`This material may be protected by Copyright law (Title 17 U.s. Code)
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`
`High-Dose Ketoconazole in Advanced Hormone-Refractory
`Prostate Cancer: Endocrinologic and Clinical Effects
`
`By Donald L Trump, Kathleen H. Havlin, Edward M. Messing, Kenneth B. Cummings.
`Paul H. Lange, and V. Craig Jordan
`
`Journal of Clinical Oncology, Vol 7, No 3 (August), 1989: pp 1093—1093
`
`presented data suggesting that antagonism of
`cxtratcsticular androgcns and suppression of tes-
`ticular androgcns substantially improves the re—
`sponsc and survival of individuals with meta-
`static prostatic cancer compared with individuals
`who undergo suppression of testicular androgens
`only. Preliminary analysis of a randomized trial
`suggests a small
`improvement
`in disease-free
`survival for patients treated with total androgen
`deprivation.2 in men whose prostatic cancer is
`progressing despite testicular androgen ablation,
`antagonism of adrenal secretion of “minor” an-
`drogcns (dehydrocpiandrosterone [DHEAS] and
`androstencdionc [A2]) occasionally appears to be
`beneficial. Improvement in approximately 20%
`or these men is scen with adrenalectomy. hy-
`pophyscctomy. anti-androgcns, or drugs that di-
`rectly antagonize adrenal steroidogenesisfi‘m
`Kctoconazolc is a substituted imidazolc. origi-
`nally developed as an antifungal antibiotic. Kcto-
`conazole inhibits ergosterol synthesis in fungi
`and cholesterol synthesis in mammalian cells.II
`Shortly after its introduction into clinical prac-
`tice,
`it was recognized that kctoconazolc also
`suppresses testicular and adrenal steroidogcnc-
`sis.12 Disruption of P-450~dcpcndcnt enzymes,
`
`High-dose ketoconaxole (400 mg orally three times a
`day) and physiologic replacement doses of glucocorti-
`coids (hydrocortisone, 20 mg 8 AM, 10 mg 4 PM, and 8
`PM) were administered to 38 patients with advanced
`prostatic cancer, refractory to at least initial tasticular
`androgen deprivation. Thirty patients were com-
`pletely evaluable; six were withdrawn due to possible
`ltetoeonazale-related toxicity and were considered
`drug failures. Two patients were unevaluable due to
`intercurrent therapy or inability to maintain lollow»
`up. Ketoconazole was generally well tolerated. Mild
`or moderate nausea and vomiting occurred in 37% of
`patients, but required dose modification or discontinu-
`ation in onlyr three patients; no hepatic damage was
`seen. Five of 36 patients (I 4%} responded to ketocon-
`azole as determined by palpable or radiographic
`
`HE IMPORTANCE of cxtratcsticular an-
`
`drogens in supporting the growth of pros-
`tatic carcinoma is uncertain. Labric at al' have
`
`tumor mass reduction of 50% or greater and normal-
`ization of acid phosphatase or bone scan. Fifty percent
`of patients entered were stable at 90 days. Plasma
`androstenedione and dehydtoepiandrosterene sulfate
`{DHEAS} were reduced markedly in almost all pa-
`tients. Plasma testosterone (T) levels were low and
`remained unchanged, while ganadattapins were per-
`sistently elevated. Mean plasma ketoconazole content
`was 6.6 rig/ml. after 28 days of therapy. While
`ketoconazole with hydrocortisone does suppress plasma
`ondrogens in advanced prostatic cancer patients, this
`infrequently causes regression of cancer that has
`progressed despite adequate testicular androgen ab-
`Iatian.
`
`J' Clin Oncol 7:!093— i098. is i989 by American Soci-
`ety of Clinical Oncology.
`
`particularly C1120 lyasc is the major mechanism
`for the disruption of androgen synthesis in pa-
`tients treated with large doses of kctocona-
`zolc.13"‘1 Soon after the recognition of this clicct.
