Clinical Study
`
`Oncology 2005;68:2–9
`DOI: 10.1159/000084201
`
`Received: March 5, 2004
`Accepted after revision: June 4, 2004
`Published online: February 28, 2005
`
`Phase III Trial of Satraplatin, an Oral Platinum
`plus Prednisone vs. Prednisone alone in
`Patients with Hormone-Refractory Prostate
`Cancer
`
`C.N. Sternberg P. Whelan J. Hetherington B. Paluchowska P.H.Th.J. Slee K. Vekemans
`P. Van Erps C. Theodore O. Koriakine T. Oliver D. Lebwohl M. Debois A. Zurlo
`L. Collette
`for the Genitourinary Tract Group of the EORTC
`
`Department of Medical Oncology, San Camillo & Forlanini Hospitals, Rome, Italy
`
`Key Words
`Satraplatin W Oral platinum W Hormone-refractory
`prostate cancer (HRPC) W Phase III W Randomized trial
`
`Abstract
`Satraplatin is a novel oral platinum (IV) complex that
`shows activity against hormone-refractory prostate can-
`cer (HRPC) in cisplatin-resistant human tumor lines in
`phase I and phase II trials [1]. A randomized multicenter
`phase III trial with a target sample size of 380 patients was
`initiated in men with HRPC. After 50 randomized patients,
`the trial was closed to further accrual by the sponsoring
`company. An ad hoc analysis of all available data is
`reported here. Eligibility criteria included pathological
`proof of prostate cancer, documented progression de-
`spite prior hormonal manipulation, WHO PS 0–2, and no
`daily intake of narcotic analgesics. Patients were random-
`ized between satraplatin 100 mg/m2 for 5 days plus pred-
`nisone 10 mg orally BID or prednisone alone. Compliance
`was excellent. 48/50 patients have progressed and 42
`have died, mostly due to prostate cancer. Median overall
`survival was 14.9 months (95% CI: 13.7–28.4) on the satra-
`platin plus prednisone arm and 11.9 months (95% CI: 8.4–
`23.1) on prednisone alone (hazard ratio, HR = 0.84, 95%
`
`CI: 0.46–1.55). A 1 50% decrease in prostrate specific anti-
`gen (PSA) was seen in 9/27 (33.3%) in the satraplatin plus
`prednisone arm vs. 2/23 (8.7%) on the prednisone alone
`arm. Progression-free survival was 5.2 months (95% CI:
`2.8–13.7) on the satraplatin plus prednisone arm as com-
`pared to 2.5 months (95% CI: 2.1– 4.7) on the prednisone
`alone arm (HR = 0.50, 95% CI: 0.28–0.92). This difference
`is statistically significant (p = 0.023). Toxicity was general-
`ly minimal in both arms. This randomized comparison of
`a combination of satraplatin and prednisone versus pred-
`nisone alone supports the antitumor activity of the com-
`bination. Its role in the treatment of HPRC remains to be
`elucidated in an appropriate phase III setting.
`Copyright © 2005 S. Karger AG, Basel
`
`Introduction
`
`The incidence of prostate cancer has increased dramati-
`cally over the past few years as a result of heightened pub-
`lic awareness, screening programs, more widespread use
`of prostate specific antigen (PSA) measurement, and ad-
`vances in imaging techniques. Approximately 30–35% of
`patients with prostate cancer will have regional or meta-
`static tumors. An additional 25% will develop metastases
`
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`ABC
`
`Fax + 41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
`© 2005 S. Karger AG, Basel
`0030–2414/05/0681–0002$22.00/0
`
`Accessible online at:
`www.karger.com/ocl
`
`Dr. Cora N. Sternberg
`Department of Medical Oncology, San Camillo & Forlanini Hospitals
`Pavilion Cesalpino II, Circonvallazione Gianicolense 87
`IT–00152 Rome (Italy)
`Tel. +39 06 6691 8008/6340, Fax +39 06 663 0771, E-Mail cstern@mclink.it
`
`Amerigen Exhibit 1113
`Amerigen v. Janssen IPR2016-00286
`
`

`
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`during the course of the disease, commonly to the bone. In
`patients with metastatic disease who are receiving andro-
`gen ablation, median overall survival is 2.5 years [2].
