Investigational New Drugs 16: 353–359, 1999.
`© 1999 Kluwer Academic Publishers. Printed in the Netherlands.
`
`353
`
`A phase II trial of irinotecan in hormone-refractory prostate cancer
`
`David M. Reese, Simon Tchekmedyian, Yvonne Chapman, Diane Prager and Peter J. Rosen
`Division of Hematology-Oncology and Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los
`Angeles, CA, USA
`
`Key words: irinotecan, prostate cancer, clinical trial, topoisomerase I
`
`Summary
`
`Irinotecan is a DNA topoisomerase I inhibitor that has a wide spectrum of activity against human tumors in both
`preclinical and clinical studies. To evaluate the efficacy of irinotecan in hormone-refractory prostate cancer, we
`conducted a phase II study in 15 men with metastatic, PSA-progressive disease after primary androgen deprivation.
`Irinotecan was administered at a dose of 125 mg/m2 weekly for four weeks followed by a two-week rest period;
`cycles were repeated every six weeks. Response was assessed by evaluation of serial changes in the serum PSA.
`None of fifteen patients had a decline in PSA of greater than 50%; eight patients had stable disease as a best
`response. None of three patients with measurable disease had a partial or complete response. Toxicity was primarily
`hematologic and gastrointestinal, with 40% of patients requiring dose modification due to granulocytopenia and
`20% requiring intravenous fluid supplementation after development of diarrhea. There were no treatment-related
`deaths. We conclude that irinotecan in the dose and schedule used in this trial does not have significant activity
`against hormone-refractory prostate cancer.
`
`Introduction
`
`The treatment of hormone-refractory prostate cancer
`(HRPC) poses a difficult clinical challenge. A variety
`of approaches have been used, including secondary
`hormonal manipulations [1], estramustine [2], use of
`investigational drugs such as suramin [3], and pal-
`liative care alone. In addition, numerous cytotoxic
`chemotherapy regimens have been investigated. Most
`single agents have reported response rates of less
`than 20% [4], although some regimens, for example
`mitoxantrone with prednisone [5] or estramustine in
`conjunction with anti-microtubule agents [6–9], may
`yield responses in 30–60% of patients. However, no
`therapy has yet demonstrated a survival benefit, and
`there remains no clear standard of care for patients
`with HRPC.
`Irinotecan (CPT-11) is a semi-synthetic derivative
`of camptothecin that is a potent inhibitor of topoi-
`somerase I, a nuclear enzyme that plays an essential
`role in DNA replication and transcription [10]. Iri-
`notecan has a broad spectrum of antitumor activity
`
`in preclinical models [11] and has demonstrated ef-
`ficacy in patients with 5-flourouracil-resistant meta-
`static colon cancer [12]. The drug is currently being
`evaluated in a wide range of human malignancies. Iri-
`notecan also inhibits the growth of prostate cancer cell
`lines in vitro and in vivo [13]. Based on these obser-
`vations, we conducted a phase II trial of irinotecan in
`patients with HRPC. Our data indicate that irinotecan,
`in the dose and schedule used in this study, does not
`have significant activity against HRPC.
`
`Methods
`
`Patient selection
`
`Between May 1997 and April 1998 15 eligible pa-
`tients were enrolled at UCLA Medical Center and
`through the UCLA Community Oncology Network.
`All patients had a pathologic diagnosis of prostate can-
`cer and documented metastatic disease by bone scan,
`MRI, CT, or X-rays. Patients had progressive disease
`after primary hormonal therapy (bilateral orchiectomy
`
`AVENTIS EXHIBIT 2203
`Mylan v. Aventis IPR2016-00712
`
`

`
`354
`
`or use of an LHRH agonist) as documented by a rising
`PSA level measured on two separate occasions at least
`two weeks apart. Since the primary endpoint of the
`study was evaluation of changes in PSA levels, pa-
`tients had to have a PSA value of at least 5 ng/dL.
