The Prostate 52:264 ^268 (2002)
`
`SWOG-9510: Evaluation of Topotecan in Hormone
`Refractory Prostate Cancer: A Southwest Oncology
`Group Study
`
`Catherine E. Klein,1* Catherine M. Tangen,2 Thomas J. Braun,1
`Maha H.A. Hussain,3 David M. Peereboom,4 Craig R. Nichols,5 Saul E. Rivkin,6
`Shaker R. Dakhil,7 and E. David Crawford1
`1Universityof Colorado, Denver,Colorado
`2Southwest Oncology Group Statistical Center, Seattle,Washington
`3Wayne State University Medical Center, Detroit, Michigan
`4Cleveland Clinic Foundation,Cleveland,Ohio
`5Oregon Health Sciences University, Portland,Oregon
`6Puget Sound Oncology Consortium, Seattle,Washington
`7Wichita Community Clinical Oncology Program,Wichita,Kansas
`
`BACKGROUND. Prostate cancer is the most common malignancy in American men, and as
`many as 70% of those initially treated for localized disease will ultimately progress and be
`considered candidates to receive therapy for metastatic cancer [1,2]. Although most will
`respond initially to hormone manipulation, essentially all will fail and require additional
`therapy. No standard chemotherapy approach has been shown to prolong survival signifi-
`cantly, and new agents are desperately needed. Topotecan is a new topoisomerase-1 inhibitor
`whose early investigation suggested possible activity in hormone-refractory prostate cancer.
`METHODS. In this phase II trial, patients having failed one or two prior androgen ablative
`therapies were treated with 21-day continuous intravenous infusions of topotecan at a dose of
`0.5 mg/m2 per day every 28 days.
`RESULTS. Twenty-six eligible patients were entered on the study. There were no confirmed
`tumor responses. Median survival was 9 months. The most common toxicities were
`hematologic, with 8 of 24 assessable patients experiencing grade 4 toxicity.
`CONCLUSION. Topotecan infusions at this dose are ineffective in the management of
`hormone-refractory prostate cancer. Prostate 52: 264–268, 2002. # 2002 Wiley-Liss, Inc.
`
`KEY WORDS: hormone refractory prostate cancer; topotecan; clinical trial
`
`INTRODUCTION
`
`Prostate cancer is the most common malignancy in
`American men and kills approximately 40,000 patients
`each year. Although many men with this tumor will
`have an indolent course and succumb to other pro-
`cesses, a large percentage will present with or develop
`metastatic disease after initial therapy and would
`benefit from effective therapy to control metastatic
`disease and its debilitating symptoms [1,2]. In the vast
`
`Grant sponsor: National Cancer Institute; Grant numbers: DHHS:
`CA38926, CA32102, CA04919, CA46113, CA20319, CA35431,
`CA63844, CA35281, CA58861, CA37981, CA45807, CA96429,
`CA12213, CA45560, CA14028, CA76462.
`*Correspondence to: Catherine E. Klein, Denver VAMC, Medical
`Oncology 11B, 1055 Clermont Street, Denver, CO 80220-3808.
`E-mail: catherine.klein@med.va.gov
`Received 15 August 2001; Accepted 29 March 2002
`DOI 10.1002/pros.10118
`
`ß 2002 Wiley-Liss, Inc.
`
`AVENTIS EXHIBIT 2207
`Mylan v. Aventis IPR2016-00712
`
`

`
`majority of such patients, androgen deprivation dra-
`matically improves symptoms and lowers prostate
`specific antigen (PSA), but unequivocal evidence that
`endocrine therapy prolongs survival is lacking, and
`cure is not a reasonable expectation. The median dura-
`tion of response to androgen ablation is 12–18 months,
`at which time essentially all responders relapse.
`Second-line hormonal therapy benefits the minority
`of patients. PSA decline or symptom improvement is
`documented in 20–25% of men after withdrawal of
`antiandrogens, administration of megestrol acetate,
`glucocorticoids, bicalutamide, and ketoconazole, but
`no survival increase has been documented after any
`second-line endocrine therapy [3–5].
