Vol. 168, 2439—2443, December 2002
`Printed in U.S.A.
`DOI: 10.1097/01.ju.0000035648.32750.00
`
`
`
`m: mama Mn: panama bVCnvagm mum: 17 Usoude)
`
`
`0022-5347/02/1686-2439/0
`THE JOURNAL or UROLOGY®
`Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
`
`PHASE III STUDY OF MITOXANTRONE PLUS LOW DOSE PREDNISONE
`VERSUS LOW DOSE PREDNISONE ALONE IN PATIENTS WITH _
`ASYMPTOMATIC HORMONE REFRACTORY PROSTATE CANCER
`
`WILLIAM BERRY,* SHAKER DAKHIL, MANUEL MODIANO, MARYANN GREGURICH
`AND LINA ASMAR
`
`From U. S. Oncology, Houston, Texas
`
`ABSTRACT
`
`Purpose: We compared median time to treatment failure of men with asymptomatic, hormone
`refractory, progressive prostate cancer treated with mitoxantrone plus prednisone versus pred-
`nisone alone.
`Materials and Methods: In a multicenter phase III trial 120 men with asymptomatic, progres-
`sive, hormone refractory prostate cancer were randomly assigned to treatment with mitox-
`antrone and prednisone or prednisone alone. Patients received 12 mg./m.2 mitoxantrone intra-
`venously once every 3 weeks for 6 cycles and 5 mg. prednisone twice daily with or without
`mitoxantrone. Time to treatment failure was assessed as an aggregate end point comprised of
`time to disease progression, time to toxicity or death, or time to initiation of alternate therapy.
`Results: Median followup was 21.8 months. Median time to treatment failure and median time
`to progression were the same: time to treatment failure and time to progression in the mitox-
`antrone and prednisone group was 8.1 months compared to 4.1 months in the prednisone alone
`group (p = 0.017 versus p = 0.018). More patients (27 or 48%) treated with mitoxantrone and
`prednisone achieved a 50% or greater reduction in prostate specific antigen levels than those who
`received only prednisone (15 or 24%, p = 0.007). There was no significant difference in median
`survival between the 2 groups, which was 23 and 19 months, respectively. Death was mainly
`attributable to disease progression.
`Conclusions: Patients with hormone refractory prostate cancer who are asymptomatic but had
`progressive disease had a significantly higher response rate when treated with mitoxantrone and
`prednisone as demonstrated by the 50% or greater decrease in prostate specific antigen compared
`to treatment with prednisone alone. Time to treatment failure was significantly prolonged in the
`chemotherapy treated group but survival rates were not different.
`KEY WORDS: prostatic neoplasms; antineoplastic agents; comparative study; mitoxantrone; treatment outcome
`
`elapsed since antiandrogen treatment, systemic corticoste-
`
`Treatment for hormone refractory prostate cancer is typi-
`cally palliative and expected survival is 6 to 12 months.1»2 As
`no single agent treatment has been found to extend this
`survival estimate?“5 efforts have focused on drug combina-
`tions that may improve palliative response and work syner-
`gistically to improve survivalfi-12 One such promising com-
`bination, mitoxantrone13 and prednisone, has been evaluated
`for the treatment of symptomatic advanced cancers. In an
`early study Moore et a1 monitored changes in analgesic
`intake and quality of life in 27 patients treated with
`mitoxantrone and prednisone.12 Pain scores improved and
`were maintained in 36% of the patients treated. Likewise,
`mitoxantrone and prednisone also provided a palliative effect
`in 29% of 161 patients enrolled in a multicenter Canadian
`study.14 In a recent report from the Cancer and Leukemia
`Group B 9182 Study patients randomized to receive mitox-
`antrone and hydrocortisone had delays in the interval to
`disease progression and improved palliation of symptoms as
`a result of combined therapy.8 Findings from each of these
`studies supported early safety data that found mitoxantrone
`to be well tolerated. The main toxicity in this patient popu-
`lation was mild to moderate myelosuppression.15-16
`In this study we extend the investigations of Tannock et
`al14 and the Cancer and Leukemia Group B8 by evaluating
`
`Accepted for publication June 21, 2002.
`Sllrpported by Immunex Corporation, Seattle, Washington.