`The development of hormonal resistance predictably
`occurs after androgen deprivation treatment. Hormone-
`refractory prostate cancer (HRPC) is defined as progres-
`sive disease despite castrate levels of serum testosterone.
`Responses to current second-line therapies are temporary,
`and the median overall survival after developing HRPC is
`approximately 12–18 months [3, 4].
`The current FDA approved treatments for HRPC in
`the United States are mitoxantrone plus prednisone and
`taxotere plus prednisone. Bone is the primary site of
`metastases in 65% of patients with metastatic prostate
`cancer. For this reason, objective measurable or evaluable
`criteria for response evaluation are often lacking. In many
`patients, bone pain and decreased performance status are
`predominant. Relief from these symptoms is as important
`as prolongation of survival. As a result, assessment of
`these symptoms has become a fundamental part of many
`prostate cancer studies, and has provided an important
`endpoint for clinical trials in this disease.
`Prednisone therapy has been shown to produce pallia-
`tion of pain symptoms for patients with advanced pros-
`tate cancer [2, 5–7]. Prednisone alone produces palliative
`responses in 12–56% of patients [6, 7].
`The combination of mitoxantrone plus prednisone
`was approved by the FDA in the United States for
`patients with symptomatic HRPC following two ran-
`domized studies [6, 8]. The combination produced pal-
`liative responses, using pain response criteria in symp-
`tomatic patients, in 29% vs. 12% of patients using pred-
`nisone alone (p = 0.01). Despite the improvement in
`painful symptoms, no improvement in overall survival
`was observed.
`Since their original discovery, platinum compounds
`(cisplatin, carboplatin) have emerged as important agents
`for the therapy of several human tumors including testicu-
`lar, bladder, lung, head and neck, ovarian, and cervical
`cancer.
`Satraplatin, bis(acetato)amminedichloro(cyclohexyl-
`amine) platinum (IV), is a novel platinum (IV) complex
`synthesized by Johnson Matthey (JM-216). Satraplatin
`exhibits in vitro cytotoxicity comparable to cisplatin. This
`platinum analog is of particular interest for two reasons: it
`has activity in platinum-resistant tumor models in vitro,
`and unlike other platinum compounds, it is absorbed
`when administered orally. In studies using murine tumors
`and human ovarian carcinoma xenografts, orally admin-
`istered satraplatin demonstrated meaningful antitumor
`
`activity, which was generally comparable to that of cispla-
`tin or carboplatin administered parenterally.
`Satraplatin has been investigated in a number of clini-
`cal studies, and over 600 patients have participated in
`satraplatin clinical trials. Three previous phase II or III
`trials were initiated evaluating satraplatin for prostate can-
`cer. Two were terminated early by the sponsor for business
`reasons, but the third one, a multicenter phase II trial for
`patients with progressive HRPC, was completed [9]. The
`study was small, with 39 patients. One partial response
`was observed in a patient with measurable liver lesions,
`and there were 10 PSA responses (150% decrease), includ-
`ing 2 complete responses. With these encouraging results,
`EORTC GU Protocol 30972 was designed as a random-
`ized phase III trial, to determine the comparative efficacy
`of satraplatin plus prednisone to that of prednisone alone.
`The primary objectives of this study were to compare the
`two treatment arms in terms of overall survival and time
`to pain progression as primary endpoints. Secondary end-
`points were: present pain intensity (PPI), response rate,
`time to overall progression, PSA response rate, complete
`and objective tumor response rates, duration of response,
`quality of life and safety (National Cancer Institute of
`Canada – Common Toxicity Criteria, NCI-CTC). Predni-
`sone alone was felt to be an appropriate control arm since
`it does provide palliation of symptoms.