`Patients receiving an antiandrogen had to discontinue
`the drug at least 4 (flutamide) or 6 (bicalutamide)
`weeks prior to study entry to exclude the antiandro-
`gen withdrawal syndrome. Patients also had to have a
`performance status of 0–2 on the ECOG performance
`scale and a life expectancy of at least 12 weeks; no
`radiation therapy for at least 3 weeks or strontium-
`89 for at least 12 weeks prior to entry; no surgery
`for at least 2 weeks prior to entry; adequate mar-
`row function including pretreatment granulocyte count
`≥ 1500/mm3, hemoglobin ≥ 9.0 g/dL, and platelet
`count ≥ 100,000/mm3; and adequate renal and hepatic
`function with serum creatinine ≤ 2.0 mg/dL, serum
`bilirubin ≤ 1.5 mg/dL, and aspartate transaminase
`(AST) ≤ 3× the upper limit of normal, unless the liver
`was involved with tumor, in which case the AST had to
`be ≤ 5× the upper limit of normal. Patients could not
`have received any prior cytotoxic chemotherapy for
`prostate cancer. In addition, patients were excluded if
`they had a history of myocardial infarction within the
`previous six months or congestive heart failure requir-
`ing therapy, uncontrolled diabetes mellitus, a history
`of prior malignancy (except adequately treated basal
`cell or squamous cell skin cancer) within the previous
`five years, central nervous system metastases, or Gil-
`bert’s disease. All patients receiving an LHRH agonist
`continued to receive this agent throughout the course
`of the study. All patients gave written informed con-
`sent in accordance with federal, state, and institutional
`guidelines.
`A two-stage accrual strategy was planned, but pa-
`tient enrollment was stopped after none of the first
`fifteen patients achieved a partial response by PSA
`criteria.
`
`Evaluations
`
`All patients underwent a screening evaluation within
`21 days of the first treatment. Required observations
`at screening included a complete history and physical
`examination, ECOG performance status, radiologic
`studies (bone scan, x-rays, CT scan, or MRI as in-
`dicated for identification of measurable or evaluable
`disease), chest x-ray, and electrocardiogram. Within
`7 days of first treatment patients underwent labor-
`atory studies including PSA, complete blood count,
`
`serum chemistry profile, and urinalysis; documenta-
`tion of analgesic intake; and completion of the FACT-P
`quality of life questionnaire.
`Patients were seen once weekly for follow-up
`while on study. Complete blood count, analgesic con-
`sumption, and vital signs were recorded weekly. Every
`6 weeks a complete physical examination, serum
`chemistry profile, PSA level, ECOG performance
`status, and FACT-P questionnaire were obtained. Ra-
`diologic studies were repeated every 12 weeks as
`clinically indicated to assess disease state.
`
`Treatment plan
`
`Irinotecan was given over 90 minutes intravenously
`in doses of 125 mg/m2 weekly for 4 weeks fol-
`lowed by a 2-week rest period. Cycles were repeated
`every 6 weeks. Patients received standard antiemet-
`ics (excluding dexamethasone and other steroids) and
`were aggressively treated for diarrhea according to a
`standardized protocol with empiric antimotility agents
`(loperamide). During a treatment course, patients ex-
`periencing any NCI grade 2 toxicity had the dose of
`irinotecan reduced one dose level (dose levels were
`125, 100, 75, and 60 mg/m2) for all remaining doses
`during that treatment course. Patients experiencing
`grade 3 or higher toxicity had a dose omitted and could
`re-start treatment at one dose level lower upon resolu-
`tion of toxicity to grade 2 or less, except in the case of
`grade 4 hematologic toxicity, in which case treatment
`was resumed at 2 dose levels lower upon resolution of
`toxicity to grade 2 or less.
`Dose modifications of the next course of treat-
`ment were based on the worst toxicity observed during
`the preceding course. Patients experiencing grade 3
`or grade 4 hematologic toxicity had doses reduced
`one or two dose levels, respectively. For grade 2
`non-gastrointestinal or grade 3 gastrointestinal tox-
`icity, doses were reduced one dose level. For all other
`grade 3 or grade 4 toxicities doses were reduced two
`dose levels. Patients who experienced toxicity requir-
`ing dose modification to levels below 60 mg/m2 were
`taken off study. Dose modifications are summarized in
`Table 1.
