Original Article
`
`IMATINIB FOR RELAPSED PROSTATE CANCER
`LIN
` et al.
`
`A phase II trial of imatinib mesylate in patients with
`biochemical relapse of prostate cancer after definitive
`local therapy
`Amy M. Lin, Brian I. Rini*, Vivian Weinberg, Kristen Fong, Charles J. Ryan, Jonathan E. Rosenberg,
`Lawrence Fong and Eric J. Small
`University of California/San Francisco, San Francisco, CA, and *The Cleveland Clinic Foundation, Cleveland, OH, USA
`Accepted for publication 16 May 2006
`
`OBJECTIVE
`
`To determine the biological effects of imatinib
`mesylate (STI-571, Gleevec®; Novartis
`Pharmaceuticals, Inc., East Hanover, NJ, USA),
`as measured by prostate-specific antigen
`(PSA) kinetics in men with biochemical relapse
`of prostate cancer after definitive local
`therapy.
`
`PATIENTS AND METHODS
`
`Men with prostate cancer, who had had
`definitive local therapy, with nonmetastatic
`recurrent disease as manifested by a rising
`PSA level, were enrolled on this phase II trial.
`Men received 400 mg of imatinib mesylate
`
`orally twice daily and continuously until
`disease progression or unacceptable toxicity.
`The PSA level was measured monthly.
`
`toxicity and the trial was stopped early due to
`toxicity.
`
`RESULTS
`
`CONCLUSIONS
`
`In all, 20 men with biochemically relapsed
`prostate cancer were treated. The median
`pretreatment PSA level was 5.4 ng/mL. Of the
`≥
`50%
`19 evaluable men, one achieved a
`reduction in PSA level and two had decreases
`<
`of
`50%. For the 16 men in whom the on-
`treatment PSA doubling time (PSADT) could
`be calculated (those with increasing PSA
`level) the median PSADT did not increase
`=
`
`P
`significantly (5.8 vs 7.2 months,
` 0.64).
`Eleven of 20 men discontinued therapy due to
`
`Based on the lack of PSA modulation and
`pronounced toxicities leading to early closure
`of this trial, further study of single-agent
`imatinib mesylate at this dose (400 mg twice
`daily) cannot be recommended in this patient
`population.
`
`KEYWORDS
`
`imatinib mesylate, prostate cancer,
`biochemical relapse
`
`INTRODUCTION
`
`About 230 110 new cases of prostate cancer
`are diagnosed annually in the USA [1]. Of men
`receiving definitive local therapy for prostate
`cancer, 20–60% (≈ 50 000 men per year) will
`develop recurrent disease [2] in which a rising
`PSA level is the only manifestation of
`treatment failure (biochemical relapse, BCR)
`[3]. Currently there is no standard of care for
`these men. Although androgen-deprivation
`therapy (ADT) is a therapeutic option, the
`short- and long-term side-effects (i.e. loss of
`libido, fatigue, muscle wasting, osteoporosis,
`anaemia) make this therapy less desirable for
`many patients and their physicians.
`
`New and effective therapies are needed with
`low toxicity profiles for these asymptomatic
`patients. Testing the efficacy of novel
`therapeutics in men with BCR is difficult
`because: (i) there is great diversity in clinically
`relevant outcomes, such as time to
`metastases and time to prostate-cancer
`specific death; and (ii) the time to these
`
`clinically relevant endpoints is long. One
`potential intermediate endpoint is the PSA
`doubling time (PSADT). There are many
`retrospective data in men with BCR
`supporting the utility of PSADT in predicting
`metastatic disease risk and prostate cancer-
`specific survival [4–7]. Although the native
`PSADT after definitive local therapy predicts
`the time to metastases and prostate cancer-
`specific survival, alterations in PSADT due to
`treatment interventions have not yet been
`proven to alter clinical outcome. Similarly,
`while a ≥50% PSA decline has been
`considered a useful screen for the activity of
`cytotoxic agents used for treating hormone-
`refractory prostate cancer (HRPC) [8], this
`endpoint has not been validated in men with
`BCR. Nevertheless, a possible screening
`method for novel agents in men with BCR
`might be to determine which agents show
`potential biological effects (e.g. slowing of
`PSA rise, i.e. PSADT, or evidence of PSA
`declines). Modulation of PSA level by a
`novel agent might indicate biological
`activity that should be further investigated.