`
`Materials and Methods
`
`Patient Population
`Eligibility criteria included: pathological or cytological diagnosis
`of adenocarcinoma of the prostate, documented evidence of progres-
`sion (worsening disease-related pain, increasing PSA, new painful
`bone lesions, or increase in measurable disease) despite sustained
`previous hormonal treatment, WHO performance status of 0–2,
`analgesic pain score of 0–3 (table 1) (patients without pain had to
`have rising PSA 1 10 ng/ml). All patients had to have had antiandro-
`gen withdrawal for at least 6 weeks before entry into the study. An
`adequate bone marrow, liver function and renal function were
`required. All patients had a life expectancy of at least 6 months and
`gave written informed consent after the protocol was reviewed by
`their individual human subjects committees.
`Patients could not have had large-field radiotherapy (1 30% of
`marrow-bearing area) within the previous 8 weeks of protocol entry.
`They could have received radiotherapy to the prostate, as long as the
`field did not include 1 30% of bone marrow-bearing area.
`
`Treatments
`Patients were randomized between satraplatin 100 mg/m2 on
`days 1–5 every 35 days plus prednisone 10 mg twice daily per os
`(continuously) and prednisone 10 mg alone twice daily. Satraplatin
`was administered orally once daily between 9:00 and 11:00 a.m. on
`an empty stomach. A light breakfast was allowed 1 h before dosing
`
`Phase III Trial of Satraplatin plus
`Prednisone in HRPC
`
`Oncology 2005;68:2–9
`
`3
`
`

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`Table 1. Analgesic pain score
`
`Analgesics not required
`0
`1 Non-narcotic analgesics required, less than daily
`2 Non-narcotic analgesics required daily
`3 Oral or parenteral narcotic analgesics required, less than daily
`4 Oral or parenteral narcotic analgesics required daily
`
`and patients were not allowed to eat for 1 h after treatment. Fluid
`intake was unrestricted.
`Prophylactic antiemetics were to be given during satraplatin ther-
`apy. Treatment with prednisone was given in both arms until overall
`progression or excessive toxicity. According to the protocol, the
`patients were to receive a maximum of 8 cycles of satraplatin plus
`prednisone and were supposed to continue with prednisone alone
`after cycle 8 in the absence of progression.
`Dose reductions and interruptions for satraplatin plus prednisone
`were made for hematological toxicities based upon nadir counts and
`nonhematological toxicities (grade II) such as a decrease of 25–50%
`in creatinine clearance from baseline in the preceding course using
`the Common Toxicity Criteria (CTC) grades.
`Patients did not receive other drugs, with the exception of lutein-
`izing hormone-releasing hormone (LHRH) agonists, while in the
`study. Palliative and supportive care for disease-related symptoms
`was allowed.
`
`Follow-Up
`In both treatment groups, clinical examinations, biochemistry,
`PSA tests and toxicity (NCI-CTC) assessment were performed at
`baseline and every 5 weeks until the end of the treatment, then every
`3 months until death. Weekly blood cell counts were performed every
`week on treatment in the combination arm only. Tumor assessment
`via physical exam, nuclear medicine scans, CT scans of abdomen and
`pelvis and other imaging techniques as clinically indicated were per-
`formed at baseline and every 10 weeks until progression in both treat-
`ment groups.
`
`Endpoints
`Overall progression had to be defined as either an increase in
`analgesic pain score (table 1) of 1 point compared to baseline, con-
`firmed by history exceeding 2 weeks or the requirement for radiation
`therapy for disease-related pain symptoms, a 2-point worsening in
`WHO performance status compared to baseline confirmed by a his-
`tory exceeding 2 weeks, progression of measurable or nonmeasurable
`disease, or confirmed doubling of PSA to 1 20 ng/ml as compared to
`baseline.
`Pain progression was defined as either: (1) an increase in analge-
`sic pain score of 1 point over baseline level and lasting 2 weeks or
`more; or (2) the requirement of radiation therapy for disease-related
`pain symptoms; or (3) an increase in PPI score of 1 point over base-
`line PPI score or of 2 points over the nadir level, lasting at least 2
`weeks; or (4) a decrease of performance status by 2 scores or more
`from the baseline level, lasting 2 weeks or more.
