Editor-in-Chief
`
`John Menddsohn
`Growth Factors, Hormones, Cell
`Growth; Radiation Therapy,
`Surgery, Subspecialry Investigation
`
`Deputy Editor
`
`WanD Ki Hong
`Clinical Trials Targeted at Specific
`Malignancies, Chemoprevention
`
`Co-Deputy Editor
`William N. Hait
`Special Features, Molecular
`Pharmacology, Clinical Trials
`
`Senior Editors
`Clinical Pharmacology and
`Pharmacokinetics, Drug
`Metabolism, Drug Sensitivity
`and Resistance, Drug
`Interactions
`Bruce A. Chabner
`
`Pathology, Metastasis
`Stanley R. Hamilton
`
`A Journal of the American Association for Cancer Research
`
`May 12, 2003
`
`Ian Judson
`CRC Centre for Cancer Therapeutics
`Clinical Pharmacology
`Institute of Cancer Research
`E-Block, 15 Cotswold Road
`Sutton, Surrey SM2 5NG
`United Kingdom
`
`RE: Manuscript # 030579, Hormonal impact of the 17a-hydroxylase/C 17 ,20-lyase
`inhibitor abiraterone acetate (CB7630) in patients with prostate cancer
`
`Dear Dr. Judson:
`
`Thank you for submitting the above-mentioned manuscript to Clinical Cancer Research. I
`regret to inform you that we will be unable to publish this paper. This decision was based
`not only on the enclosed reviewer comments, which we hope will be helpful to you, but also
`upon the editors' evaluation of the merits and amount of novel information in your
`manuscript compared with those of many others we receive. Many worthwhile papers must
`be declined simply for lack of space, and yours is one of these.
`
`Immunotherapy and Cytokines-
`Preclinical, Clinical Trials, and
`
`Hematologic Malignancies
`Jerome Ritz
`
`We are returning the file copies of your manuscript along with our reviewer comments.
`Thank you again for giving us the opportunity to review your work. We encourage you to
`submit future manuscripts to Clinical Cancer Research, and I hope you will do so.
`
`Cell Cycle Regulation, Cell Death,
`Pharmacology
`Edward A. Sausville
`
`Sincerely,
`
`Molecular Pathogenesis, Molecular
`Correlates
`David Sidransky
`
`Experimental Therapeutics,
`Preclinical Pharmacology,
`Combined Modality Regimens,
`Animal Therapy Models
`Beverly A. Teicher
`
`Genetics, Cytogenetics
`Barbara L. Weber
`
`Waun Ki Hong, M.
`Deputy Editor
`
`--
`
`Clinical Cancer Research
`
`enclosures
`
`r{~ r
`f A~A.
`
`,..r~
`
`D0
`
`Waun Ki Hong, M.D., Deputy Editor. Thoracic/Head & Neck Medical Oncology. Box 432
`The University of Texas M.D. Anderson Cancer Center .1515 Holcombe Boulevard. Houston, TX 77030-4009
`Phone: (713)
`3) 563-9798
`
`
`
`JANSSEN EXHIBIT 2030
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`
`

`

`Page 2 of3
`
`REVIEWER'S RECOMMENDATIONS (please type)
`
`Manuscript no. and title:
`
`030579/Honnonal impact of the 17a-hydroxylase/C17,2o-lyase inhibitor
`abiraterone acetate (CB7630) in patients with prostate cancer
`
`O'Donnell and colleagues describe a "first in human" trial of CB7630 in prostate cancer.
`The authors should consider:
`
`3.
`
`1. In this reviewer's opinion, the authors over-emphasize the role of androgens in
`stimulating prostate cancer growth in castrate men. Much work in this area and
`little persuasive data that residual androgens are important. A more balanced
`view would be preferable.
`2. How important would it be to have another drug that suppresses testosterone to
`castrate levels? (specific aims of study B and study C).
`It is unclear why the target testosterone for studies B and C is <0.7 nmol/L "based
`on local unpublished data". There are hundreds of patients Qublished. If the
`authors chose to use local controls... they should at least provide the data and
`describe the populations and their quality controls on medication adherence.
`Three patients in study A did not adhere to LHRH it appears. Why do authors
`think their unpublished controls did?
`4; How was starting dose chosen? How was dose escalation plan established?
`5. The authors should define what Synacthen test is. Presumably it is a low dose
`ACTH stimulation test. This description is preferred because it. is direct, easily
`understood, and not a proprietary name.
`6. The conclusions the authors draw are unclear. It seems it will take> 800 mg,
`there is LH "override", but only 3 patients were treated so conclusions -short of
`saying it is safe -are tenuous.
`7. The 10 fold variation in A UC at a dose is much higher than with most drugs; not
`common as the authors imply.
`8. How important is another drug to antagonize extragonadal androgen production in
`conjunction with LHRH analogues? The role of anti androgens in this setting is
`controversial -at best. 5 alpha reductase inhibitors also could work in a similar
`way, but do not clearly help. Why would this drug that suppresses adrenal
`corticoids be useful?'9.
`What is the plan for the drug/class?
`
`