`
`Imatinib mesylate (STI-571, Gleevec®;
`Novartis Pharmaceuticals Inc., East Hanover,
`NJ, USA), a phenylaminopyrimidine derivative,
`is an inhibitor of the receptor tyrosine kinase
`inhibitor BCR-Abl, c-kit and platelet-derived
`growth factor receptor (PDGF-R). PDGF is
`involved in autocrine stimulation of tumour
`cells, regulation of tumour stromal fibroblasts,
`and tumour angiogenesis [9]. PDGF-R has two
`subunits, α and β, which either homo- or
`heterodimerize upon binding of PDGF.
`PDGF-R was reported to be expressed on
`prostate cancer cells in several studies. Using
`immunohistochemistry (IHC), Ko et al. [10]
`showed that PDGF-R α and β were expressed
`in 88% of primary prostate tumours
`(hormone-sensitive, n = 23) and in 80% of
`bone marrow metastases (hormone-refractory,
`n = 15). Fudge et al. [11,12] similarly showed
`IHC expression of PDGF-R α in prostate
`adenocarcinomas and prostatic intraepithelial
`neoplasia, but not BPH specimens.
`
`Previous trials of PDGF-R inhibitors showed
`only limited activity in metastatic HRPC. Ko
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`© 2 0 0 6 T H E A U T H O R S
`J O U R N A L C O M P I L A T I O N © 2 0 0 6 B J U I N T E R N A T I O N A L | 9 8 , 7 6 3 – 7 6 9 | doi:10.1111/j.1464-410X.2006.06396.x
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`7 6 3
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`AVENTIS EXHIBIT 2201
`Mylan v. Aventis IPR2016-00712
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`L I N
`
`E T A L .
`
`et al. [10] reported that 8% of 44 men with
`
`≥
`metastatic HRPC had a
`50% PSA level
`decline in response to single-agent SU101
`(Sugen, Inc., South San Francisco, CA, USA), an
`i.v. PDGF-R inhibitor with a short half-life.
`
`et al. [13] reported that
`Similarly, Mathew
`none of 28 men with metastatic HRPC had a
`≥
`50% PSA decline during a 30-day lead-in
`phase of imatinib 600 mg daily alone,
`administered before the addition of
`chemotherapy.
`
`As PDGF-R is expressed by prostate cancer
`cells and tumour vasculature, there is a
`biological rationale for targeting this
`particular signalling pathway for prostate
`cancer. Although the efficacy of the PDGF-R
`inhibitors in men with metastatic HRPC
`appeared limited, the men in these trials not
`only had more advanced disease, but were
`also heavily pre-treated. Potentially, the use of
`a biological agent such as imatinib in men
`with less advanced disease would be more
`effective. Thus, a prospective phase II trial in
`men with BCR after definitive local therapy
`was conducted. The primary endpoint for this
`trial was to determine the effects of imatinib
`on inducing declines in PSA level and
`modulating PSA kinetics.
`
`PATIENTS AND METHODS
`
`This was a single-arm phase II study
`conducted at the University of California, San
`Francisco (UCSF). Men with histologically
`confirmed adenocarcinoma of the prostate
`who had previous definitive local therapy
`with radical prostatectomy (RP), external
`beam radiotherapy, or brachytherapy were
`eligible. Disease progression after local
`therapy was defined as a rising PSA level
`based on three PSA determinations, each
`≥
`2 weeks apart, and an absolute PSA value of
`≥
`0.4 ng/mL. The men were required not to
`have metastatic disease, as shown by a
`negative bone scan and CT of the abdomen
`and pelvis within 6 weeks before initiating
`treatment. Adequate bone marrow, liver and
`renal function were required within 2 weeks
`of initiating treatment, including: absolute
`≥
`µ
`neutrophil count of
`1500 cells/
`L,
`≥
`8.0 g/dL, platelets
`haemoglobin of
`≥
`3
`120 000 cells/m
`, serum creatinine level of
`≤
`1.5 times the upper limit of normal, bilirubin
`≤
`1.5 times the upper limit of normal, and
`aspartate aminotransferase (AST) and alanine
`≤
`aminotransferase (ALT) of
`1.5 times the
`upper limit of normal. A Karnofsky
`≥
`70% was required.