`PSA response was evaluated according to the Bubley criteria [10].
`Overall survival was measured from the date of randomization until
`the date of death (any cause) or the date of most recent information
`(censored observation).
`
`Statistical Design
`The trial was planned to be a randomized phase III trial of 380
`patients with two primary endpoints: overall survival and time to
`pain progression. To correct for the presence of 2 primary endpoints,
`a significance level of 0.025 was to be used in the statistical analysis
`of each primary endpoint, so as to ensure an overall 5% risk of erro-
`neously claiming statistical significance for either endpoint. The
`sample size was determined to provide 80% power to detect an
`increase of 4 months in median overall survival (from 9 months on
`prednisone alone to 13 months for the combination) and 90% power
`to detect a difference of 3 months in time to pain progression (from 6
`to 9 months).
`
`Early Trial Closure and ad hoc Analysis Plan
`After a few months of recruitment and a total of only 50 random-
`ized patients, the trial was closed due to a decision of the sponsor
`(Bristol-Myers-Squibb, BMS) not to study the experimental treat-
`ment further. This was apparently based upon the low commercial
`priority for this drug by BMS at the time.
`With only 50 patients entered, the objectives of the phase III trial
`were not met. However, the EORTC followed all patients until pro-
`gression and most until death. In the present report, we attempt an ad
`hoc analysis of all available data. The endpoint of ‘time to overall
`progression’ was assessed and is available with the maximum poten-
`tial power as 49 of 50 patients have progressed and all have finished
`treatment. The endpoint ‘overall survival’ was also analyzed as 42 of
`50 patients have died (84%).
`At the time the trial was stopped, the assessment of the PPI scores
`was stopped. Therefore, the endpoints time to pain progression and
`pain response could not be assessed. Quality of life was also not
`assessed due to the limited sample size.
`
`Results
`
`Eighteen institutions participated in this trial and en-
`tered 50 patients until the development of satraplatin was
`stopped by the sponsoring company. We present below all
`available information concerning the toxicity and activity
`of the experimental and reference treatments.
`
`Recruitment and Patient Characteristics
`Eligibility of the patients and compliance to the treat-
`ment was evaluated by the study coordinator and the
`EORTC medical advisor.
`Of the 50 randomized patients, 27 patients were as-
`signed to the prednisone plus satraplatin arm and 23 to
`the prednisone alone arm. Patient characteristics are de-
`tailed in table 2.
`
`Treatment Compliance and Toxicity
`Treatment compliance is detailed in table 3. Dose
`reductions due to hematological or other toxicities were
`rare. The median dose of satraplatin administered was
`3,150 mg (range 900–15,250 mg). The median dose of
`
`4
`
`Oncology 2005;68:2–9
`
`Sternberg et al.