`
`Toxicity and response criteria
`
`Toxicity was graded according to the revised common
`toxicity criteria (Cancer Therapy Evaluation Program,
`National Cancer Institute). Protocol treatment was ad-
`ministered until disease progression or the toxicity
`was unacceptable to the patient. The primary efficacy
`
`

`
`Table 1. Dose modifications for irinotecan
`
`NCI
`toxicity grade
`
`0
`1
`2
`3
`4
`Febrile
`neutropenia
`
`NCI
`toxicity grade
`
`0
`1
`2
`3
`4
`Febrile
`neutropenia
`
`Hematologic
`toxicitya
`
`None
`None
`↓ One dose levelc
`Omit dosed
`Omit dosee
`Omit dose
`
`Hematologic
`toxicity
`↑ One dose level
`None
`None
`↓ One dose level
`↓ Two dose levels
`↓ Two dose levels
`
`Dose modification during a course of treatment
`Non-hematologic toxicitya
`Non-GI
`toxicity
`
`None
`None
`↓ One dose level
`Omit dosee
`Omit dosee
`
`355
`
`GI
`toxicityb
`
`None
`None
`↓ One dose level
`Omit dosed
`Omit dosee
`
`Dose modifications for the next course of treatment
`Non-hematologic toxicity
`Non-GI
`toxicity
`↑ One dose level
`None
`↓ One dose level
`↓ Two dose levels
`↓ Two dose levels
`
`GI
`toxicity
`↑ One dose level
`None
`None
`↓ One dose level
`↓ Two dose levels
`
`a Dosage not adjusted for anemia, lymphocytopenia, or alopecia
`b GI toxicity includes nausea, vomiting, diarrhea, and mucositis/stomatitis and is scored after maximal medical management (e.g.,
`antiemetics, antimotility agents)
`c Dose levels: 125, 100, 75, and 60 mg/m2
`d Upon resolution of toxicity to grade 2 or less, treatment to be resumed at one lower dose level and maintained at that level for the remainder
`of the course
`e Upon resolution of toxicity to grade 2 or less, treatment to be resumed at two lower doses and maintained at that level for the remainder of
`the course
`
`endpoints of the trial included changes in PSA levels
`and/or measurable disease. For PSA data, a complete
`response (CR) was defined as normalization of the
`PSA for at least 4 weeks. A partial response (PR) was
`a decline in PSA by 50% for at least 4 weeks. Pro-
`gressive disease (PD) was considered a 25% or greater
`increase in PSA measured on two separate occasions
`at least two weeks apart. Stable disease was present if
`patients did not meet criteria for CP, PR, or PD.
`For patients with measurable disease, complete re-
`sponse required disappearance of all measurable and
`evaluable disease, no new lesions, and no evidence
`of nonevaluable disease. A partial response required
`a ≥ 50% decrease in the sum of the products of the
`longest perpendicular diameters of all measurable le-
`sions, no progression of evaluable disease, and no
`new lesions. Progressive disease was a ≥ 25% in-
`
`crease in the sum of products of measurable lesions,
`reappearance of any lesion which had disappeared, or
`appearance of any new lesion.
`Exploratory analyses were conducted to assess the
`clinical benefit of the therapy and included determin-
`ation of changes in performance status as measured
`on the ECOG scale, analgesic consumption, time to
`disease progression, and survival.
`
`Results
`
`The pretreatment characteristics of the 15 patients en-
`rolled in the study are shown in Table 2. All fifteen
`patients were evaluable for toxicity and response.
`All patients had a rising PSA after orchiectomy
`or use of an LHRH agonist. Twelve patients had dis-
`
`

`
`356
`
`Table 2. Patient characteristics
`
`Table 3. Treatment results
`
`Characteristic
`
`No. of patients
`
`Patient
`
`# of cycles
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`
`2
`2
`2
`1
`4
`2
`2
`1
`2
`5
`1
`2
`1
`2
`1
`
`PSA levels (ng/mL)
`baseline
`off-study
`
`316
`109
`146
`81
`24
`650
`132
`95
`74
`19
`212
`116
`17
`62
`211
`
`786
`129
`193
`70
`28
`685
`422
`153
`380
`29
`234
`201
`17
`75
`690
`
`Number enrolled
`Median age, years (range)
`ECOG performance status
`0
`1
`2
`PSA, ng/mL
`Median
`Mean
`Range
`Sites of disease
`Bone
`Lymph nodes
`Lung
`Soft tissue
`Prostate bed/bladder
`Prior therapy
`Prostatectomy
`Radiation to prostate
`Orchiectomy
`LHRH agonist
`Antiandrogen
`Ketoconazole
`Aminoglutethimide
`Hydrocortisone
`Megestrol acetate
`Diethylstilbestrol
`Radiation to metastases
`Strontium-89
`
`15
`68 (48–85)
`
`4
`10
`1
`
`109
`151
`17–650
`
`12
`3
`0
`0
`2
`
`3
`6
`5
`10
`13
`4
`1
`5
`1
`1
`3
`1
`
`ease detectable only in bone, while 3 had lymph node
`metastases that were measurable. Thirteen patients
`had received therapy with an antiandrogen at some
`point in their disease course, and all discontinued it at
`least 4 (flutamide) or 6 (bicalutamide) weeks prior to
`protocol therapy; none experienced a withdrawal de-
`cline in PSA. Six patients received at least one form of
`secondary hormonal therapy prior to ironotecan treat-
`ment, 3 had prior radiation to bone metastases, and 1
`had received strontium-89.