`performance status of
`
`7 6 4
`
`Previous hormonal therapy (LHRH agonist
`and/or antiandrogen) for the treatment of
`progressive disease was not permitted, but
`previous adjuvant and/or neoadjuvant ADT
`≤
`was permitted if the ADT was
`12 months in
`≥
`duration and was completed
`12 months
`from the date of enrolment. The testosterone
`level at enrolment was required to be
`>
`250 ng/mL. Previous chemotherapy,
`ketoconazole, and PC-SPES (or other herbal
`preparations intended to lower testosterone)
`were not permitted. Concurrent use of
`
`
`finasteride or saw palmetto (Serenoa repens)
`was not allowed and men must have
`≥
`discontinued the drug for
`4 weeks before
`study enrolment. No supplements, with the
`exception of conventional multivitamins,
`selenium, lycopene, and soy supplements,
`were permitted. Men receiving therapeutic
`anticoagulation with warfarin (coumadin)
`were excluded from the study because of the
`potential interaction with imatinib. All
`patients signed an informed consent form
`approved by the UCSF Institutional Review
`Board.
`
`The men received imatinib 400 mg (all
`doses are expressed as orally twice daily)
`continuously, with one cycle consisting of 4-
`week intervals. This dose was selected on the
`basis of doses used in other diseases (chronic
`myelogenous leukaemia, gastrointestinal
`stromal tumour) that were felt to be safe with
`effective receptor inhibition. The men were
`evaluated at monthly intervals with
`laboratory and PSA measurements for the
`first 6 months, and every 3 months thereafter.
`Testosterone, dihydrotestosterone (DHT),
`androstenedione (DHEA), oestradiol and sex-
`hormone binding globulin (SHBG) levels were
`measured at the same time as PSA. Changes
`in hormone levels were expressed as a
`percentage change from baseline to make
`comparisons between men who had
`laboratory values measured at different
`facilities. After an interim analysis leading to
`early study closure due to excess toxicity, men
`who chose to continue on study had monthly
`laboratory and clinical assessments even if
`>
`they had been treated for
`6 months. Men
`had a baseline (pretreatment) bone scan and
`CT of the abdomen and pelvis that was
`repeated at the time of disease progression by
`PSA criteria (see above) or if clinically
`indicated. The criteria for PSA progression
`were based on PSA changes after the
`≥
`administration of imatinib for
`3 months, so
`that men were not removed from the study
`prematurely. This decision was based on not
`
`a priori the impact of a biological
`
`knowing
`agent such as imatinib on PSA levels, and the
`desire for an adequate time to follow the PSA
`trajectory. Disease progression and time to
`progression was defined by the PSA
`Consensus Criteria [8]. The PSADT, an estimate
`of the rate of change of PSA, was calculated
`before and during treatment as an additional
`=
` natural
`measure of treatment effect (PSADT
`log 2/slope of the rate of change of natural
`log PSA). The treatment continued until
`patients had evidence of disease progression
`by PSA Consensus Criteria, development of
`metastases, or experienced unacceptable
`toxicity.
`
`The National Cancer Institute Cancer Clinical
`Trials Common Toxicity Criteria version 2.0
`was used to assess toxicities. For all grade 2, 3
`or 4 non-haematological toxicities, imatinib
`≤
`was held until resolution to
`grade 1 and
`the drug dose was adjusted as follows:
`for the first occurrence of grade 2 non-
`haematological toxicities, the drug was
`resumed at the same dose (400 mg). If there
`was recurrence of the grade 2 toxicity, the
`drug was restarted at a reduced dose of
`300 mg. If there was second recurrence of the
`grade 2 toxicity, the drug was discontinued
`but an option of remaining on the drug at a
`further reduced dose (200 mg) was permitted
`if the patient was responding. For the first
`occurrence of grade 3 or 4 non-hematological
`toxicity, imatinib was restarted at a lower dose
`of 300 mg. If there was a recurrence of the
`grade 3 or 4 toxicity, imatinib was restarted
`200 mg. If there was a second recurrence of
`the grade 3 or 4 toxicity, imatinib was
`discontinued. Discontinuation of imatinib was
`recommended if there was interruption of
`≥
`treatment for
`14 days to allow for recovery
`from toxicity.
`
`No dose interruptions or reductions were
`undertaken for grade 1 or 2 haematological
`toxicities. For grade 3 or 4 haematological
`toxicities, excluding anaemia, imatinib was
`≤
`grade 1. If
`held until toxicity had resolved to
`the toxicity resolved within 2 weeks of
`discontinuing the drug, drug was resumed at
`the same dose. If the grade 3 or 4 toxicity
`>
`recurred or persisted for
`2 weeks, the drug
`was held and resumed at a lower dose
`≤
`(300 mg) if the toxicity resolved to
`grade 1.