`Clinical trials of conventional cytotoxic chemother-
`apeutic agents in the treatment of hormone-refractory
`prostate cancer have been disappointing. Yagoda and
`Petrylak [6] reviewed 26 studies completed between
`1988 and 1991 and found an overall response rate of
`only approximately 9%, and no indication of any
`prolongation in average survival. More recent studies
`have combined the most promising of the single
`agents, including mitoxantrone, estramustine, and tax-
`anes. Although these reports suggest that combination
`chemotherapy may increase the response rate among
`hormone-refractory prostate cancer patients, no cur-
`rent treatment clearly improves survival to any mean-
`ingful extent [7,8].
`Topotecan is a semisynthetic analogue of camp-
`tothecin, a plant alkaloid derived from the stem wood
`of the Chinese tree Camptotheca acuminata. Its mecha-
`nism of action is the inhibition of the enzyme topo-
`isomerase I, important in DNA replication where it
`produces reversible single-strand breaks to relieve the
`torsional strain ahead of the replication fork, allowing
`the free replicating DNA strand to proceed.
`In preclinical studies,
`topotecan demonstrated
`activity in chemorefractory murine colon carcinomas,
`in B16 melanoma, Lewis lung carcinoma and L1210
`leukemia [9,10]. In human tumor cloning assays, it has
`activity against ovary, breast, renal, gastric, and lung
`carcinoma cells [11,12]. Early data suggest that the
`drug activity is more related to target enzyme level
`rather than to cell proliferative rate, an indication that
`slower-growing prostate cancer might be susceptible
`to topotecan administration [13]. Phase I studies have
`indicated that topotecan has activity in ovarian, non-
`small cell lung cancer, colorectal, renal cancer, and acute
`leukemia, other tumors often regarded as chemorefrac-
`tory [14,15]. Consistent with its known S-phase–specific
`mechanism of action, drug delivery by continuous
`infusion in these models is more effective than short-
`term administration [16]. Consequently the South-
`west Oncology Group initiated a phase II trial to assess
`the activity of continuous intravenous infusion of
`
`Topotecan in Prostate Cancer
`
`265
`
`topotecan in the treatment of hormone-refractory
`prostate cancer.
`
`PATIENTS AND METHODS
`
`Patient Population
`
`Patients with a SWOG criteria performance status
`of 0–2 and a histologic diagnosis of metastatic adeno-
`carcinoma of the prostate unresponsive or refractory
`to hormone therapy were eligible for the study. They
`must have failed at least one, but not more than two,
`prior androgen ablative therapies, and PSA must have
`risen after 1 month after cessation of all hormone
`therapy other than maintenance leuprolide. Patients
`were required to have bidimensionally measurable or
`evaluable disease. Baseline PSA 20 was considered
`evaluable disease. No prior chemotherapeutic agents
`or biologic response modifiers and no concomitant
`radiotherapy were permitted. Eligible patients were
`required to have adequate organ function as defined
`by a granulocyte count > 1,500 mm3 and platelet count
`of > 100,000 mm3, normal hepatic function, and a
`serum creatinine < 1.6 mg/dl. Prior radiation was
`allowed if it encompassed less than 25% of the bone
`marrow volume and had to be completed at least
`3 weeks before entry on the study. Patients with prior
`nonskin malignancies were excluded. All patients
`gave written, informed consent.
`
`Treatment Plan
`
`After insertion of a semipermanent venous access
`device, topotecan was administered as a continuous
`intravenous infusion of 0.5 mg/m2 per day for 21 days,
`followed by a 7-day rest period. Treatment cycles were
`continued at 28-day intervals until disease progression
`(after a minimum of two cycles), unacceptable toxicity,
`or patient decision to withdraw. All patients were
`followed until death.
`
`Toxicity
`
`Toxicity was evaluated according to the standard
`Southwest Oncology Group criteria.
`
`Dose Modif|cations
`
`Infusions were suspended for the rest of the cycle
`for ANC < 1,000 mm3, platelet count of < 50,000 mm3,
`unresolvable Grade 3 toxicity or any Grade 4 toxicity.
`Routine, prophylactic use of colony stimulating factors
`was prohibited. Dose reduction to 0.4 mg/m2 per day
`was undertaken for nadir ANC < 500/mm3, platelet
`count < 50,000/mm3 or any Grade 3 or greater toxicity.
`If, after dose reduction, nadir ANC was again
`< 500/mm3 or platelet count was <50,000/mm3, the
`
`

`
`266
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`Klein et al.
`
`patient was withdrawn from the protocol therapy. No
`dose escalation was permitted.