`ciiicacy of kctoconazolc in advanced prostatic
`camcr patients was described.” Most experience
`with kctoconazolc in prostatic cancer has bccn in
`previously untreated patientsié'm Because of our
`interest in the role of adrenal androgen supprcs~
`sion in “endocrine-refractory” prostatic cancer.
`we conducted this phase [I trial of kctoconazolc
`in patients whose cancer had ceased to respond to
`testicular androgen deprivation. Dctailcd clinical
`and cndocrinologic monitoring of these patients
`was performed.
`
`
`
`From the University of Wisconsin Clinical Cancer Center.
`and the Williorri S. Middleton Memorial Veterans Hospital
`Madison li’lmnd the University ofMinrrs-soto and Minneap-
`all: Veterans Administration Hospital.
`Submitted January 27, l 5389; accepted March 27. l 089.
`Supported in part by the Paul 3. Cohen Memorial Fand.
`Dr Trump‘s current address is Duke University Medical
`Center. Durham NC: Dr Hovlin's current address is Divi-
`riot: of'Mediral Oncologv. University of Texas San Antonio.-
`Dr Lunge's current address is Department of Urology.
`University of Washington. Seattle.
`Address reprint requests to Donald L. Trump, MD, Dulce
`University Medical Center. Box 33.08. Durham. NC 277 M.
`It‘ Willil by American Society ofCTlinicol Oncologv.
`0732-lS3Xf80/FJPflS—Ofll85300/0
`
`MYLAN PHARMS. INC. EXHIBIT 1107 PAGE 1
`
`

`

`METHODS
`
`Treatment
`
`Ketoconazole. 400 mg. was administered orally every eight
`hours. All patients received physiologic glucocortioojd replace-
`ment therapy with 20 mg of hydrocortisone in the morning,
`10 mg at 4 PM. and 10 mg at 8 PM.
`
`Study Parameters
`Patients were evaluated by history. physical examination.
`serum electrolytes. crcatinine, liver function tests. and acid
`phosphatase before therapy, 2 weeks after beginning therapy,
`and then at monthly intervals. Chest
`radiographs were
`repeated monthly if initially abnormal or every 3 months if
`initially normal; bone scans and pelvic computerized tomog—
`raphy (CT) scans were done before therapy and every 3
`months. if initially abnormal, to assess response.
`
`Endocrinologic Assessment
`Plasma testosterone (T).
`follicle-stimulating hormone
`{FSH}, luteinizing hormone (Ll-I), DHEAS. A2, and estra—
`diol
`(E1) were measured before therapy and at monthly
`intervals using standard radioimmunoassay procedures. Ketc-
`conazole plasma levels were also assessed monthly using a
`described microbiologic assay.1 Plasma prostate-specific anti-
`gen (PSA) was assessed before therapy and monthly by
`radioimmunoassay (Hybritech). All blood samples were
`drawn between 3 AM and 10 AM.
`
`Response Criteria
`Responses were assessed using the prostate cancer response
`criteria oi" the ECOG. Measurable disease: partial response
`was defined as a 50% or greater reduction in the sum of the
`products of the perpendicular diameters of measurable tumor
`
`TRUMP ET AL
`
`masses persisting for more than I month in the absence of the
`appearance of new lesions. Evaluable bone scan response was
`defined as a return to normal in 50% or more of the abnormal
`areas noted on pretreatment scan without the appearance of
`new lesions. Progression was defined as (l) a 25% or greater
`increase in the product of the perpendicular diameters of
`measurable tumor masses or, (2) development of new areas of
`metastatic disease as assesaed by plain radiograph, bone scan.
`CT scan, or physical examination or detericration by 2 levels
`in PS.
`
`RESULTS
`
`Thirtyseight patients were entered in this trial.
`Patient characteristics are listed in Ta ble 1.