`*
`'nancial interest and/or other relationship with Bristol Myers
`Squibb; Immunex and Aventis.
`
`mitoxantrone and prednisone in asymptomatic patients with
`progressive hormone refractory prostate cancer. The primary
`objective was to compare time to treatment failure in each
`patient group. Secondary objectives included comparison of
`objective response rate, prostate specific antigen (PSA) de-
`crease, duration of response and survival.
`
`PATIENTS AND METHODS
`
`The study population for this open label, randomized,
`phase III trial consisted of 120 patients diagnosed with ade-
`nocarcinoma of the prostate. The U. S. Oncology Institutional
`Review Board approved the study protocol and informed
`consent was obtained from all trial participants. Recruitment
`took place from March 1997 to January 1999 and patients
`were randomly assigned to treatment with mitoxantrone and
`prednisone or prednisone alone. Surviving patients were fol-
`lowed for 4 years.
`All study participants exhibited asymptomatic, hormone
`refractory carcinoma of the prostate that had progressed on
`at least 1 hormonal regimen (orchiectomy or therapy with a
`luteinizing hormone releasing hormone analogue or diethyl-
`stilbestrol). Pretreatment disease progression was defined as
`increasing PSA (2-fold or greater increase over 2 determina-
`tions), 25% increase in number of bone scan lesions or 25%
`increase in size of soft tissue lesions.
`‘ Patients were eligible for enrollment if at least 4 weeks had
`
`MYLAN PHARMS. INC. EXHIBIT 1116 PAGE 1
`
`

`

`2440 MITOXANTRONE AND PREDNISONE FOR ASYMPTOMATIC HORMONE REFRACTORY PROSTATE CANCER
`
`time to 50% decrease in PSA, number of patients with objec-
`tive response, duration of response, time to development of
`symptoms of progressive disease and survival.
`Tumor response was judged by PSA and performance sta-
`tus and objective response by patients with measurable tu-
`mors. Treatment safety was evaluated by incidence of ad-
`verse experiences, changes
`from baseline in physical
`examination findings, changes from baseline in laboratory
`values, and changes in performance status and preexisting
`conditions. In this study toxicity referred to grade 3 and 4
`side effects (National Cancer Institute toxicity criteria)
`which occurred after exposure to the study drug. The treating
`physician assessed the relationship of each event to treat-
`ment.
`
`The study was designed to detect a difference in median
`time to treatment failure, which was 10 months for patients
`randomized to receive mitoxantrone and prednisone versus 4
`months
`for patients randomized to prednisone alone.
`Assuming a 2-year accrual period with a 1-year followup, 45
`evaluable patients per group were needed to detect this dif-
`ference using a 2-sided significance level of 0.05 and a power
`of 85%. In addition, it was assumed that there would be a
`dropout rate of 15 patients per group in year 1 resulting in 60
`patients per group, for a total of 120 patients.
`Efficacy analysis included 119 patients, and all patients
`who received at least 1 dose of study drug were analyzed for
`safety. Survival curves and time to progression were gener-
`ated using the Kaplan-Meier method,17 and the log-rank
`test18 was used to measure differences between the curves.
`Statistica ’99 Edition (StatSoft, Inc., Tulsa, Oklahoma) and
`SPSS for Windows, Release 10.0.5 (SPSS, Inc., Chicago,
`Illinois) were used for analysis.
`
`sion. The percentage of progression-free survival in the mi-
`
`roid therapy or radiotherapy, or at least 3 weeks had elapsed
`since major surgery. Requirements for pretreatment hema—
`topoietic status included an absolute neutrophil count of
`1,500 cells per ill. or greater (normal 1,500 to 7,500), platelet
`count 150,000 cells per Ml. or greater (normal 140 to 450,000)
`and hemoglobin 9 gm./dl. or greater (normal 12 to 18).
`Registered patients were also required to have adequate
`pretreatment liver and cardiac function, and an Eastern
`Cooperative Oncology Group (ECOG) performance status of 0
`to 2. Patients were excluded from study if they had a history
`of other malignancy within the last 5 years, parenchymal
`brain metastases, prior immunotherapy, prior chemotherapy
`or concurrent use of exogenous corticosteroids.