`Ten patients received two or more cycles of ther-
`apy, and 5 patients received one cycle. Of the 5
`patients who received one cycle of treatment,
`two
`discontinued treatment due to the development of pro-
`gressive disease by PSA criteria, two were taken off
`study at their request due to toxicity (diarrhea), and
`one was removed due to a rapid decline in perform-
`
`ance status. The median dose intensity per cycle for
`those patients receiving more than one cycle of ther-
`apy was 78% of the scheduled dose (125 mg/m2
`weekly) over the first two cycles of therapy, reflect-
`ing the necessity to reduce doses for hematologic or
`gastrointestinal toxicity.
`
`Response
`
`Changes in PSA level were evaluated as the primary
`marker of antitumor activity (Table 3). No patient ob-
`tained a 50% reduction in PSA. Of the 15 patients,
`7 (47%) had increases in PSA by ≥ 25% after at
`least one cycle of treatment, while 8 (53%) had stable
`disease as a best response by PSA protocol criteria.
`One patient (#10) had a stable PSA for four cycles
`but developed progressive disease after a fifth cycle
`of treatment. Two of the eight patients with stable
`disease had slight declines in PSA (11% and 18%, re-
`spectively), while the remainder had increases in PSA
`≤ 25%. None of the three patients with measurable
`disease had a partial or complete response in these
`lesions. The median time to PSA progression was 8
`weeks.
`Clinical parameters including performance status
`and analgesic consumption were not primary response
`endpoints of the study but were evaluated to assess
`potential clinical benefits. One patient with minor
`symptoms had an improvement in ECOG performance
`status from 1 to 0; this patient had stable disease by
`
`

`
`Table 4. Toxicities ≥ grade 2 (worst any cycle)
`
`Toxicity
`
`Granulocyte
`Platelet
`Hemoglobin
`Fatigue
`Nausea/vomiting
`Diarrhea
`
`Number with toxicity
`Grade 2
`Grade 3
`
`Grade 4
`
`2
`0
`4
`7
`5
`4
`
`4
`0
`0
`1
`0
`2
`
`0
`0
`0
`0
`1
`1
`
`PSA criteria after two cycles of therapy. All other pa-
`tients had stable (n = 7) or worse (n = 7) performance
`status. In addition, of eight patients requiring routine
`narcotic analgesic use for pain at baseline, none had
`a decrease in analgesic consumption while receiving
`the study drug. One patient not requiring analgesics
`at entry was utilizing ibuprofen after two cycles of
`therapy; this patient had a 70% increase in PSA. The
`remaining six patients did not require analgesics at any
`point in the trial.
`Seven patients (47%) have died (survival range, 4–
`16 months), while eight patients remain alive (survival
`range, 7–17+ months).
`
`Toxicity
`
`No unexpected drug-related side effects were en-
`countered in the study, and there were no therapy-
`related deaths. As anticipated, the most common tox-
`icities were hematologic and gastrointestinal (Table 4).
`Six patients (40%) experienced granulocytopenia
`severe enough to warrant dose modification; four had
`grade 3 and 2 had grade 2 toxicity. There were no
`episodes of febrile neutropenia or other infectious
`complications, however, and no significant thrombo-
`cytopenia was encountered.
`Gastrointestinal
`toxicity consisted primarily of
`nausea, vomiting, and diarrhea (Table 4). Nausea oc-
`curred in 6 patients (40%), but was severe (grade 4)
`in only one (7%); three patients (20%) had grade 2
`vomiting. All patients were instructed to take empiric
`loperamide with the development of loose stools or
`diarrhea, but 6/15 (40%) developed grade 2 or grade
`3 diarrhea. Two patients received outpatient intraven-
`ous fluid hydration to prevent volume depletion. One
`patient was admitted for dehydration after continuing
`to use laxatives, stool softeners, and multiple enemas
`
`357
`
`despite the development of loose stools during a cycle
`of therapy.
`Eight patients (53%) experienced fatigue during at
`least one cycle of therapy, but this was mild in all but
`one.