`
`

`
`Table 2. Baseline characteristics
`
`Median age, years (range)
`Baseline Hb (NCIC-CTC)
`0
`1
`2
`
`Analgesic pain score
`0 No analgesics (with PSA 1 10 ng/ml)
`1 Non-narcotics, ! daily
`2 Non-narcotics, daily
`3 Narcotics, ! daily
`4 Narcotics, daily
`
`WHO performance status
`WHO 0
`WHO 1
`WHO 2
`
`Bone scan result
`Normal
`1–5 hot spots
`6–15 hot spots
`1 15 hot spots
`Superscan
`Unknown
`
`Prednisone
`(n = 23)
`
`n
`
`%
`
`Prednisone + satra-
`platin (n = 27)
`
`n
`
`%
`
`72.5 (53.3–81.4)
`
`70.4 (42.2–79.9)
`
`1
`19
`3
`
`8
`4
`10
`1
`0
`
`7
`9
`7
`
`2
`5
`4
`7
`4
`1
`
`4.3
`82.6
`13.0
`
`34.8
`17.4
`43.5
`4.3
`0.0
`
`30.4
`39.1
`30.4
`
`8.7
`21.7
`17.3
`30.4
`17.4
`4.3
`
`1
`26
`0
`
`10
`4
`8
`4
`1
`
`12
`10
`5
`
`2
`3
`10
`6
`2
`4
`
`3.7
`96.3
`0.0
`
`37.0
`14.8
`29.6
`14.8
`3.7
`
`44.4
`37.0
`18.5
`
`7.4
`11.1
`27.0
`22.2
`7.4
`14.8
`
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`Table 3. Treatment compliance
`
`Prednisone
`(n = 23)
`
`Prednisone + satraplatin
`(n = 27)
`
`median
`
`range
`
`median
`
`range
`
`Total duration of treatment, weeks
`Average cycle duration, weeks
`Number of cycles of prednisone
`Dose intensity prednisone, mg/day
`Dose reduction due to hyperglycemia grade 3
`Number of cycles of satraplatin
`Dose intensity satraplatin, mg/m2/day
`Dose reduction due to hematological toxicity
`Cycle delayed due to toxicity
`Satraplatin discontinued due to toxicity or refusal
`
`15
`5.0
`3
`20.2
`2 (8.7%)
`–
`–
`–
`–
`–
`
`5–15
`4.4–6.1
`1–12
`16.4–20.6
`
`–
`–
`–
`–
`–
`
`1–103
`0.9–5.8
`1–20
`14.4–23.3
`
`1–15*
`39.4–103.1
`
`20
`5.0
`4
`20.1
`0
`4
`100.0
`6 (22.2%)
`9 (33.3%)
`4 (14.8%)
`
`* One patient received 9 cycles and 1 patient 15 cycles, all patients have now finished treatment.
`
`prednisone administered was 2,090 mg (range 700–
`7,020 mg) in the prednisone alone arm as compared to
`2,800 mg (140–14,440 mg) in the satraplatin plus predni-
`sone arm.
`
`In the prednisone alone arm, a median of 3 cycles
`(range 1–20) were delivered and in the satraplatin arm, a
`median of 4 cycles (range 1–15) were given. The median
`cycle duration was 35 days. Antiemetics were given on
`
`Phase III Trial of Satraplatin plus
`Prednisone in HRPC
`
`Oncology 2005;68:2–9
`
`5
`
`

`
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`Table 4. Toxicity
`
`Prednisone
`(n = 23)
`
`Prednisone +
`satraplatin
`(n = 27)
`
`Hematological toxicity
`WBC grade 3 °
`Platelets grade 3 °
`ANC grade 3–4
`Hb grade 3–4
`
`n
`
`–
`–
`–
`–
`
`Biochemical toxicity
`1
`Serum creatinine grade 4*
`2
`SGOT grade 3 °
`Alkaline phosphatase grade 3–4 7
`
`Nonhematological toxicity
`Diarrhea grade 3 °
`Vomiting grade 3 °
`Infection grade 3 °
`Cardiovascular grade 3 °
`Renal grade 3 °
`Hyperglycemia grade 3 °
`
`0
`0
`1
`2
`1
`4
`
`%
`
`4.3
`8.7
`30.4
`
`0.0
`
`4.3
`8.7
`4.3
`17
`
`n
`
`7
`8
`4
`0
`
`0
`0
`3
`
`2
`2
`2
`2
`0
`2
`
`%
`
`25.9
`29.6
`14.8
`
`11.1
`
`7.4
`7.4
`7.4
`7.4
`
`7.4
`
`° No grade 4 was observed; * no grade 3 was observed.
`
`Table 5. PSA response
`
`PSA response (Bubley)
`
`Response
`Stable disease
`Progression
`Not evaluable
`
`Prednisone
`(n = 23)
`
`Prednisone +
`satraplatin (n = 27)
`
`n
`
`2
`3
`17
`1
`
`%
`
`8.7
`13.0
`73.9
`4.3
`
`n
`
`9
`5
`12
`1
`
`%
`
`33.3
`18.5
`44.4
`3.7
`
`days 1–5 in 26/27 (96.3%) of patients on the satraplatin
`arm.