`If there was another recurrence of grade 3 or
`4 toxicity, imatinib was discontinued.
`
`The primary endpoint for the present study
`≥
`was the proportion of PSA declines of
`50%
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`J O U R N A L C O M P I L A T I O N
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`I M A T I N I B F O R R E L A P S E D P R O S T A T E C A N C E R
`
`Characteristic
`Age, years
`Primary local therapy
`RP
`RT
`RP and RT
`Previous ADT with local therapy
`Previous investigational therapy
`Pretreatment PSA level, ng/mL
`Gleason score
`5
`6
`7
`8
`9
`Unknown
`Baseline testosterone level, ng/mL
`Pretreatment PSADT, months
`
`Median (range) or N (%)
`67.5 (54–85)
`
`TABLE 1
`The patients’ characteristics
`(20 patients)
`
`3 (15)
`6 (30)
`11 (55)
`6 (30)
`4 (20)
`5.4 (0.5–13.3)
`7 (5–9)
`1 (5)
`3 (15)
`11 (55)
`3 (15)
`1 (5)
`1 (5)
`434.5 (277–990)
`6.7 (2.9–38.5)
`
`RT, radiation therapy
`(external-beam,
`brachytherapy).
`
`observed with imatinib treatment. The sample
`size was determined using Gehan’s two-stage
`design. Overall, if 15% of patients had PSA
`≥
`declines of
`50%, this would be considered
`worthy of further study. If there were no PSA
`≥
`declines of
`50% in the first 19 patients, no
`more patients would be enrolled (because the
`probability of observing at least one response
`if the expected probability of response is 15%
`<
`is
`5%). This sample size would result in a
`±
`maximum 95% CI of length
` 17.9%. If at
`≥
`least one PSA decline of
`50% occurred,
`accrual would continue for a total of 30
`patients.
`
`Descriptive statistics were calculated to
`characterize the patient group including the
`proportion responding with a 95% CI. The
`Wilcoxon-matched pairs test was used to
`compare the pretreatment and on-treatment
`PSADTs. For a safety evaluation, with 30
`patients the study had 87% power to reject a
`<
`null hypothesis of
`5% probability of serious
`adverse events vs a 20% rate, with a level of
`significance of 0.061. Thus, if there were four
`or more grade 3 or 4 toxicities, the null
`hypothesis would be rejected due to lack of
`safety.
`
`RESULTS
`
`In all, 20 men with serological progression of
`prostate cancer were enrolled between April
`2003 and October 2004. Table 1 lists the
`patient characteristics before treatment.
`The men had a median (range) age of
`
`67.5 (54–85) years. The primary therapy
`included RP in three men, radiation in six, or
`RP followed by radiation therapy in 11. Six
`men (one who had a previous RP and five who
`had previous radiation therapy) had received
`previous neoadjuvant and/or adjuvant ADT.
`These men received a median (range) of
`4 (3–12) months of ADT that had been
`discontinued for a median (range) of 58
`(28–106) months before treatment with
`imatinib. Four men had received previous
`investigational treatments including APC8015
`(Provenge®; Dendreon, Seattle, WA, USA),
`granulocyte-macrophage colony-stimulating
`factor (Leukine ®; Berlex, Seattle, WA, USA),
`bevacizumab (Avastin®; Genentech, South
`San Francisco, CA, USA), and rosiglitazone
`(Avandia®; GlaxoSmithKline, Philadelphia, PA,
`USA). The median (range) duration from the
`last investigational therapy before enrolling
`on the imatinib study was 11.43 (2–50.6)
`months. The median pretreatment PSA was
`5.4 (0.50–13.30) ng/mL. Fifteen men (75%)
`≥
`7. The median
`had a Gleason score of
`baseline testosterone level was 434.5
`(277.0–990.0) ng/mL. The PSA values to
`calculate the pretreatment PSADT were not
`prospectively obtained before imatinib
`therapy. Pretreatment PSADT was calculated
`based on available pre-enrolment PSA values
`(see below). The median pretreatment PSADT
`for all men was 6.7 (2.9–38.5) months.