`
`These patients had good PS and were not heavily
`pretreated with systemic therapies. Twenty-one
`of 38 patients had received only a single systemic
`hormonal
`therapy for prostate cancer (13. or-
`chiectomy; five. DES; and three GnRi—la}. While
`45% of the patients had received two or more
`systemic therapies. only three had received cyto-
`toxic chemotherapy (one, carboplatin; one, doxo-
`rubicin; and one, estramustinc phosphate). OF 38
`patients entered. two were declared unevaluablc:
`one due to the initiation of radiation on day 3 of
`ketoconazole therapy. and the other due to inabil-
`ity to maintain follow—up. Six ofthe remaining 36
`patients (16%) discontinued ketoconazole due to
`possible or definite drug-related toxicity. Unman-
`ageable nausea and vomiting prompted discontin-
`uation of ketoconazole in three patients (3%). In
`two of these three patients, nausea and vomiting
`developed after 11!; and 2 months of therapy. was
`accompanied by evidence of progressive disease.
`
`5 {13%)
`21 (55%}
`11 [28%)
`1 (2%)
`
`5 (13%)
`B (21%)
`15 {399(1)
`B (21 9h]
`2 (5%]
`
`Table 1. Characteristics of Patients Treated (N = 38)
`Age (yr)
`5059
`60159
`flit-3'9
`30-39
`Interval from initial diagnosis oi prostate cancer
`to studv entry or]
`1 or less
`1-2
`2-5
`5- l 0
`10 or more
`Prior syslen'lk 'lhoropy
`Single hormonal therapy
`Two or more prior systemic treatments
`Prior cytotoxic therapy
`
`Eligibility
`Patients eligible for this trial were required to have
`symptomatic progressive, disseminated pmstatie cancer. de-
`spite primary endocrine management (orchiectorny,
`l mg I d
`or more of diethylstilbestrol [DES], or gonadotropin hormone—
`releasing hormone analogues [Gan—lan and were treated
`only at the University of Wisconsin. At least one evaluable or
`measurable parameter of disease was
`required. Lesions
`deemed evaluable included soft tiSSoe masSes evaluated by
`radiographic or physical exam or abnormal bone scan.
`Patients were required lo have a WBC of 2,00IquL ptatelet
`count of 50,000juL. creatinitte < 3.1 mg/dl. and hilirubin,
`lactic dehydrogenase (LDH), and SGOT less than twice
`normal. An Eastern Cooperative Oncology Group (ECOG)
`performance status (PS) of U. l. or 2 was required." Patients
`must not have had major surgery or cytotoxic chemotherapy
`within 2 weeks. and those with a history of active liver
`disease. neurologic deficit secondary to spinal cord compres»
`sion. or a coexisting second primary malignancy were ineligi-
`ble. There were no restrictions in the extent of prior systemic
`therapy patients may have received. All patients gave inv
`formed consent according to the Department of Health.
`Education and Welfare [DH EW) and University of Wiscon~
`sin guidelines.
`
`10 {26%)
`
`PS
`
`21
`1?
`3
`
`4 (10%}
`24 (sass)
`
`MYLAN PHARMS. INC. EXHIBIT 1107 PAGE 2
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`

`

`KETACONAZOLE IN ADVANCED PROSTATE CANCER
`
`l 095
`
`and did not resolve with discontinuation of keto-
`
`conazole: in the third patient, nausea and vomit-
`ing began immediately on initiation of ketocona-
`sole. persisted despite dose reduction, and
`prompted drug discontinuation on day 15 of
`treatment. The other events leading to termina-
`tion of therapy were (I) acute myocardial infarc-
`tion, cardiogenic shock, and death on day 7 in a
`man with known coronary artery disease; (2)
`reversible mild renal dysfunction (creatinine 2.3
`mg/dL). which resolved with discontinuation of
`ketoconazole and nonsteroidal antiinflammalory
`agents; and (3) itchy teeth and hair loss without
`physical signs of toxicity or other toxic symptoms
`in this patient. Thirty patients were able to
`continue therapy without undue toxicity until
`clear cut response or progression occurred. and
`are evaluable for response.