`Pre-study evaluation included complete medical history
`and physical examination. Laboratory assessments included
`a complete blood count with differential and platelet counts,
`PSA (normal less than 4.0 ng./ml.), serum glucose (normal 65
`to 110 mg./dl.) and liver chemistry screen. Additionally, each
`case was assessed clinically. Objective assessments of indi-
`cator lesions (computerized tomography, magnetic resonance
`imaging, bone scan, liver scan, ultrasound and/or x-rays)
`were performed within 6 weeks of study entry. Cardiac func-
`tion was evaluated before starting mitoxantrone. Patients
`randomized to mitoxantrone and prednisone received 12 mg./
`m.2 mitoxantrone by intravenous infusion for 15 to 30 min-
`utes once every 3 weeks for 6 cycles. A dose of 5 mg. pred-
`nisone was administered orally twice daily to all patients and
`was continued even after mitoxantrone therapy was stopped.
`All patients who had not undergone orchiectomy continued
`androgen suppressive therapy for the duration of the study.
`All other
`forms of hormone therapy were disallowed.
`Supportive care was administered at the discretion of the
`investigator. Patients were closely monitored for evidence of
`cardiac or hepatic toxicity that would require discontinuation
`or delay of treatment. Hematopoietic growth factors were
`administered according to American Society of Clinical
`Oncology guidelines as needed, and a maximum of 2, 25%
`dose reductions for mitoxantrone were allowed per patient.
`No dose reductions were made for prednisone. Treatment
`was delayed no more than 2 weeks to allow for recovery from
`acute toxicity. Patients were removed from the study for
`significant intercurrent illness, unacceptable toxicity, pro—
`gressive disease or patient request to withdraw.
`During treatment complete blood count with differential,
`platelet counts and liver function tests were assessed weekly
`in cycle 1 and before each succeeding cycle. PSA assessments
`were performed every other cycle through cycle 6, every 3
`months after cycle 6 and again at study termination.
`Radiological assessments were performed at the end of cycle
`6, every 3 months if PSA values were more than 50% over
`baseline and at study termination. Physical examination,
`complete tumor assessment and ECOG evaluation were per-
`formed at the end of every cycle. Patients who completed
`treatment were followed every 3 months for progression and
`survival. However, patients with disease progression or who
`withdrew from the study were followed forward only for
`survival. Patients who had progressive disease were then
`treated at the discretion of the attending physician. The
`study did not allow for crossover.
`The primary end point was time to treatment failure, an
`aggregate end point, defined by the interval between the
`start date of treatment and occurrence of progressive disease,
`removal from study or initiation of other antitumor therapy.
`Progressive disease was defined as a greater than 25% in-
`crease in sum of products of bidimensionally measurable
`masses, new soft tissue lesions or increasing bone lesions.
`Increasing PSA alone was not a criterion of progressive dis-
`ease but was considered to be indicative of progression if
`present with 1 of the aforementioned signs. Secondary effi-
`cacy end points were achievement of a 50% or greater de-
`crease in PSA with stable or improved performance status,
`
`RESULTS
`
`A total of 120 eligible patients with asymptomatic, progres-
`sive hormone refractory prostate cancer were registered for
`the study. Data were unavailable for 1 patient. Of the 119
`patients analyzed 56 were randomized to receive mitox-
`antrone and prednisone and 63 were randomized to receive
`prednisone alone. Median followup was 21.8 months (range
`2.4 to 50).
`Patient characteristics, including age, performance status
`and extent of disease involvement, were well balanced be-
`tween the 2 groups and no statistically significant differences
`were detected (table 1). Median serum PSA at study entry
`ranged from 3.7 to 2,375.0 ng./ml. (median 56.7) in the mi-
`toxantrone and prednisone group and 1.1 to 1,233.0 ng./ml.
`(median 71.0) in the prednisone group. A total of 71 patients
`(60%) had received prior radiation therapy and 65 (55%) had
`undergone prior surgery. The ECOG performance status was
`0, 1 and 2, respectively, in 42, 13 and 1 patients in the
`mitoxantrone and prednisone group and 47, 16 and 0 in the
`prednisone group.
`Tumor characteristics at baseline are given in table 2.