`Toxicity was generally minimal in both arms and is
`described in table 4. No grade 3–4 toxicity was observed
`for hemoglobin, nausea, fever, or pulmonary toxicity. In
`the combination arm, 2 patients experienced grade 3
`vomiting and 2 had grade 3 diarrhea. In the prednisone
`alone arm, prednisone was reduced for grade 3 hypergly-
`cemia in 2 (8.7%) patients or for other reasons in another
`2 (8.7%) patients; it was discontinued in a further 2
`(8.7%) patients. In the satraplatin arm, the chemotherapy
`was reduced at any time in only 6 (22.2 %) out of all the
`
`patients. One patient on each arm may have died due to
`stomach perforation, most likely related to prednisone.
`For complete discontinuation of the protocol treat-
`ment: all but 3 patients stopped the treatment due to pro-
`gression of disease. One on prednisone refused treatment,
`and 2 on the prednisone plus or minus satraplatin arm
`discontinued the treatment due to toxicity.
`
`Efficacy
`PSA response was observed in 9 (33.3%) patients on
`the satraplatin plus prednisone arm and 2 (8.7%) patients
`on the prednisone alone arm (odds ratio of response =
`5.26, 95% CI: 1.00–2.78). Stable disease was seen in 5
`(18.5%) patients in the satraplatin arm and in 3 (13%) on
`the prednisone arm. Progression was observed in 17
`(73.9%) patients on the prednisone alone arm and 12
`(44.4%) on the satraplatin plus prednisone arm. Re-
`sponses are detailed in table 5.
`The progression-free survival (fig. 1) was 5.2 months
`(95% CI: 2.8–13.7) on the satraplatin plus prednisone
`arm compared to 2.5 months (95% CI: 2.1–4.7) on the
`prednisone alone arm. The hazard ratio (HR) was 0.50
`(95% CI: 0.28–0.92). This difference is statistically signif-
`icant (p = 0.023). Table 6 presents the type of first failure
`in the patients who had progression as the first event. One
`patient on prednisone alone died of stomach perforation
`in the absence of progression.
`Overall survival (fig. 2) was 14.9 months (95% CI: 13.7–
`28.4) on the satraplatin plus prednisone arm compared to
`11.9 months (95% CI: 8.4–23.1) on the prednisone alone
`arm. The HR was 0.84 (95% CI: 0.46–1.55). This difference
`was not statistically significant (p = 0.579).
`
`Discussion
`
`Patients with metastatic prostate cancer are initially
`treated with hormone therapy, but hormonal resistance
`develops in most patients after androgen deprivation. The
`current FDA-approved treatments for HRPC in the
`United States are mitoxantrone plus prednisone and taxo-
`tere plus prednisone [11, 12]. These combinations are also
`approved in the EU. Mitoxantrone plus prednisone pro-
`duces a palliative response in patients with pain, but there
`is no improvement in survival. Two recent studies com-
`paring a docetaxel-containing arm to a mitoxantrone-con-
`taining arm demonstrated a survival advantage for the
`docetaxel arms. Thus, cytotoxic chemotherapy can im-
`prove survival in this disease, however, there continues to
`be a medical need for chemotherapeutic agents that may
`
`6
`
`Oncology 2005;68:2–9
`
`Sternberg et al.
`
`

`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`0
`
`N
`
`23
`27
`
`O
`
`23
`25
`
`Hazard ratio: 0.50 (95% CI: 0.28 – 0.92)
`
`p = 0.023
`
`Median
`
`Prednisone alone: 2.5 months (95% CI: 2.1 – 4.7)
`
`Prednisone+Satraplatin: 5.2 months (95% CI: 2.8 – 13.7)
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`27
`
`months
`
`Number of patients at risk :
`
`10
`18
`
`5
`11
`
`3
`11
`
`3
`11
`
`1
`6
`
`1
`5
`
`0
`5
`
`0
`3
`
`Pred
`Pred+Satraplatin
`
`Fig. 1. Progression-free survival.
