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`(Id. at 1179).
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`27. We also reported that 2 out of the 15 patients (13%) “suffered minor
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`bruising believed to be secondary to prednisone.” (Id.). Besides monitoring liver
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`functions and blood chemistry and questioning the participants regarding
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`treatment-related side effects, however, we did not evaluate the “safety” of
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`ketoconazole and prednisone.
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`3 As noted in my later comment regarding Gerber, even for patients who reported
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`“a clear reduction in analgesics” this subjective improvement was “short-lived.”
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`(Ex. 2049 (Blackard) at 1622).
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`28. The results reported in Gerber did not establish that the combination
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`of ketoconazole and prednisone was “safe and effective” in hormone-refractory
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`prostate cancer patients. While PSA was measured and patients were asked about
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`their pain at each visit, no objective clinical response criteria (e.g. imaging
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`procedures such as bone scan) were reported in the Gerber paper. In fact, as I
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`discuss in more detail in Section V, as of August 2006, no scientific conclusions
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`about ketoconazole and prednisone or PSA could be drawn from the Gerber paper.
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`C. Glucocorticoid Replacement for Ketoconazole
`29. When we administered ketoconazole to patients as reported in Gerber,
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`we co-administered prednisone only for purposes of glucocorticoid replacement
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`therapy. At the time, we knew that ketoconazole was an unselective drug that
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`decreased the production of all steroids (including glucocorticoids and
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`mineralocorticoids) and could cause adrenal insufficiency.
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`30. Nevertheless, we were also aware in 1990 that ketoconazole had been
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`safely administered without glucocorticoid replacement to patients with prostate
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`cancer. (Ex. 1004 (Gerber) at 1179).
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`IV. REACTIONS TO GERBER
`31. Following its publication, prostate cancer researchers commented on
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`the limitations of the results described in Gerber. Specifically, in a December 1991
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`letter to the editor of the journal in which Gerber was published, Dr. Clyde
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`Blackard of the Park Nicollet Medical Center, Minneapolis, Minnesota, noted that
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`the decrease in PSA levels reported in Gerber likely did not reflect clinical
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`improvement:
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`It is likely that the effects of ketoconazole and prednisone
`in decreasing PSA levels have little or nothing to do with
`clinical improvement.
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` (Ex. 2049 (Blackard) at 1621) (emphasis added).
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`32. Dr. Blackard also noted that the reductions in bone pain reported in
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`Gerber were “largely subjective and difficult to evaluate” and “could have been
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`related partly to bed rest, simultaneously administered analgesics and/or the
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`prednisone.” (Id.). And, Dr. Blackard emphasized that none of the 15 patients in
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`Gerber “showed a significant improvement in terms of increased survival.” (Id.)
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`In our response to Dr. Blackard, we acknowledged that “we have insufficient data
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`to determine the impact on survival.” (Id. at 1622). Dr. Blackhard concluded, and
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`we agreed, that “[w]e definitely need more research in this area.” (Id. at 1621) Dr.
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`Blackard’s 1991 letter reflects the pressing concern shared among clinicians at the
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`time that experimental treatments for refractory prostate cancer consistently failed
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`to meet the ultimate goal of improving survival.
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`33. Other publications from the 1990s similarly confirmed that Gerber did
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`not teach that ketoconazole, alone or in combination with prednisone, was “safe
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`and effective.” (See, e.g., Ex. 2053 (Lara) at 140 (noting “objective (measurable)
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`responses [to ketoconazole] are unusual (<5%), the duration of PSA response is
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`only 3-4 months, and there is no improvement in overall survival”); Ex. 2054
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`(Kuzel) at 1965 (noting the short duration of PSA response in Gerber); Ex. 2055
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`(Scher) at 2928 (noting that ranges of response rates to second- and third-line
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`hormonal therapies is “less clear because a range of response proportions have
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`been reported” which is “the result of patient- and tumor-related factors”); Ex.
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`2056 (Sternberg) at 331 (citing Gerber to say “[w]hile changes in PSA are a good
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`indicator of disease activity in men with metastatic prostate cancer treated with
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`hormonal manipulation, the role in patients treated with second line therapy is less
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`clear”) (emphasis added).
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`34.
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`Indeed, by the early 2000s, over a decade after the Gerber paper was
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`published, peer-reviewed clinical trials confirmed that ketoconazole-based
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`therapies, like so many other therapies that were studied, did not improve survival
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`in patients with hormone refractory prostate cancer. (Ex. 2063 (Small (2004)) at
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`1031 (“no difference in survival was observed” for patients treated with either anti-
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`androgen withdrawal alone or antiandrogen withdrawal plus simultaneous
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`ketoconazole and hydrocortisone replacement therapy); Ex. 2064 (Millikan) at 115
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`(“we found no evidence that either of these regimens [ketoconazole and
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`hydrocortisone or ketoconazole, hydrocortisone, and doxorubicin] is likely to
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`substantially improve the survival of patients with androgen independent prostate
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`cancer.”). These larger studies in the early 2000s confirmed that ketoconazole
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`offered, at best, a “last resort” therapeutic option for such patients, particularly in
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`view of the fact that docetaxel-based chemotherapy was the first (and only) therapy
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`shown to improve overall survival in patients with metastatic hormone refractory
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`prostate cancer. Ketoconazole has never been approved by the FDA for prostate
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`cancer treatment because no randomized trial has shown it to be either safe and/or
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`effective for patients with hormone-refractory prostate cancer.
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`V. DEVELOPMENTS IN THE USE OF PSA AS OF AUGUST 2006
`35. As of August 2006, researchers’ understanding of the use of PSA in
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`diagnosing and evaluating prostate cancer response and progression had evolved
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`significantly.