`
`TABLE I. Baseline Demographics for 25 Evaluable
`Patients*
`
`Study Design
`
`Initially 20 patients were to be accrued. If at least
`one of the first 20 patients responded, then an addi-
`tional 20 patients would be accrued. Five or more
`responses out of 40 patients would be considered evi-
`dence warranting further study of the regimen, pro-
`vided other factors such as toxicity and survival also
`appeared favorable. This design has a significance
`level of 5% and a power of 92%.
`
`Response Criteria
`
`Response to treatment was assessed after every
`cycle with PSA level and after every second cycle with
`radiologic evaluation. Standard solid tumor response
`criteria were used. Complete response was defined as
`the total disappearance of all measurable and evalu-
`able disease, with no new disease, no disease-related
`symptoms and no evidence of nonevaluable disease,
`including the resolution of all abnormal serum
`markers and lab values. PSA must have declined
`to < 4.0 ng/ml.
`Partial response was defined only in those with
`measurable disease and required a 50% or greater
`decrease from baseline in the sum of products of
`perpendicular diameters of all measurable disease, no
`progression of evaluable disease, and no appearance
`of new disease.
`Progression was defined as a 50% increase or an
`increase of 10 cm2 (whichever was smaller) in the sum
`of products of all measurable lesions over the smallest
`sum obtained, clear worsening of evaluable disease,
`reappearance of any lesion which had disappeared,
`the appearance of any new lesion or a 50% increase
`over minimum PSA obtained. PSA 4ng/ml after
`previous normalization was also considered to be
`progression.
`
`RESULTS
`
`Demographic Data
`
`A total of 31 patients were entered on the trial
`between November 1, 1996, and January 1, 1998. Of
`these patients, five were ineligible and one was not
`analyzable because no protocol treatment was ever
`received, for a total of 25 patients to be included in the
`analysis of this study (Table I). Patients were ineligible
`for the following reasons: rising PSA in the 42 days
`before registration was not documented in two
`patients; PSA level was obtained over 42 days before
`registration in one patient; in one patient, no prestudy
`
`Median age (range) years
`Median PSA (range) ng/ml
`Mean hematocrit (range)
`Mean Gleason score (range)
`Gleason score 8–10 (%)
`Visceral involvement (%)
`Performance status 0–1(%)
`Prior orchiectomy (%)
`>1 prior hormone (%)
`Prior radiation (%)
`
`*PSA, prostate specific antigen.
`
`68
`135
`35.2
`7.2
`11
`6
`21
`15
`8
`16
`
`(54–83)
`(20–3724)
`(25.2–46.5)
`(6–10)
`(44)
`(24)
`(84)
`(60)
`(32)
`(64)
`
`chest radiograph was obtained; and one patient did
`not have a testosterone level obtained within 28 days
`of registration.
`The median age was 68.0 years (range, 54–83 years).
`Eighteen patients were white, 4 were African
`American, 2 were Hispanic, and 1 was Asian. Twenty-
`one patients had a performance status of 0–1, 4 had
`performance status of 2. Six patients had visceral
`involvement. Median PSA was 135 ng/ml (range, 20–
`3724 ng/ml).
`
`Treatment
`
`Fifteen patients were removed from treatment for
`progressive disease, 7 because of unacceptable toxi-
`city, 1 patient refused to continue therapy, and
`2 patients died while on study from causes not
`believed to be treatment-related. (One died of heart
`failure 1 day after starting therapy. He had triple vessel
`coronary disease. The other died of progressive dis-
`ease.) Of the 15 patients removed from treatment for
`progression, 3 had rise in PSA as the only indication of
`worsening disease. Thirteen patients completed at
`least two cycles of therapy (range, 1–6).
`
`Toxicity
`
`Twenty-four patients could be assessed for toxicity.
`The one patient not assessable for toxicity is the eligible
`and evaluable patient who died of heart failure 1 day
`after initiating therapy, hence no toxicity notation was
`done. There were no treatment-related deaths. Eight
`patients experienced grade 4 toxicity (1 epistaxis,
`6 granulocytopenia, and 1 leukopenia without granu-
`locytopenia). Eleven patients experienced grade 3 toxi-
`city as their worst grade: most commonly anemia
`(9 patients), thrombocytopenia (8 patients), leukope-
`nia (7 patients), and 1 each experienced hematuria,
`confusion, infection, and nausea (Table II).