`Measurable tumors were present in 8 of the mitoxantrone
`and prednisone and 9 of the prednisone cases. Nonmeas-
`urable tumors and increased PSA levels were present in 46
`(82%) of the mitoxantrone and prednisone and 49 (78%) of
`the prednisone cases. An increasing PSA was the only sign of
`disease in 7 patients. Of the patients 98 (82%) had bone as
`the metastatic site, 21 (18%) had metastasis in the lymph‘
`nodes and 7 (6%) had metastasis in the liver or lung.
`By treatment arm time to treatment failure and time to
`progression were found to be equivalent. Estimated median
`time to treatment failure/time to progression from treatment
`start was 8.1 months (range 1 to 50) for the mitoxantrone
`and prednisone group and 4.1 months (range 1 to 37) for the
`prednisone group (p = 0.017 versus p = 0.018). For simplicity
`the remaining results will be presented as time to progres-
`
`MYLAN PHARMS. INC. EXHIBIT 1116 PAGE 2
`
`

`

`TABLE 1. Pretreatment patient characteristics by randomized group
`Mitoxantrone
`Prednisone
`and
`Alone Total
`
`Prednisone
`No. race (%):
`White
`Black
`Hispanic
`Age:
`Median
`Range
`No. performance status (%):
`
`52 (93)
`4 (7)
`0 (0)
`
`70
`49—87
`42 (75)
`13 (23)
`1
`(2)
`
`53 (84)
`6 (10)
`4
`(6)
`
`74
`51—90
`47 (75)
`16 (25)
`0 (0)
`
`105 (89)
`10 (8)
`4 (3)
`
`71
`49—90
`89 (75)
`29 (24)
`1
`(1)
`
`No. diagnosis stage (%):
`A
`B1
`B2
`C1
`C2
`D1
`D2
`D3
`Unknown
`No. radical prostatectomy (%):
`Yes
`No
`No. definitive local radiotherapy (%):
`
`2 (4)
`4 (7)
`10(18)
`3 (5)
`5 (9)
`9(16)
`19 (33)
`1
`(2)
`3 (5)
`
`5 (8)
`2 (3)
`9(14)
`9(14)
`2 (3)
`13 (21)
`21 (34)
`O (0)
`2 (3)
`38 (60)
`25 (40)
`
`7 (6)
`6 (5)
`19 (16)
`12 (10)
`7 (6)
`22 (18)
`40 (34)
`1
`(1)
`5 (4)
`
`65 (55)
`54 (45)
`
`27(48)
`29 (52)
`71 (60)
`36 (64)
`35 (56)
`47 (39)
`27 (43)
`20 (36)
`1
`(1)
`0 (0)
`1
`(1)
`
`
`2441
`MITOXANTRONE AND PREDNISONE FOR ASYMPTOMATIC HORMONE REFRACTORY PROSTATE CANCER
`line lasting 2 or more months with stabilization or improve—
`ment of performance status for at least 2 weeks occurred in
`27 (48%) patients who received mitoxantrone and prednisone
`and 15 (24%) who received P alone (p = 0.007). As shown in
`table 3 'median time to achieve a serum PSA decrease of 50%
`or greater was 2.2 months for both groups.
`'
`Table 4 presents a comparison of time to progression for
`PSA responders and nonresponders. There was no statis-
`tically significant difference in estimated median time to
`progression for patients with a PSA response, which was
`13.5 months (range 3.5 to 46.5) in the mitoxantrone and
`prednisone group and 11.7 months (range 6.5 to 46) in
`the prednisone group. However, estimated median time to
`progression for patients who did not have a PSA response
`was 6.9 months (range 1.1 to 35) in the mitoxantrone and
`prednisone group (p = 0.007) versus 3.2 months (range 0.9
`to 34.5) in the prednisone group. Of the patients with
`measurable tumors 2 (25%) in the mitoxantrone and pred-
`nisone group and 2 (22%) in the prednisone group had partial
`responses. No patient experienced a complete response.
`Among the 119 patients analyzed 91 (76%) died within 4
`years of the start of the study, including 43 (77%) in the
`mitoxantrone and prednisone group and 48 (76%) in the
`prednisone group, and death was mainly attributable to pro-
`gressive disease. As shown in figure 2 estimated median
`survival from treatment start for the mitoxantrone and pred—
`nisone group was 23 months (range 3 to 49) compared to 19
`months (range 2 to 50) for the prednisone group (p = 0.48).