`
`Table 6. Type of progression
`
`Variable
`
`Increase in pain
`Decline in WHO performance status
`Doubling of PSA
`Measurable disease progression (WHO)
`Pleural effusion progression
`Clinical local progression with
`worsening of WHO PS
`Stomach perforation
`Slow but sustained PSA rise
`
`Treatment
`
`prednisone
`(n = 23)
`
`Total
`(n = 47)
`
`prednisone +
`satraplatin (n = 27)
`
`n
`
`19
`10
`12
`10
`1
`
`0
`1
`0
`
`%
`
`86.4
`45.5
`54.5
`45.5
`4.5
`
`0.0
`
`0.0
`
`n
`
`15
`11
`13
`5
`1
`
`1
`1
`1
`
`%
`
`60.0
`44.0
`52.0
`20.0
`4.0
`
`4.0
`
`4.0
`
`n
`
`34
`21
`25
`15
`2
`
`1
`
`1
`
`%
`
`72.3
`44.7
`53.2
`31.9
`4.3
`
`2.1
`
`2.1
`
`Note that the patients may have several progressions concurrently; therefore, the numbers in the rows need not
`add up to the total number with progression.
`
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`provide continued palliation and improved survival, and
`randomized trials should continue in order to identify
`new agents for the treatment of HRPC.
`Cisplatin, used as single agent, has been evaluated in
`six trials for the treatment of HRPC [13–19]. The primary
`endpoints in these studies were response rates in measur-
`able disease. The response rates to single agent cisplatin
`are comparable to those seen to other agents in this dis-
`ease [13, 20].
`
`Why then evaluate satraplatin in a traditionally plati-
`num-resistant malignancy? In vitro satraplatin has activi-
`ty in platinum-resistant tumor models, and unlike other
`platinum compounds, it is absorbed when administered
`orally. It has a favorable toxicity profile as well. Of 149
`patients studied in 6 phase I trials, no significant cardiac,
`renal, hepatic, or central nervous system toxicity was
`observed. Nausea, vomiting, and diarrhea were generally
`mild to moderate, and were controlled with oral anti-
`emetics and antimotility drugs.
`
`Phase III Trial of Satraplatin plus
`Prednisone in HRPC
`
`Oncology 2005;68:2–9
`
`7
`
`

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`Hazard ratio: 0.84 (95% CI: 0.46 – 1.55)
`
`p = 0.579
`
`Prednisone alone: 11.9 months (95% CI: 8.4 – 23.1)
`
`Prednisone+Satraplatin: 14.9 months (95% CI: 13.7 – 28.4)
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Fig. 2. Duration of survival.
`
`0
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`42
`
`48
`
`months
`
`O N
`19 23
`23 27
`
`Number of patients at risk :
`18
`11
`7
`6
`24
`18
`10
`9
`
`4
`6
`
`4
`4
`
`1
`1
`
`Pred
`Pred+Satraplatin
`
`In the one previous completed phase II trial evaluating
`39 patients with HRPC, satraplatin appeared to be active
`[9]. Among 12 patients with measurable disease, there
`was one partial response in liver lesions. Among the 24
`patients with PSA responses, there were 2 complete PSA
`responses and 8 partial PSA responses. The median PSA
`progression-free survival was 33.1 weeks. Analgesic use to
`determine pain response was not performed due to the
`small number of data points available. Only 20 patients
`reported the use of analgesics for pain at any timepoint
`during the study.
`The current trial was initiated based upon the encour-
`aging results of this single arm phase II study. Our trial
`had accrued 50 of a planned 380 patients when it was
`closed to further accrual. It does not have the statistical
`power of a phase III trial, but it can be viewed as a ran-
`domized phase II comparison. The results suggest the pos-
`sibility of an advantage in terms of PSA response and in
`progression-free survival.