`
`Clinical Response to Ketoconazole
`
`therapy. Characteristics of the responding pa-
`tients are noted in Table 2. The objective re-
`sponse rate following ketoconazole was low: 17%
`of evaluable patients and 13% of all patients
`entered. All five responding patients had under-
`gone orchicctomy prior to treatment with ketocon-
`azole. Disease-free interval. age, PS, disease
`distribution, and initial endocrinologic data were
`not remarkably difi'erent
`in these five patients
`compared with nonresponding patients.
`
`Endocrine Eflecls of
`Kemconazole/Hydrocortisone Therapy
`
`Improved
`No ch unge
`
`Improved
`Stable
`
`Total plasma T was low at entry in these
`patients (mean, 24.4 ng/dL; range, 0 to 26]
`ng/dL). Thirty of 3| patients, in whom pretreat-
`ment data were available. had plasma T < 100
`ng/dL. Nineteen patients with [0w plasma T had
`previously undergone Orchiectomy;
`in ll pa-
`tients,
`low T was aSSociated with hormonal
`therapy other than orchiectomy. One patient
`Of 30 patients completely evaluable for re
`entered this study with a low normal T (26]
`sponse. 24 developed progressive disease. The
`median time to progression was 82 days (range,
`ng/dL), though purportedly having received 3
`nine to 347 days). One patient remains stable
`mg/d DES within l week before study entry.
`without objective evidence of response or progres-
`Plasma T was not further diminished in patients
`during ketoconazole/hydrocortisone therapy. In
`sion at 455 days. This patientstopped ketocona-
`zole after 300 days. and continues to be stable on
`two nonorchiectomized patients, plasma T in the
`no treatment. Eighteen of 36 patients (50%) had
`low normal range {l27 ng/dL and l52 ng/dIL]
`either stable disease or bad responded 90 days
`was measured during ketoconazole/hydrocorti-
`sone therapy. In one of these patients, concomi-
`after beginning ketoconazole. Patients stopping
`therapy due to toxicity were considered treat-
`tant ketoconazole plasma concentration was 9.6
`ment failures. In five patients, objective evidence
`ug/dL, while in the second patient. ketoconazole
`was undetectable in the plasma. In the patient
`of tumor reduction was seen during ketoconazole
`
`Table 2. Patients Responding to Kelmnuole
`Tumor Masses P5 Bone Stun
`
`
`A'dd Phosphatase
`Normalized
`Normalized
`
`'Criterie met Ior obieclive tumor response.
`
`NE
`) 50% reduction pelvic“
`soil tissue masses
`> 50% reducfion* retro-
`peritoneol, retrocrurol
`udenopathy
`> 50% reduction‘ retro-
`peritoneal. pelvic aden-
`ope-thy
`> 50% reduction“ rem»
`peritoneal udenopo’rhy
`complete regression of
`palpable inguinal aden-
`opu‘lhy; improvement,
`biOpsyrpu-oven pulmo-
`nary infiltrate
`
`) 50% Reduction
`
`No ch unge
`
`Stable
`
`Normal on Eludy
`
`No change
`
`Normal on study
`
`No change
`
`Improved {resolution of
`coug h}
`
`Abbreviations: NE, not evaluable; PS, performance status; 'ITF. time to treatment failure.
`
`MYLAN PHARMS. INC. EXHIBIT 1107 PAGE 3
`
`

`

`l 096
`
`TRUMP ET Al.
`
`who entered the trial with plasma T of 261
`ng/dL. T decreased on kctoconazole/hydrocorti-
`sone to < 50 ng/dL on day 28.
`Plasma A2 content varied among patients at
`entry: it ranged from 6.9 to 202 ng/dL (normal,
`80 to 200 ng/dL).
`In 32 patients, data after
`initiation oftherapy were available; in 28.1%; was
`well below the lower limit of normal. In these 28
`
`patients. A; was 4:. 30 ng/dL, and in 22 A;
`content was undetectable (Fig 1). In four pa-
`tients. A; levels were not reduced by ketocona-
`zole/hydrocortisone therapy. However,
`in each
`of these, ketoconazole was not measurable in
`plasma samples obtained when A; was still detect-
`able.