`Percent survival at 12 and 24 months in the mitoxantrone
`and prednisone group compared to the prednisone group was
`82% and 45% versus 76% and 44%, respectively. Median
`survival times for patients who responded in the mitox-
`antrone and prednisone and prednisone alone groups were 32
`and 33 months, respectively (ranges 11.2 to 46.5 and 9.5 to
`50). A summary of toxicities occurring at any time during
`treatment is presented in table 5. There were no treatment—
`related deaths.
`
`3.0—22.2
`
`TABLE 2. Pretreatment tumor characteristics by randomized group
`No. Mitoxantrone
`.
`.
`No. Prednisone
`Total No. (%)
`and Predmsone
`
`(%)
`Alone (%)
`Tumor:
`Measurable
`PSA only
`Nonmeasurable
`Metastatic sites:*
`98 (82)
`50(79)
`48 (86)
`Bone
`21(18)
`11(18)
`10 (18)
`Lymph nodes
`5 (4)
`4 (6)
`1
`(2)
`Lung
`2 (2)
`Liver
`0 (0)
`2 (4)
`
`* Some patients had more than 1 metastatic site.
`
`8 (14)
`2 (4)
`46 (82)
`
`9 (14)
`5 (8)
`49 (78)
`
`17 (14)
`7 (6)
`95 (80)
`
`toxantrone and prednisone group at 12 and 24 months after
`treatment start compared to the prednisone group was 36%
`and 13% versus 15% and 10%, respectively (fig. 1).
`Patients were evaluated according to serum PSA changes,
`performance status and, when possible, by objective re-
`sponse. A 50% or greater decrease in serum PSA from base-
`
`— MOP = 56 Pts
`'
`P=63Pts
`P-D.D1B
`
`91215 18 2124 27
`Months
`
`30 3336
`
`39
`
`42
`
`45
`
`48
`
`FIG. 1. Estimated time to progression (TTP) for patients who re-
`ceived mitoxantrone and prednisone (M + P) versus prednisone (P)
`alone.
`
`DISCUSSION
`
`Recent large, randomized studies have confirmed a role for
`systemic therapy with mitoxantrone and corticosteroids for
`hormone refractory prostate cancerfi- 14 Our results extend
`the earlier findings by indicating a benefit of mitoxantrone
`and prednisone in a subgroup of patients with asymptomatic
`hormone refractory prostate cancer. Time to treatment fail-
`ure was improved for patients who received mitoxantrone
`and prednisone versus those who were treated with pred-
`nisone alone. However, as noted in other efficacy trials of
`mitoxantrone, survival benefit could not be demonstrated for
`mitoxantrone and prednisone in this study population. This
`finding may, in part, be explained by study design. Patients
`whose disease progressed on prednisone alone and who were
`taken off the study likely received mitoxantrone and pred-
`nisone or another systemic chemotherapy regimen at the
`
`
`
`TABLE 3. Median time to 50% or greater serum PSA responses by
`treatment arm
`
`Increase After
`PSA
`Reduction
`Nad" Nadir
`Mitoxantrone and prednisone (56):
`N0.
`Av. mos.
`Range
`P alone (63):
`
`27
`2.2
`0.6—4.6
`15
`2.2
`0.2—7.1
`
`27
`5.0
`l.6—18.5
`15
`4.2
`1.6—16.5
`
`15
`7.2
`3.0—22.2
`9
`8.0
`4.6—10.6
`
`42
`2.2
`0.2—7.1
`
`42
`4.7
`1.6—18.5
`
`24
`7.3
`
`MYLAN PHARMS. INC. EXHIBIT 1116 PAGE 3
`
`

`

`2442 MITOXANTRONE AND PREDNISONE FOR ASYMPTOMATIC HORMONE REFRACTORY PROSTATE CANCER
`
`TABLE 4. Median survival and time to progression by serum PSA
`reduction
`
`PSA Reduction
`50% or Greater
`Less Than 50%
`
`Mitoxantrone and prednisone (56):
`No. (%)
`Av. survival (mos.)
`Av. time to progression (mos)
`P alone (63):
`No. (%)
`48 (76)
`15 (24)
`18.3
`32.9
`Av. survival (mos.)