`
`CLINICAL OUTCOMES
`
`The median (range) treatment duration for all
`20 men was 16.3 (3.1–67.7) weeks. Fifteen
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`>
`3 months of treatment; 19 men
`men had
`were evaluable for assessment of on-
`treatment PSA changes with a median follow-
`up of 12.6 months. One patient withdrew
`consent due to toxicity and did not have an
`on-treatment PSA sample drawn. Four men
`stopped protocol therapy before 3 months of
`therapy because of toxicity, while one stopped
`because of a rapid rise in PSA after 7 weeks of
`treatment. One of the 19 evaluable patients
`≥
`(5%) had a PSA decline of
`50%. His
`pretreatment PSA was 6.0 ng/mL and the
`pretreatment PSADT was 11.4 months. By
`week 8 (at the end of 2 months of treatment),
`his PSA had declined to 0.1 ng/mL and by
`week 16 (at the end of 4 months of
`<
`treatment), his PSA level was
`0.1 ng/mL.
`However, he was removed from treatment
`due to the discovery of asymptomatic
`‘cotton-wool spots’ (grade 2) on routine eye
`examination after 17 weeks of treatment.
`
`<
`50%;
`Two other men had PSA declines of
`both declines (29% and 9.6%) were not
`sustained, occurring after 12 and 16 weeks of
`treatment, respectively. Both men eventually
`came off treatment for PSA progression, after
`67 weeks and 53 weeks of treatment,
`respectively.
`
`To determine the pretreatment PSADT, a
`median of six PSA values were used (range
`3–17) and were collected over a median
`(range) of 11.2 (1.1–61.9) months. The median
`estimated pretreatment PSADT for all 20 men
`was 6.7 months, with a broad range of
`2.9–38.5 months. Of the 19 evaluable men,
`three could not have an on-treatment PSADT
`calculated because they had declining PSA
`values. For the remaining 16 men for whom
`an on-treatment PSADT could be calculated,
`the median pretreatment and on-treatment
`PSADT was 5.8 vs 7.2 months, respectively
`=
`
`P
`(
` 0.64) (Table 2). Figure 1 shows the paired
`pretreatment and on-treatment PSADTs for
`each patient. There was no statistically
`significant difference in pretreatment and on-
`treatment PSADT among the 16 evaluable
`men, as well as among those who received
`>
`3 months of therapy. Overall, five of the 16
`men for whom an on-treatment PSADT could
`>
`be calculated had a
`100% increase in their
`on-treatment PSADT compared with their
`pretreatment PSADT, with increases of 118%,
`143%, 145%, 200% and 393%.
`
`Upon discontinuation of imatinib and in the
`absence of further therapy, eight of the 19
`men had transient declines in their PSA levels
`
`7 6 5
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` Pts. with
`decreasing slopes
`
`FIG. 1.
`The paired pretreatment and on-
`treatment PSADTs.
`
`P = 0.64
`
`120
`
`96
`
`72
`
`48
`
`24
`
`0
`
`PSADT, months
`
`Pre PSADT
`
`On Study PSADT
`
`Characteristic
`Pretreatment PSA, ng/mL
`Median (range)
`PSADT, months
`Median (range)
`Mean
`
`Pretreatment
`
`On-treatment
`
`5.1 (0.5–13.3)
`
`5.8 (2.9–38.5)
`11.8
`
`7.2 (2.8–115.5)
`15.2
`
`TABLE 2
`The pretreatment and on-
`treatment PSA kinetics for
`the 16 evaluable patients
`
`periorbital oedema, requiring dyazide after
`1 week of treatment; after holding imatinib
`and restarting at the same dose, he developed
`grade 2 hypocalcaemia after 4 weeks of
`treatment. Imatinib was held and restarted
`at the same dose. Subsequently, after 7
`weeks of treatment, he developed grade 2
`conjunctivitis that was being treated with
`antibiotics. Imatinib was again held and
`restarted at the same dose. After 10 weeks of
`treatment, he developed grade 4 dyspnoea
`requiring diuretics and a dose reduction to
`300 mg. At this reduced dose, he developed
`recurrent grade 2 conjunctivitis after a total
`of 12 weeks of therapy and was removed
`from treatment. Two men developed toxicities
`thought not to be related to imatinib,
`including a grade 4 large bowel obstruction
`and a grade 3 infection (perinephric abscess).