`

`Clinical Cancer Research
`REVIEWER'S RECOMMENDATIONS (please type)
`
`Page 3 of3
`
`Manuscript no. and title:
`
`030579/Hormonal impact of the 17a-hydroxylase/CI7,2o-lyase inhibitor abiraterone
`acetate (CB763) in patients with prostate cancer
`
`General Comments:
`
`Abiraterone Acetate is a very interesting drug that appears to have some potential for the
`treatment of advanced prostate cancer. However, the manuscript is not clearly written and
`there is concern on how the doses that the authors chose for each study were selected and
`what is the appropriate dose to bring forward. Many details of the studies were excluded
`and need to be included.
`
`Specific Comments:
`
`Introduction. page 1. second garagraph: Castration does produce objective,
`1.
`biochemical and palliative effects but rarely if ever produces "remission" of the tumor.
`This needs to be clarified.
`
`Methods: Investigational agents. Rage 8: Please provide additional information on
`2.
`the formulation of the capsules and the stability of the formulation at room temperature.
`Any data on bio-availability in animals?
`
`Dosage and Administration: Eliminate the following sentence: "Dealing with each
`3.
`study in turn:".
`
`Dosage and administration: The dose escalation schemes used in Study A, B and
`4.
`C were not traditional, but presumed each study built upon the other and provided the
`starting dose. This is needs to be clarified in the text.
`In study B please provide
`explanation why the starting dose was 200 mg was used. The author needs to clearly
`define maximum tolerated dose and dose limiting
`toxicities for all three studies. A
`standard dose escalation scheme was not utilized in this study (3 patients initially and
`expand to 6 if DLT). Please provide a description and rationale for the schema that the
`authors used.
`
`Pre-treatment Assessment and Follow-up Investigations:
`5.
`the exact blood test that were obtained pre and post-therapy.
`
`Authors need to clarify
`
`Endocrine Assessment: Please provide all manufacture and normal ranges for the
`6.
`testosterone, cortisol, 17 a-hydroxyprogesterone, androstenedione, LH and FSH.
`Information on the preparation and storage of these samples needs to be provide. Were
`these samples batched?
`
`

`

`Pham1acokinetics- Analytic method. Assays and Sampling:
`7.
`detection limit of the assay for the drug?
`
`What is the lower
`
`Results: The Authors should provide more baseline information for each study.
`8.
`This should include median testosterone level, HGB, alkaline phosphatase, LDH and
`PSA. In addition, the prior treatment history; extent of disease; patients with testosterone
`level < 0.6 nmol/L, ~
`0.6 nmol/L or non-castrate level. How many patients had
`orchiectomy or GnRH analog? This could be provided in table.
`I
`
`Results, page 15: In part A, the authors escalated the dose from 100 mg to 500 mg
`9.
`after only one patient was treated at 200 mg due to the lack of pharamcodynamic effect.
`This is a safety study and please provide a better rationale why you would skip the dose
`level? Three patients treated at 500 mg dose level had a reduction in Testosterone. Please
`provide the breakdown of the decline (ie how many were not detectable verses> 75%
`decline). The authors need to provide details on duration of suppression in days. Please
`explain why three additional patients were added at the 500 mg dose level if not DLTs
`were encountered and why dose escalation did not continue over 500 fig?
`",j"
`
`Results. Qage 17: In study B, why was the dose not escalated above 500 mg as
`10.
`written? In addition, table for each study with all the endocrine results would be useful. I
`
`11. Overall Toxicity: The description of adverse events needs to be detailed further
`using common toxicity criteria and placed in a table.
`
`The authors should include outcome data for the patients. Any changes ih
`12.
`biochemical markers such as PSA?
`I
`
`