`
`DHEAS plasma content was variable at the
`time of study entry (0 to 242 ag/mL) and was
`less completely reduced by this regimen.
`In 29
`patients, serial data were available and measur-
`able plasma levels of ketoconazole were present
`(Fig 2).
`In I? of these 29. a 50% or greater
`decrease in plasma DHEAS content occurred
`with ketoconazole/hydroeortisone therapy.
`Among the 'five patients who responded to
`therapy. A2 fell to undetectable levels in all five.
`and DHEAS was reduced by more than 50% in
`three of the four patients in whom serial data
`were available. However, the frequency of these
`endocrinologic effects are not strikingly different
`among responders and nonresponders.
`Estrogens were low at entry (mean. 7.0 pg/
`mL; normal. 40 to 115 pg/mL). Total estrogens
`remained at this low level throughout the study
`in all patients.
`Mean plasma ketoconazole concentration on
`150
`
`ysis did not appear to substantially change the
`
`56
`
`84
`
`112
`
`140
`
`153
`
`196
`
`Day
`
`of Therapy
`
`Fig 2. Mean plasma DHEAS concentrations before and
`during therapy with high-dose keloconozole. Error bars
`represent upper portion of standard error lot each meon
`value.
`
`day 23 of therapy was 6 ,ug/mL (range, 1.33 to
`15.5 ag/rnL). No significant
`relationship be-
`tween response or
`toxicity and ketoconazole
`plasma levels was evident. It is of interest that
`approximately l0% of patients at each monthly
`interval had plasma ketoconazole concentrations
`below the lower limit of detection. This indicates
`
`that appreciable levels of kctoconazole were not
`maintained in approximately 10% of patients.
`either because of rapid drug clearance or poor
`patient compliance.
`
`PSI‘A and Acid Phosphatase
`
`Among the five responders. acid phosphatase
`returned to normal in two. decreased by more
`than 50% in one. and was always normal in the
`remaining two patients. PSA decreased by more
`than 80% in four of five patients: in the fifth. the
`PSA was slightly increased and did not change
`during therapy, despite a reduction in retroperito-
`neal lymph nodes. In the small number of re-
`sponding patients. PSA seemed to reflect re-
`sponse better than acid phosphatase. Among 30
`nonresponders. serial acid phosphatase and PSA
`data were available in 26. In 12 patients (46%).
`PSA and acid phosphatase increased by more
`than 25%, coincident with clinical evidence of
`progressive diseaSe. In 13 patients. one or both
`markers either were stable or diminished when
`
`clinical progression was evident. In one patient
`with stable disease, PSA diminished and the acid
`phosphatase remained normal. Overall. PSA anal-
`
`125 _'
`
`100—
`
`75
`
`USE—'dfihtfl-HO‘Ifl)
`
`56
`
`84
`
`112 HO 168
`
`196
`
`DrayI
`
`of Th Eta py
`
`Fig I. Mean plasma A, concentrations before and during
`therapy with high-date hetoconozole. Error bars represent
`upper portion of standard error for each mean value.
`
`MYLAN PHARMS. INC. EXHIBIT 1107 PAGE 4
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`

`

`KETACONAZOlE IN ADVANCED PROSTATE CANCER
`
`1 097
`
`judgement regarding response or progression in
`these patients with advanced prostatic cancer.
`
`Toxicity
`
`of a randomized trial comparing CrnRHa with
`GnRHa plus antiandrogcns suggests a small. but
`significant,
`improvement
`in time to systemic
`progression for the combined treatment group.2
`Ketoconazole plus hydrocortisone as employed
`in our trial consistently reduces adrenal steroid
`production. Plasma DHEAS and A2 levels were
`substantially reduced in all patients in whom
`detectable ketoconazole levels could be mea-
`sured. This finding differs from the report of
`Ahmartn et a].21 who found that
`the adrenal
`steroid synthesis inhibitors aminoglutethimide
`and hydrocortisone were not effective in reducing
`plasma A2 levels. In the study of aminoglutethi-
`mide. DHEAS level fell in a manner similar to
`the changes we noted with ketoconazole plus
`hydrocortisone.