`
`Six men had multiple grade 1 or 2 toxicities
`leading to removal from or withdrawal of
`consent from the study (Table 5). Two of the
`six had previously had grade 3 or 4 toxicities
`and had their dose reduced when they
`developed the grade 1 or 2 toxicities, leading
`to treatment discontinuation. The only man to
`≥
`<
`have a
`50% PSA decline (to
`0.1 ng/mL) was
`removed from the study for development of
`asymptomatic, ‘cotton-wool’ spots (grade 2)
`discovered during a routine eye examination
`after 17 weeks of treatment. He had no
`history of hypertension, diabetes or vasculitis;
`
`TABLE 3
`
`Patient disposition
`
`Reason for coming off study
`Number of patients
`Toxicity
`PSA progression
`Objective progression
`Patient choice (at study closure)
`Treating physician’s discretion
`
`N (%)
`20
`11 (55)
`5 (25)
`1 (5)
`2 (10)
`1 (5)
`
`2 months after imatinib was discontinued, a
`follow-up eye examination showed resolution
`of the cotton-wool spots and the toxicity was
`thus attributed to imatinib. His PSA levels
`after discontinuing imatinib remained low;
`his last PSA value, at 9 months after imatinib
`discontinuation, was 0.5 ng/mL.
`
`EARLY STUDY CLOSURE
`
`At the interim analysis after enrolment of the
`first 20 patients, the study met its efficacy
`≥
`endpoint (one of 19 patients with a
`50%
`PSA level decline) and could continue to enrol
`patients with a target accrual goal of 30
`patients. Five men developed grade 3 or 4
`toxicities attributable to imatinib, indicating
`that the acceptable toxicity level of 5% could
`not be achieved. The number of men (11) who
`stopped therapy because of toxicity (ranging
`from grade 1 to 4) had exceeded the number
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`J O U R N A L C O M P I L A T I O N
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`L I N
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`E T A L .
`
`compared with their last PSA value on-study,
`ranging from 11.1% to 44.8%. There were no
`>
`declines of
`50%.
`
`The overall disposition of the men is outlined
`in Table 3. Of the 20 enrolled men, six
`developed progressive disease by PSA
`Consensus Criteria, with a median time to
`progression 3.56 (range, 1.75–14.43) months,
`and were removed from treatment. All six of
`these men had a follow-up bone scan and CT
`after stopping treatment. Four of five men
`had a positive bone scan at the time of PSA
`progression while the sixth was found to have
`enlarged perirectal nodes. Eleven men
`discontinued therapy due to toxicity (see
`below). Three men stopped protocol therapy
`before meeting the PSA progression criteria at
`16, 31 and 40 weeks of treatment at the time
`of study closure, when an interim analysis
`revealed excess treatment toxicity.
`
`TOXICITY
`
`Table 4 lists the observed toxicities. The most
`common haematological toxicities were
`grade 1 anaemia and grade 2 lymphopenia,
`with no clinically relevant consequences. The
`most common non-hematological toxicities
`were grade 1 periorbital oedema, fatigue and
`rash. Five men (25%) required dose reductions
`secondary to toxicity and 11 (55%) had
`toxicities leading to removal or withdrawal
`from the study.
`
`Seven men developed grade 3 or 4 toxicities,
`five of which were attributable to imatinib.
`The first developed grade 4 neutropenia after
`4 weeks of therapy and required a dose
`reduction to 300 mg. However, at 11 weeks,
`he developed grade 3 neutropenia and was
`removed from the study. The second
`developed a grade 3 rash and pruritus after
`2 weeks of therapy and required a drug dose
`reduction to 300 mg. Subsequently, he
`developed multiple grade 2 side-effects
`(headache, nausea, malaise, fatigue, nausea)
`after a total of 5.5 weeks of treatment and
`withdrew consent. The third developed
`grade 3 diarrhoea after 14 weeks of
`treatment and withdrew consent. The fourth
`developed a grade 3 rash and grade 2 lower
`extremity oedema as well as grade 2 elevated
`AST, ALT and alkaline phosphatase after