`
`Discussion
`
`The development of effective new therapies for
`hormone-refractory prostate cancer is essential, since
`currently available treatments have not demonstrated
`a survival benefit. The evaluation of new agents is
`complicated by the fact that the majority of patients
`have disease limited to bone;
`in this study, 12/15
`patients (80%) had bone-only metastases, a finding
`typical in clinical trials for HRPC. Recently, how-
`ever, use of changes in serum PSA has emerged as
`a relatively reliable indicator of antitumor effect for
`cytotoxic compounds. Kelly and colleagues noted that
`a 50% decline in PSA level two months after ther-
`apy was associated with improved outcome in patients
`treated with a variety of systemic agents, an observa-
`tion confirmed in an independent data set [14]. More
`recently, investigators at the University of Michigan
`analyzed PSA responses in 114 patients treated with
`estramustine and etoposide on sequential clinical tri-
`als. Their data also suggest that a decline of PSA of
`≥ 50% correlates with improved survival [15].
`In the current trial we used changes in serum PSA
`as the primary endpoint in assessing treatment re-
`sponse, requiring at least a 50% decrease to achieve
`a partial response. By this criterion, there were no
`objective responses in 15 patients. In addition, none
`of 3 patients with measurable disease had a partial
`response by traditional criteria. It is unlikely that the
`patients in this study had exceptionally advanced or
`resistant disease: fourteen of 15 had an ECOG per-
`formance status of 0 or 1; less than 50% had been
`treated with secondary hormonal manipulations; only
`three had received prior radiation to bony metastases;
`and none had received prior chemotherapy. Further-
`more, the median PSA was comparable to that repor-
`ted in other recent trials investigating cytotoxics for
`HRPC [5–9,16–18]. Thus, the patients enrolled in this
`trial appear to be representative of those with HRPC
`for whom cytotoxic chemotherapy is considered an
`appropriate treatment option.
`It has also been suggested that measures of clin-
`ical benefit, such as improvements in performance
`status or quality of life, changes in pain level or an-
`
`

`
`358
`
`algesic consumption, and weight gain or loss should
`be primary endpoints when evaluating new therapies
`for HRPC [19,20]. We conducted exploratory analyses
`of changes in clinical parameters such as performance
`status and analgesic consumption and were unable to
`detect a meaningful impact of irinotecan treatment on
`these outcomes. It should be noted, however, that a
`significant fraction of the patients had excellent per-
`formance status and/or minimal or no pain at baseline.
`Thus, only a relatively small number of patients could
`be evaluated for clinical benefit using these criteria; a
`larger data set would be required to exclude an effect
`of irinotecan on these endpoints.
`The fact that irinotecan, a potent inhibitor of topoi-
`somerase I, had little efficacy in this patient population
`is disappointing and perhaps unexpected given its
`activity in preclinical models and other human ma-
`lignancies. These data are however consistent with
`a recently reported trial of topotecan, another topo I
`inhibitor, in patients with HRPC [21]. Hudes et al.
`treated 34 patients with intravenous topotecan using
`conventional dosing and scheduling and noted that
`only 6 (18%) had PSA reductions of ≥ 50%. Four
`patients had significant reductions in pain and anal-
`gesic use. The authors concluded that topotecan had
`minimal activity in patients with HRPC.
`Despite the limited therapeutic activity of iri-
`notecan observed in this trial, further investigation
`of the compound employing alternative dosing or
`scheduling, or integrating the drug into combination
`regimens, may be reasonable. Some investigators are
`using irinotecan in an every other week schedule to
`minimize hematologic toxicity, and this may allow for
`greater dose intensity. In addition, use of the drug in
`combination regimens is potentially attractive, for ex-
`ample by combining irinotecan with a topoisomerase
`II inhibitor such as etoposide. To determine whether
`irinotecan has a role in the treatment of HRPC will
`require further clinical trials exploring these hypo-
`theses, as it is unlikely that therapy using the conven-
`tional dose and scheduling employed in this study has
`meaningful impact on the disease.
`
`Acknowledgement
`
`Supported in part by a grant from Pharmacia & Up-
`john, Kalamazoo, MI, USA.
`
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`Address for offprints: David M. Reese, Urologic Oncology, 5th
`Floor, UCSF/Mount Zion Cancer Center, 2356 Sutter Street, San
`Francisco, CA 94115, USA; Phone: 415-885-7838; Fax: 415-474-
`9173; E-mail: dreese@itsa.ucsf.edu