`From studies in which hydrocortisone has been
`used in conjunction with an adrenal antagonist, it
`is not clear what the relative roles of the antago-
`nist and the glucocorticoid are in reducing plasma
`androgens.
`In the present study. a physiologic
`replacement dose of hydrocortisone was em-
`ployed. It is unlikely that direct antiproliferative
`effects or nonspecific constitutional effects of
`hydrocortisone contributed to the responses that
`Wflf'C SCEU.
`
`addition. Rochlitz et a] have recently reported
`
`The major toxicity ol‘this regimen was nausea
`and vomiting. Thirty-seven percent of patients
`experienced at least grade 2 nausea and vomiting:
`one patient required dose reduction to control
`nausea and vomiting.
`In three patients, emesis
`was uncontrollable and prompted discontinuav
`tion of ketoconazole. Hepatic toxicity was not an
`important problem. Three patients experienced
`increase in plasma alkaline phosphatase without
`change in transaminases or bilirubin.
`In these
`three patients, progressive bone disease was
`present. In a fourth patient. hyperbilirubinemia
`occurred during ketoconazole therapy at a time
`when progressive hepatic metastases were evi-
`dent. Dose modification was not required for
`hepatic toxicity. No other serious or important
`drug-related toxicity was encountered. A com-
`mon complaint among patients in this trial was
`dryness of the skin. No objective findings were
`noted coincident with this complaint.
`
`DISCUSSION
`
`Treatment of men with prostatic cancer pro-
`gression despite antagonism of testicular andro-
`gens is unsatisfactory. For many years. attempts
`to further deprive these cancer cells of remaining
`androgens have been employed. A2 and DHEAS
`are the main androgens of adrenal origins. These
`compounds are weak androgens in their own
`right and may additionally be converted by a
`variety of peripheral body tissues to' T and
`dihydrotestosteronem'z' Adrenalectomy. hy-
`pophysectomy. antiandrogens. progestational
`agents. and aminoglutethimide have been used to
`either inhibit secretion of adrenal androgens or
`to antagonize androgen action on the tumor
`cells.3"“ While response rates as high as 40% to
`50% have been reported with these measures.
`clear-cut. objective tumor mass reduction is infre-
`quently seen. No improvement
`in survival
`is
`associated with the use of adrenal androgen
`antagonists as secondary hormonal therapy. Lab-
`rie et alI have proposed the use of adrenal and
`testicular androgen antagonists as part of total
`androgen deprivation in the initial treatment of
`advanced prostatic cancer.1 Preliminary analysis
`
`If one were to use stable disease at 90 days
`after initiation of therapy, a response criterion
`employed in other studies. 50% of patients would
`be considered responders. Overall, ketoconazole
`plus hydrocortisone Would have to be judged
`generally inefi‘ective as secondary hormone ther-
`apy for most patients with advanced prostatic
`cancer. However,
`it
`is provocative that definite
`tumor mass reduction was documented in five
`patients.
`
`It appears that a small subset of previously
`hormone-treated patients with prostatic cancer
`may respond to kctoconazole plus hydrocorti~
`sone. Responses were limited to patients who had
`undergone orchiectomy. This regimen was reason-
`ably well tolerated in prostatic cancer patients.
`The results of this study.
`the responses seen
`following aminoglutethimide. and the prelimi-
`nary data from the leuprolide plus or minus
`flutamide trial, all suggest a small. but poten-
`tially important. role for antagonism of adrenal
`androgens in individuals with prostate cancer. In
`
`MYLAN PHARMS. INC. EXHIBIT 1107 PAGE 5
`
`

`

`direct antiproliferative effects of ketoconazole, as
`well as the enhancement of the antiproliferative
`effects of
`fluorodeoxyuridine and etoposide
`(VPl 61.233“ This latter effect appears to be asse-
`
`ciated with enhanced intracellular retention of
`
`cytotoxic drug. Further exploration of ketocona-
`zole-cytetexic drug interaction may be war-
`ranted.
`
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`
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