`3 weeks of treatment. Because of the severity
`of the rash, in addition to the development of
`extremity oedema and transaminitis, he was
`removed from study without attempting a
`dose reduction. The fifth developed grade 2
`
`7 6 6
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`I M A T I N I B F O R R E L A P S E D P R O S T A T E C A N C E R
`
`TABLE 4
`
`Maximum grade of toxicity observed
`
`Toxicity
`Haematological:
`Anaemia
`Lymphopenia
`Leukopenia
`Neutropenia
`Non-haematological:
`Periorbital oedema
`Fatigue
`Rash
`Diarrhoea
`Muscle cramps
`Elevated ALT
`Lower extremity oedema
`Nausea
`Flatulence
`Elevated AST
`
`Number of patients (%)
`Grade 1
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Total
`
`16 (80)
`1 (5)
`5 (25)
`4 (20)
`
`14 (70)
`7 (35)
`8 (40)
`4 (20)
`6 (30)
`4 (20)
`4 (20)
`4 (20)
`4 (20)
`3 (15)
`
`0
`12 (60)
`5 (25)
`1 (5)
`
`2 (10)
`5 (25)
`1 (5)
`2 (10)
`0
`1 (5)
`1 (5)
`1 (5)
`0
`2 (10)
`
`0
`1 (5)
`0
`0
`
`0
`0
`2 (10)
`2 (10)
`0
`1 (5)
`0
`0
`1 (5)
`0
`
`0
`0
`0
`1 (5)
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`16 (80)
`14 (70)
`10 (50)
`6 (30)
`
`16 (80)
`12 (60)
`11 (55)
`8 (40)
`6 (30)
`6 (30)
`5 (25)
`5 (25)
`5 (25)
`5 (25)
`
`TABLE 5
`
`Toxicities leading to discontinuation of therapy
`
`Treatment
`duration,
`weeks
`11
`5.5
`19
`
`Patient
`2
`3
`7
`
`8
`9
`10
`
`11
`12
`15
`16
`20
`
`17
`19.5
`12
`
`14
`23
`7
`7
`3
`
`Toxicity
`Recurrent grade 3 neutropenia
`Grade 3 rash, pruritus; grade 2 headache, nausea, malaise, fatigue
`Grade 1 periorbital oedema, fatigue, arthritis, diarrhoea, visual
`light sensitivity
`Recurrent grade 2 anorexia, taste alteration, weight loss
`Grade 2 asymptomatic retinal cotton-wool spots
`Grade 3 dyspnoea; grade 2 periorbital oedema, hypocalcaemia,
`recurrent conjunctivitis
`Grade 3 diarrhoea
`Grade 3 diarrhoea; grade 4 large bowel obstruction
`Grade 2 airway oedema
`Grade 3 infection
`Grade 3 rash; grade 3 transaminitis, peripheral oedema
`
`Related to
`imatinib
`Yes
`Yes
`Yes
`
`Yes
`Yes
`Yes
`
`Yes
`No
`Yes
`No
`Yes
`
`(six) who had stopped therapy for disease
`progression. Therefore, the decision was made
`to close the study early to further accrual.
`Men still receiving therapy were given the
`option of continuing the study treatment or
`withdrawing consent. Of the four men who
`were on study at the time, two chose to
`continue on study, and two withdrew
`consent.
`
`HORMONAL CHANGES
`
`To ensure that an effect of imatinib on PSA
`levels could not be attributed to changes in
`
`hormone levels, testosterone, DHT, DHEA,
`oestradiol, and SHBG levels were measured.
`There was no evidence of changes in the
`testosterone, DHT, DHEA, or oestradiol levels
`over time, although SHBG levels tended to rise
`slightly (data not shown). For the patient with
`a dramatic PSA decline from 6.0 ng/mL to
`<
`0.1 ng/mL, his testosterone initially declined
`by 43% (404 ng/mL to 231 ng/mL) and
`subsequently rose to 651 ng/mL while on
`treatment. His DHT levels fell from above
`normal limits to below normal limits
`(maximum decline of 83%) and subsequently
`returned to normal levels while on imatinib.
`
`©
`2 0 0 6 T H E A U T H O R S
`
`J O U R N A L C O M P I L A T I O N
`
`©
`
` 2 0 0 6 B J U I N T E R N A T I O N A L
`
`His PSA remained undetectable throughout
`treatment despite these androgen level
`fluctuations.
`
`DISCUSSION
`
`There is no standard of care for men with BCR
`prostate cancer. While ADT is commonly used,
`many patients and physicians seek to delay its
`use. Imatinib is a reasonable agent to test in
`this setting, given the presence of PDGF-R on
`prostate cancer cells. Unfortunately, for men
`with BCR prostate cancer, single-agent
`imatinib had little effect, as measured by PSA
`declines and changes in PSADT. Only three of
`the 19 evaluable patients (16%) had a PSA
`decline and only one (5%) had a decline
`≥
`of
`50%. The median PSADT was not
`significantly prolonged (5.8 vs 7.2 months,
`=
`
`P
` 0.64) although five of the 16 evaluable
`≥
`patients had a
`100% increase in PSADT.