`3.2
`11.7
`Av. time to progression (mos.)
`Patients who experienced an increase in PSA from baseline were included in
`the analysis of patients with less than 50% PSA reduction.
`
`27 (48)
`31.8
`13.5
`
`29 (52)
`18.3
`6.9
`
`
`
`ProportionSurvlvlng
`
`This study also confirmed the value of prednisone as a
`single agent for the treatment of hormone refractory prostate
`cancer. In the prednisone group 24% were PSA responders,
`and the time to progression and survival were similar to
`those of PSA responders in the mitoxantrone and prednisone
`group. Although a greater percentage (48% versus 24%) of
`the mitoxantrone and prednisone group were PSA respond-
`ers, prednisone alone is a potentially beneficial therapy for
`selected patients with hormone refractory prostate cancer.
`
`CONCLUSIONS
`
`This study reaffirms the efficacy of mitoxantrone and pred-
`nisone for the treatment of hormone refractory prostate can-
`cer and suggests that potential benefit exists in treating
`asymptomatic men with this disease. In this patient group
`mitoxantrone and prednisone using a regimen of reasonably
`low toxicity delayed the onset of progressive disease. Survival
`benefit has not been demonstrated and, thus, future studies
`of treatment of patients with varying stages of advancing
`prostate cancer are warranted. The Southwest Oncology
`Group (SWOG) is pursuing 2 such studies. SWOG 9916/
`Cancer and Leukemia Group B is an intergroup trial that
`will compare the effectiveness of mitoxantrone and pred-
`nisone to docetaxe] and estramustine for the treatment of
`androgen independent metastatic carcinoma of the prostate.7
`SWOG 9921 will compare the effectiveness of mitoxantrone
`and prednisone combined with androgen ablation in patients
`presenting with high risk local disease.
`
`1997
`
`. Ripple, G. H. and Wilding, G.: Drug development in prostate
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`. Smith, D. C.: Chemotherapy for hormone refractory prostate
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`. Vogelzang, N. J., Crawford, E. D. and Zietman, A.: Current
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`. Hussain, M. H., Pienta, K. J., Redman, B. G., Cummings, G. D.
`and Flaherty, L. E.: Oral etoposide in the treatment of
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`. Roth, B. J., Yeap, B. Y., Wilding, G., Kasimis, B., McLeod, D. and
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`. Dowling, A. J., Czaykowski, P. M., Krahn, M. D., Moore, M. J.
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`. Hussain, M., Petrylak, D., Fisher, E., Tangen, C. and Crawford,
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`(Taxotere) and estramustine versus mitox-
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`cer: scientific basis and design of Southwest Oncology Group
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`. Kantofi', P. W., Halabi, S., Conaway, M., Picus, J., Kirschner, J.,
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`_
`. Osaba, D., Taxmock, I. E, Ernst, D. S. and Neville, A. J.2 Health-
`related quality of life in men with metastatic prostate cancer '
`treated with prednisone alone or mitoxantrone and pred-
`nisone. J Clin Oncol, 17: 1654, 1999
`. Savarese, D., Halabi, S., Hars, V., Akerley, W. L., Taplin, M. E.,
`Godley, P. A. et al: Phase II study of docetaxel, estramustine,
`and low-dose hydrocortisone in men with hormone-refractory
`prostate cancer: a final report of CALGB 9780 (Cancer and
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`. Siu, L. L. and Moore, M. J.: Other chemotherapy regimens in-
`cluding mitoxantrone and suramin. Semin Urol Oncol, 15: 20,
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`27
`
`30
`
`33
`
`36
`
`24
`Momhs
`
`39
`
`42
`
`45
`
`48
`
`Many patients, U. S. Oncology physicians, coordinators,
`project managers and data reviewers assisted in this study.
`
`REFERENCES
`
`for patients who received mitox-
`FIG. 2. Estimated survival
`antrone and prednisone (Ill + P) versus prednisone (P) alone.
`
`
`TABLE 5. Incidence of drug related toxicities (grade greater than 3)
`No. Mitoxantrone
`Total
`No. Prednisone
`and Prednisone
`No. (%)
`Alone (%)
`(%)
`27 (48)
`Neutropenia
`ll (20)
`Leukopenia
`4 (7)
`Pulmonary complications
`3 (5)
`Asthenia
`1
`(2)
`Renal complications
`3 (5)
`Gastrointestinalcomplications
`2 (4)
`Sepsis
`1
`(2)
`Melanoma
`Some patients had more than 1 toxic reaction.
