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`Annals of Oncology
`
`original articles
`
`Annals of Oncology 24: 1813–1821, 2013
`doi:10.1093/annonc/mdt107
`Published online 27 March 2013
`
`Ipilimumab alone or in combination with radiotherapy in
`metastatic castration-resistant prostate cancer: results
`from an open-label, multicenter phase I/II study
`S. F. Slovin1*, C. S. Higano2, O. Hamid3, S. Tejwani4, A. Harzstark5, J. J. Alumkal6, H. I. Scher1,
`K. Chin7, P. Gagnier7, M. B. McHenry7 & T. M. Beer6
`1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York; 2Department of Medicine, Seattle Cancer Care Alliance, University of Washington, Seattle;
`3Department of Translational Research/Immunotherapy, The Angeles Clinic and Research Institute, Santa Monica; 4Department of Hematology-Oncology, Henry Ford
`Health System, Detroit; 5Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; 6Division of Hematology and
`Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland; 7Department of Oncology Global Clinical Research, Bristol-Myers Squibb,
`Wallingford, USA
`
`Received 15 November 2012; revised 4 February 2013; accepted 5 February 2013
`
`Background: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored
`ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic
`antitumor activity between anti-CTLA-4 antibody and radiotherapy.
`Patients and methods: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at
`3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50
`patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs),
`prostate-specific antigen (PSA) decline, and tumor response.
`Results: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea
`(54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One
`treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA
`declines of ≥50% (duration: 3–13+ months), one had complete response (duration: 11.3+ months), and six had stable
`disease (duration: 2.8–6.1 months).
`Conclusions: In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with
`disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/
`kg ± radiotherapy are ongoing.
`ClinicalTrials.gov identifier: NCT00323882.
`Key words: ipilimumab, metastatic castration-resistant prostate cancer, phase I/II trial, prostate-specific antigen and
`radiotherapy, immunotherapy
`
`introduction
`Cancer immunotherapy, based on active immunization with
`tumor antigens, can induce antitumor immune responses and
`has been widely tested in prostate cancer [1]. Sipuleucel-T, an
`immunotherapy targeting prostatic acid phosphatase,
`demonstrated improvement in overall survival (OS) in patients
`with metastatic castration-resistant prostate cancer (mCRPC),
`with no demonstrable effects on the serum prostate-specific
`antigen (PSA) level or tumor growth in phase III trials [2].
`This and other treatments, including docetaxel, cabazitaxel,
`
`*Correspondence to: Dr S. F. Slovin, Department of Medicine, Sidney Kimmel Center for
`Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York
`Avenue, New York, NY 10065, USA. Tel: +1-646-422-4470; Fax: +1-212-988-0701;
`E-mail: slovins@mskcc.org
`
`abiraterone, enzalutamide, and radium-223 chloride, showed
`only incremental OS improvements [3–7], so there is a need
`for novel therapeutic approaches providing durable disease
`control.
`Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a negative
`regulator of T-cell activation, has emerged as a target for
`cancer immunotherapy [8–10]. Ipilimumab, a fully human
`monoclonal antibody, specifically blocks the binding of CTLA-
`4 to its ligands (CD80/CD86) and thereby augments T-cell
`activation and proliferation and tumor regression [11–15].
`Early clinical trials with ipilimumab showed clinical activity in
`several cancers including melanoma, renal cell carcinoma, non-
`Hodgkin lymphoma, pancreatic adenocarcinoma, lung and
`ovarian cancer [16–24]. Two randomized phase III trials
`demonstrated OS improvements and durable objective
`
`© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
`All rights reserved. For permissions, please email: journals.permissions@oup.com.
`
`002004002033
`
`AVENTIS EXHIBIT 2033
`Mylan v. Aventis, IPR2016-00712
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`original articles
`
`responses in patients with metastatic melanoma [25, 26].
`Follow-up showed that 19%–36% of patients with metastatic
`melanoma treated with ipilimumab had long-term (4-year) OS
`[27–29]. Adverse events (AEs) associated with ipilimumab
`were often immune-related and occurred mainly within the
`skin, gastrointestinal tract, and liver; these were generally
`managed by established treatment guidelines [25, 26, 30].