`More significantly, the leading cause of
`treatment discontinuation was toxicity
`(11 men), not progressive disease (six men).
`While only 25% of patients had a grade 3 or 4
`toxicity attributable to imatinib, many of
`the milder toxicities had the potential to
`compromise quality of life in this normally
`asymptomatic group of patients, as shown by
`the number who discontinued therapy due
`to such toxicities. Based on the lack of
`significant efficacy as measured by changes in
`PSA, together with pronounced toxicities
`leading to early closure of this trial, further
`study of single-agent imatinib at this dose
`(400 mg) cannot be recommended in such
`patients. Notably, imatinib did not appreciably
`alter hormonal levels consistently, and the
`PSA declines that occurred did not appear to
`be mediated by androgen deprivation.
`
`The present findings are similar to those
`
`
`
`et al. [14] and Bajaj et al. [15].
`reported by Rao
`
`et al.
`Using a similar study design, Rao
`conducted a phase II study of single-agent
`imatinib in 21 men with BCR prostate cancer.
`Patients received a similar dose of imatinib at
`400 mg twice daily for 24 weeks. None of the
`16 evaluable men had any PSA decline and
`seven had PSA progression. Toxicities were
`also encountered, with seven men (33%)
`requiring a dose reduction and six (29%)
`unable to complete the 24 weeks of therapy
`because of toxicity. The toxicities were similar
`to those in the present report, including rash,
`neutropenia, diarrhoea, shortness of breath,
`and chest pain. IHC staining of primary
`tumours in four patients showed staining for
`
`7 6 7
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`

`
`L I N
`
`E T A L .
`
`β
`α
`. One of the four men
` and
`both PDGF-R
`had PSA progression despite expression of
`PDGF-R in his primary tumour. That study was
`terminated early because of concern about
`five men who were felt to have unacceptably
`rapid rises in PSA levels on therapy.
`
`et al. [15] reported a phase II study of
`
`Bajaj
`single-agent imatinib in 27 men with BCR
`prostate cancer, administered at a similar
`
`et al. and the present
`dose to that in Rao
`study, with a planned treatment duration of
`<
`4 weeks
`12 months [15]. Three men received
`of therapy and were deemed not evaluable.
`Of the 24 men evaluated for biochemical
`≥
`response, only two had a
`50% PSA decline
`≥
`for
`4 weeks. The duration of the response in
`those men was 5 and 12 months. Unlike the
`
`et al. and the present study,
`study by Rao
`the toxicities reported were considered
`acceptable (leukopenia, 3.7%; transaminitis,
`7.4%; and rash, 18.5%) and did not appear to
`limit the patients’ ability to remain on therapy.
`
`In the present study, six men stopped
`treatment because of PSA progression. Of
`these, five had objective disease progression
`(four bone scan, one CT evidence of
`lymphadenopathy). Although scans were not
`routinely done for all men coming off study
`(i.e. those who came off for toxicity), it is
`worth considering regular periodic scans
`while on study for men with BCR prostate
`cancer, given these findings.
`
`One possible explanation for the apparent
`lack of activity of single-agent imatinib is the
`overestimation of PDGF-R expression in
`prostate cancer cells. A more recent
`evaluation of PDGF-R expression in various
`prostate tissue samples, including benign
`tissue, prostatic intraepithelial neoplasia,
`localized prostate cancer, and metastatic
`prostate cancer [16], revealed moderate or
`β
`strong PDGF-R
` protein expression in only
`5% of localized prostate cancer and 16% of
`metastatic prostate cancer via IHC of tissue
`microarrays. If weak protein expression was
`included, it only increased the proportion to
`24% and 23%, respectively. These estimates
`are much lower than those reported by Ko
`
`et al. [10], which were also based on IHC
`staining for PDGF-R. Explanations for these
`discrepancies were the inclusion of different
`study populations and different thresholds
`for grading PDGF-R expression. In addition,
`IHC expression of a receptor does not
`necessarily correlate with clinical response to
`targeted therapies directed at the receptor.
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`The present results suggest that single-agent
`imatinib should not be further evaluated in
`this setting. However, if imatinib were to be
`considered for a future study in men with BCR
`prostate cancer, it should be conducted as a
`randomized placebo-controlled trial and at a
`lower dose than 400 mg twice daily. This
`might prevent many of the toxicities that
`were experienced. In addition, although there
`have been reports that imatinib causes rises in
`PSA level [14], the effects of imatinib