`
`33 (28)
`16 (13)
`(7)
`(5)
`(3)
`(3)
`(2)
`(1)
`
`6 (10)
`(8)
`(6)
`(5)
`(5)
`(2)
`(0)
`(0)
`
`time of progression, and some of those patients would likely
`have responded to subsequent treatment. As a result it was
`anticipated that survival curves for the 2 arms of the trial
`were likely to be similar.
`This study reaffirmed the value of PSA as a reasonably
`good surrogate marker of disease response.19 As noted in
`other studies, a PSA response of 50% or more in either
`treatment arm correlated with improvement in time to treat-
`ment failure and survival.6"5'-20 PSA response in the present
`study was higher (48%) than in either the Canadian14 (33%)
`or Cancer and Leukemia Group B3 studies (33%). Median
`overall survival for all patients in our study was estimated to
`be 23 months, as opposed to 12 months in the Canadian and
`Cancer and Leukemia Group B studies. Better survival time
`is not unexpected given that patients who were enrolled in
`our study were asymptomatic and had lower median baseline
`PSA than those in the Cancer and Leukemia Group B and
`Canadian trials. Nevertheless, the observation that PSA re-
`sponse was higher in this progressing but asymptomatic
`group of patients than in either of the studies of symptomatic
`patients is noteworthy.
`
`MYLAN PHARMS. INC. EXHIBIT 1116 PAGE 4
`
`

`

`'
`
`12. Moore, M. J., Osoba, D., Murphy, K., Tannock, I. F., Armitage,
`A., Findlay, B. et a1: Use of palliative end points to evaluate
`the effects of mitoxantrone and low-dose prednisone in pa—
`tients with hormonally resistant prostate cancer. J Clin Oncol,
`12: 689, 1994
`13. Poirier, T. 1.: Mitoxantrone. Drug Intell Clin Pharm, 20: 97, 1986
`14. Tannock, I. F., Osoba, D., Stockler, M. R., Ernst, D. S., Neville,
`A. J., Moore, M. J. et a1: Chemotherapy with mitoxantrone
`plus prednisone or prednisone
`alone
`for
`symptomatic
`hormone-resistant prostate cancer: a Canadian randomized
`trial with palliative end points. J Clin Oncol, 14: 1756, 1996
`15. Wiseman. L. R. and Spencer, C. M.: Mitoxanh‘one. A review of its
`pharmacology and clinical eflicacy in the management of hormone-
`resistant advanced prostate cancer. Drugs Aging, 10: 473, 1997
`16. Kantoff, P. W., Block, C., Letvak, L. and George, M.: 14-Day
`continuous infusion of rnitoxantrone in hormone-refractory
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`2443
`MITOXANTRONE AND PREDNISONE FOR ASYMPTOMATIC HORMONE REFRACTORY PROSTATE CANCER
`metastatic adenocarcinoma of the prostate. Am J Clin Oncol,
`16: 489, 1993
`17. Kaplan, E. L. and Meier, P.: Nonparametric estimation from
`incomplete observations. J Am Stat Assoc, 53: 457, 1958
`18. Mantel, N.: Evaluation of survival data and two new rank order
`statistics arising in its consideration. Cancer Chemother Rep,
`50: 163, 1966
`19. Bubley, G. J., Carducci, M., Dahut, W., Dawson, N., Daliani, D.,
`Eisenberger, M. et a1: Eligibility and response guidelines for
`phase II clinical trials in androgen-independent prostate can-
`cer:
`recommendation from the Prostate—Specific Antigen
`Working Group. J Clin Oncol, 17: 3461, 1999
`20. Kelly, W. K., Scher, H. I., Mazumdar, M., Vlarnis, V., Schwartz,
`M. and Fossa, S. D.: Prostate-specific antigen as a measure of
`disease outcome in metastatic hormone-refractory prostate
`
`cancer. J Clin Oncol, 11: 607, 1993
`
`MYLAN PHARMS. INC. EXHIBIT 1116 PAGE 5
`
`