`Based on the antitumor immunity of the anti-CTLA-4
`antibody in preclinical models of prostate cancer [31, 32],
`several studies of ipilimumab in mCRPC patients were carried
`out. These initial studies showed that ipilimumab 3 mg/kg
`given every 4 weeks for four doses had acceptable safety and
`preliminary antitumor activity [33–35]. We chose to evaluate
`ipilimumab 3, 5, or 10 mg/kg given every 3 weeks, because
`phase II data in melanoma patients showed a higher objective
`response rate (11.1%) at 10 mg/kg than at 3 mg/kg (4.2%) or
`0.3 mg/kg (0%) [18].
`Localized radiotherapy can cause immune-mediated tumor
`death and induce tumor regression at sites distant from the
`primary site of radiotherapy (abscopal effect) in an immune-
`mediated process [36, 37]. In murine models of breast and
`colon cancer, the combination of the anti-CTLA-4 antibody
`and localized tumor irradiation resulted in the synergistic
`inhibition of metastases [38, 39]. Furthermore, the abscopal
`effect involving immune response has been reported in two
`cases of metastatic melanoma treated with ipilimumab and
`localized radiotherapy [40, 41]. Therefore, we hypothesized
`that tumor antigens released during radiation-induced cell
`death may enhance the antitumor activity of ipilimumab in
`patients with mCRPC. Accordingly, we performed a phase I/II
`study in patients with mCRPC to systematically assess
`ipilimumab at various doses given alone or in combination
`with external-beam radiotherapy (XRT).
`
`patients and methods
`patients
`Men diagnosed with mCRPC (rising PSA or progression on scans with a
`serum testosterone concentration of <50 ng/dl) and the evidence of
`progression after the discontinuation of anti-androgen therapy who had no
`more than one prior chemotherapy were enrolled. Adenocarcinoma of the
`prostate was confirmed histologically, and the extent of disease was
`documented radiographically by bone scan and computed tomography.
`Patients had a life expectancy of >12 weeks, an Eastern Cooperative
`Oncology Group (ECOG) performance status of 0 or 1, and adequate
`hematologic, hepatic, and renal functions. Patients with radiation-induced
`diarrhea within 12 months of study entry or with prior colitis or irritable
`bowel syndrome were excluded. Other key exclusion criteria were
`autoimmune disease (except for vitiligo) requiring systemic steroids or
`immunosuppressive agents, other prior malignancy within 5 years, active
`infection, bone pain severe enough to require routine narcotic analgesics,
`and prior treatment with anti-CTLA-4 therapies. All patients gave
`informed consent before enrollment. The study was conducted according
`to the principles of the Helsinki Declaration. The protocol was approved by
`Institutional Review Boards in all participating centers.
`
`study design and treatment
`This was a phase I/II, non-randomized, open-label, multicenter study
`(ClinicalTrials.gov identifier: NCT00323882). In the dose-escalation phase,
`
`Annals of Oncology
`
`eligible patients (≥6 patients per cohort) received ipilimumab at 3, 5, or 10
`mg/kg or at 3 or 10 mg/kg + XRT (Figure 1). Starting with the lowest
`monotherapy dose, ipilimumab was administered intravenously once every
`3 weeks (days 1, 22, 43, and 64) in a cycle of up to four doses with a
`response assessment 3 weeks after the last dose (day 85). Dose escalation
`occurred after all six patients in the preceding cohort received at least two
`doses of ipilimumab and were observed for an additional 2 weeks with no
`more than one of the six patients experiencing a dose-limiting toxicity
`(DLT) during this 5-week period. The DLT was defined as a grade 3/4
`immune-related AE (irAE) or other grade 3/4 treatment-related AE, which
`required surgical intervention or did not resolve to ≤grade 2 within 14 days
`of the start of immunosuppressive therapy. Dose escalation continued until
`the last monotherapy-dose cohort was enrolled or the maximum tolerated
`dose (MTD, defined as the highest dose at which no more than one of the
`six patients experienced a DLT) was identified.