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`36.
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`In 1999, the Prostate-Specific Antigen Working Group (“Working
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`Group”), a group of 26 leading clinical researchers, published eligibility and
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`response guidelines for clinical trials in androgen-independent prostate cancer,
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`explaining that “it was important for investigators to agree on definitions and
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`values for a minimum set of parameters for eligibility and PSA declines and to
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`develop a common approach to outcome analysis and reporting” in clinical trials.
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`(Ex. 2057 (Bubley) at 3461).
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`37. The Working Group had found that “[u]nfortunately, even among
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`investigators who have reported a decline in serum PSA as an end point, there is no
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`consistency in how a PSA decline is measured and reported.” (Id. at 3462).
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`Nevertheless, the Working Group also noted that “many but not all investigators
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`have observed an association between a decline in PSA levels of 50% or greater
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`and survival.” (Id. at 3461).
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`38. Therefore, the Working Group proposed that investigators define a
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`“PSA response” as, at a minimum, a PSA decline of at least 50% confirmed by a
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`second PSA value 4 or more weeks later:
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`[I]nvestigators should report, at minimum, a PSA decline
`of at least 50%, which must be confirmed by a second
`PSA value 4 or more weeks later. The reference PSA for
`these declines should be a PSA measured within 2 weeks
`before starting therapy. Patients may not demonstrate
`clinical or radiographic evidence of disease progression
`during this time period.
`
`(Id. at 3464). The goal of the proposed guidelines was “to use [PSA] as an
`
`outcome measure to guide the development of further trials, generally
`
`randomized.” (Id.).
`
`39. By 2006, the Working Group guidelines had been adopted and were
`
`widely applied by researchers and clinicians for evaluating response to therapeutic
`
`agents in hormone refractory prostate cancer patients. Accordingly, researchers
`
`and clinicians who used PSA as a measurement of outcome understood that only
`
`patients who showed a greater than 50% decrease in PSA were likely to have
`
`actually experienced a clinically significant response. Publications that reported a
`
`
`ACTIVE 217581642v.3
`
`19
`
`
`
`
`
`PSA decline of less than 50% as a “response” were not given much weight and
`
`were often repeated or superseded by studies that applied the Working Group
`
`guidelines.
`
`40.
`
`In light of the Working Group guidelines, as of August 2006, a
`
`physician or researcher working in the field of prostate cancer would have
`
`understood that the patient outcomes described in Gerber, which reported any
`
`decline in PSA as a “response,” and also did not include any other objective
`
`response criteria, did not establish that ketoconazole and prednisone were “safe
`
`and effective” for the treatment of hormone refractory prostate cancer. Indeed, a
`
`physician or researcher working in the field of prostate cancer reading Gerber
`
`would have understood that the paper’s conclusion that “there appears to be a small
`
`subgroup of patients who will derive significant benefit from the combination of
`
`ketoconazole and glucocorticoid replacement therapy” overstated the observed
`
`outcomes and that the results of Gerber were, at best, inconclusive.
`
`
`
`
`
`
`
`
`ACTIVE 217581642v.3
`
`20
`
`
`
`3 dxtcizmx azzékcr gznmaffiy gs? ;:m;§u2g: mzém“ 3%: éawzs sfkéw éfgziim Sizwsg «:2?
`
`;%::am%¢3 am: ziaa faraggéag
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`¥;s:;:a% am zrrsxsvm.
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`
`
`APPENDIX A
`
`I have relied upon the following documents (and any other documents cited in my
`declaration) in connection with the development of my opinions set forth in this
`declaration.
`
`U.S. Patent No. 8,822,438
`
`Gerber and Chodak, “PROSTATE SPECIFIC ANTIGEN FOR ASSESSING
`RESPONSE TO KETOCONAZOLE AND PREDNISONE IN PATIENTS WITH
`
`HORMONE REFRACTORY METASTATIC PROSTATE CANCER,” J.
`
`Urology, 144:1177-1179 (1990)
`
`Altman et al., “The Revised CONSORT Statement for Reporting Randomized
`Trials: Explanation and Elaboration,” Ann. Intern. Med, 134:663-694 (2001)
`
`Blackard, “Letters to the Editor,” Journal ofUrology, 146(6): 1621-1622 (1991)
`
`Bubley et al., “Eligibility and Response Guidelines for Phase II Clinical Trials in
`Androgen-Independent Prostate Cancer: Recommendations From the Prostate-
`Specific Antigen Working Group,” J, Clin. Oncology, 173461-3467 (1999)
`
`Kuzel et al., “A Phase 11 Study of Continuous Infusion 5-Fluorouracil in Advanced
`Hormone Refractory Prostate Cancer,” Cancer, 72(6):l965-1968 (1993)
`
`Lara and Meyers, “Treatment Options in Androgen-Independent Prostate Cancer,”
`Cancer Investigation, 17(2): 137-144 (1999)
`
`Scher et al., “Bicalutamide for Advanced Prostate Cancer: The Natural Versus
`Treated History of Disease,” J. Clin. Oncology, 1522928-2838 (1997)
`
`Small et al., “Antiandrogen Withdrawal Alone or in Combination With
`Ketoconazole in Androgen-Independent Prostate Cancer Patients: A Phase III Trial
`(CALGB 9583),” J. Clin. Oncology, 22(6):lO25—1033 (2004)
`
`Stamey et al., “Prostate-Specific Antigen As A Serum Marker For
`Adenocarcinoma Of The Prostate,” NEJM, 317(l5):909—916 (1987)
`
`Sternberg, “Hormone refractory metastatic prostate cancer,” Annals of Oncology,
`3:331-335 (1992)
`
`22
`
`
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