`PSA response is not universally considered as a surro-
`gate marker for clinical benefit, but it has been associated
`with favorable survival and palliation of symptoms [21–
`23]. In our protocol, progression-free survival reflected a
`variety of factors including pain score, performance sta-
`tus, progression of disease, confirmed rise of PSA to twice
`the baseline level and to greater than 20 ng/ml, or death.
`Whether progression-free survival as defined here may be
`considered as a surrogate endpoint for survival remains to
`be established. In reality, it is difficult to conclude from
`this study whether or not overall survival would have
`
`been different in the two arms, based upon the limited
`numbers of patients.
`It should be noted that 44.4% of patients on the combi-
`nation arm had a performance status of 0, compared to
`30.4% on the prednisone alone arm, and that 18.5% on
`the combination arm had a performance status of 2, com-
`pared to 30.4% on the prednisone alone arm. However,
`these differences are not statistically significant.
`
`Conclusions
`
`The combination of satraplatin plus prednisone was
`feasible in a multicenter international randomized trial
`that was, unfortunately, stopped early due to a company
`decision. The analysis lacks power due to the small num-
`ber of patients entered. No definitive conclusions on the
`impact of the combination of satraplatin plus prednisone
`on pain or overall survival can be reached. However, PSA
`response and time to progression were suggestive of the
`compound’s activity in combination with prednisone.
`The combination of satraplatin plus prednisone shows
`promise in HRPC and should be further evaluated. That
`combination is currently being tested in a large-scale mul-
`ticenter, multinational double-blind, randomized phase
`III trial, sponsored by GPC Biotech, comparing the com-
`bination of satraplatin plus prednisone to placebo plus
`prednisone in the treatment of HRPC in patients who
`have previously been treated with one cytotoxic chemo-
`therapy regimen.
`
`8
`
`Oncology 2005;68:2–9
`
`Sternberg et al.
`
`

`
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`
`Acknowledgements
`
`Princess Royal Hospital, Hull, UK – Mr. J. Hetherington (6
`patients).
`Maria Sklodowska – Curie Memorial Cancer Center, Warsaw,
`Poland – Dr. B. Paluchowska (5 patients).
`Sint Antonius Ziekenhuis, Niewegein, The Netherlands – Dr.
`P.H.Th. Slee (4 patients).
`Virga Jess Hospital, Hasselt, Belgium – Dr. K. Vekemans (3
`patients).
`Allgemeine Ziekenhuis Middleheim, Antwerpen, Belgium – Dr.
`P. Van Erps (3 patients).
`Cancer Research Center, Moscow, Russia – Pr. A.M. Garin (3
`patients).
`Institut Gustave Roussy, Villejuif, France – Dr. Ch. Théodore (3
`patients).
`Medical Radiological Research Center, Obninsk, Russia – Dr. O.
`Koriakine (3 patients).
`Sint Batholomeews Hospital, London, UK – Pr. R.T.D. Oliver (3
`patients).
`
`National Institute of Oncology, Budapest, Hungary – Dr. I.
`Bodrogi (2 patients).
`Hospices Civils de Strasbourg, Strasbourg, France – Dr. B.
`Duclos (2 patients).
`Hospital Edouard Herriot, Lyon, France – Dr. M. Colombel (2
`patients).
`Academisch Medisch Centrum, Amsterdam, The Netherlands,
`Dr. P.J.M. Bakker (2 patients).
`Hospital General Vall d’Hebron, Barcelona, Spain – Dr. J. Bell-
`munt (2 patients).
`Donauspital, Vienna, Austria – Dr. G. Studler (2 patients).
`Institut Jules Bordet, Brussels, Belgium – Dr. Th. Gil (1 patient).
`Onze Lieve Vrouw Gasthuis, Aalst, Belgium – Dr. P. Carpentier
`(1 patient).
`Krankenanstalt Rudolfstiftung, Vienna, Austria – Dr. W. Al-
`brecht (1 patient).
`‘Bosch Medicentrum’s, Hertogenbosch, The Netherlands – Dr.
`J.J. Croles (1 patient).
`Sint James Hospital, Leeds, UK – Dr. P. Whelan (1 patient).
`
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