`
`

`
`TABLE II. Number of Patients and Degree of Toxicity
`
`Grade
`
`Toxicity
`
`1/2
`
`Alopecia
`Anemia
`Confusion
`Diarrhea
`Epistaxis
`Fatigue
`Fever
`Hematuria
`Leukopenia
`Nausea
`Neutropenia
`Stomatitis
`Thrombocytopenia
`Vomiting
`Weakness
`Max grade any toxicity
`
`3
`14
`23
`32
`2
`13
`5
`1
`10
`13
`4
`4
`9
`7
`3
`5
`
`3
`
`0
`9
`1
`0
`0
`0
`0
`1
`7
`1
`3
`0
`8
`0
`0
`11
`
`4
`
`0
`0
`0
`0
`1
`0
`0
`0
`5
`0
`6
`0
`0
`0
`0
`8
`
`Response
`
`Nine patients had inadequate tumor-response
`assessment and are considered nonresponders. Five
`patients had stable disease, no patient had a docu-
`mented complete or partial response. Four patients
`(16%) had a decline of PSA by 50% from baseline. Only
`one of these patients had stable disease by standard
`response criteria. At the time of reporting, all but one
`patient have died. The median survival for the group
`was 9 months.
`
`DISCUSSION
`
`Effective therapy for hormone-refractory prostate
`cancer has been elusive; progress in this area has been
`hampered by a dearth of effective agents and by the
`inherent difficulty in measuring tumor response in the
`majority of prostate cancer patients whose evident
`metastatic disease is limited to bony structures. Re-
`cently, however, reports have indicated that change in
`serum PSA is a reliable indicator of tumor response in
`patients with hormone refractory prostate cancer [17].
`In addition, a variety of new agents have been eval-
`uated in these patients, and response rates have been
`encouraging [18,19].
`Our study allowed evaluation of PSA change from
`baseline for tumor response measurement in patients
`without traditional bidimensionally measurable dis-
`ease. Change in PSA could be used to define a complete
`response, but no ‘‘partial PSA response’’ was defined.
`By using these criteria, our study has demonstrated
`that topotecan administered as a 21-day infusion of
`
`Topotecan in Prostate Cancer
`
`267
`
`0.5 mg/m2 per day to men with hormone-refractory
`prostate cancer is of no therapeutic benefit and is
`associated with significant, largely hematologic toxi-
`city. The median survival of 9 months in this group,
`somewhat less than seen in similar contemporary
`series, further indicates that topotecan offered no signi-
`ficant benefit. A review of the demographic features of
`our patient population at study entry does not reveal
`an obvious explanation for the poor response rate seen
`in this study. Median age, Gleason score, and intensity
`of prior therapy are in line with prior SWOG trials.
`However, ours is not the first study failing to demon-
`strate topotecan activity in the treatment of hormone
`refractory prostate cancer. Hudes et al. evaluated
`30-min infusions daily for 5 consecutive days in
`37 patients. One response was seen in the first
`14 patients treated, allowing continued accrual, but
`the final reported response rate was only 2.9% [13].
`As anticipated, the major toxicity from topotecan
`infusion in our study was hematologic. Nearly two
`thirds of assessable patients experienced grade 3 or
`4 hematologic toxicity. Six of 40 administered cycles
`(16%) required dose modification or delay in treat-
`ment. Whether growth factor support would allow
`better adherence to treatment dose and schedule is
`unknown. One published report of a Phase I study
`allowing granulocyte colony stimulating factors sup-
`port in conjunction with 5-daily 30-min topotecan
`infusions, suggests it would not [14]. The relatively
`young age of our population (median, 68 years) and
`their overall good performance status would indicate
`that patient selection was not an important variable in
`our inability to demonstrate activity of topotecan in
`this setting. The large number of patients whose re-
`sponse was not adequately assessed is troubling and
`not readily explained. The baseline demographic fea-
`tures of this group are not significantly different from
`the others. Several were removed from the study for
`early toxicity before tumor assessment was required. It
`is also possible that the logistics of the study treatment
`and evaluation with an unfamiliar drug may have
`been overly burdensome for either the treating physi-
`cians or the patients themselves.
`Based on our results, we conclude that topotecan
`administered as a 21-day continuous infusion every
`28 days is an ineffective and moderately toxic treat-
`ment for patients with hormone refractory prostate
`cancer.
`
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