`Once the monotherapy cohorts were fully enrolled, patients were
`assigned to 3 mg/kg + XRT, and after completion of accrual in this arm, to
`10 mg/kg + XRT. Radiotherapy was given focally at a single dose of 8 Gy
`per target bone lesion for up to three bone lesions per patient at 24–48 h
`before the first ipilimumab dose. Single administration of 8 Gy has been
`shown to be therapeutically equivalent to fractionated regimens in terms of
`pain palliation and better tolerated [42]. Target lesions had to be ≥10 mm
`long in at least one direction when measured by radiologic imaging. The
`timing of XRT delivery was designed to provide CTLA-4 blockade at a time
`when antigen presentation due to radiation was expected to peak [43].
`For the phase II portion, additional patients were assigned to
`monotherapy (at the MTD or at 10 mg/kg if the MTD was not reached),
`and after monotherapy accrual was completed, to combination therapy.
`Patients who progressed following an initial response or stable disease
`could have received up to three additional cycles of ipilimumab. No
`retreatment with XRT was allowed. After the initial treatment period (days
`1–112), patients had follow-up visits every 4 weeks for 3 months and then
`every 12 weeks for 9 months or until disease progression, intolerance, or
`death. Patients who withdrew from the study due to disease progression or
`who completed all planned study visits were followed for survival every 3
`months for up to 5 years.
`
`assessments
`AEs including irAEs were based on assessments by investigators of patients
`treated between the first dose and 70 days after the last ipilimumab dose.
`An irAE was defined as a treatment-related AE consistent with immune-
`mediated events. AEs, irAEs, and clinical laboratory tests were graded using
`the NCI Common Terminology Criteria for Adverse Events, version 3.0.
`The protocol defined guidelines for evaluation and treatment of irAEs of
`the gastrointestinal tract, liver, skin, eye, and endocrine glands; irAE
`management consisted of corticosteroids (e.g. prednisone or budesonide)
`given orally or intravenously. Additional immunosuppressive agents (e.g.
`infliximab for colitis and mycophenolate mofetil for hepatic irAEs) and
`hormone replacement therapy for endocrine irAEs were also used at the
`investigator’s discretion. No dose reductions were allowed. For a grade 2
`drug-related skin irAE or grade 3 skin irAE (regardless of causality),
`ipilimumab administration was delayed until its resolution to ≤grade 1.
`Ipilimumab administration was permanently discontinued for any
`non-skin-related AE of ≥grade 3 or any other AE of ≥grade 4.
`Antitumor effects were assessed by serum PSA status using criteria
`consistent with guidelines of the Prostate Cancer Clinical Trials Working
`Group 1 (PCWG1) [44], the standard when the study was being designed,
`and by tumor status using Response Evaluation Criteria in Solid Tumors
`(RECIST) for soft tissue disease [45]. PSA assessments were performed on
`days 22, 43, 64, and 85 and every month thereafter. Tumor assessments
`were carried out on day 85 and every 3 months thereafter. This time
`
` | Slovin et al.
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`Volume 24 | No. 7 | July 2013
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`Annals of Oncology
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`original articles
`
`Figure 1. The study schema. XRT, external-beam radiotherapy; PD, progressive disease; PSA, prostate-specific antigen.
`
`schedule was chosen, because responses to ipilimumab have been observed
`weeks to months after therapy initiation [46]. Both the decline in PSA to
`≥50% from baseline (PSA decline) and tumor response, as determined by
`investigators, were confirmed by repeat assessments at 4 weeks or later after
`the initial assessments. The PSA decline was calculated by comparing the
`greatest decline in post-therapy PSA concentration to baseline. End points
`included PSA decline by day 85, PSA decline at any time, tumor response
`at any time, time to and duration of tumor response, and OS.
`
`statistical considerations
`The primary objective of this study was to determine the safety of
`ipilimumab alone or in combination with a single dose of XRT. The
`secondary objective was to determine clinical antitumor activity based on
`PSA and radiologic responses. For the phase II portion of the study, the
`initial sample size of 30 patients was based on the design of the dose
`escalation for safety. For the phase II portion of the study, there were to be
`16 assessable patients treated with ipilimumab monotherapy and 32 treated
`with the combination of ipilimumab + XRT (chemotherapy-naïve, 16;
`chemotherapy-experienced, 16). A sample size of 16 assessable patients was
`required to provide >80% power in a one-sample exact binomial test at
`the significance level of 0.05. Data were summarized using descriptive
`statistics. The Kaplan–Meier product limit method was used to estimate
`the median OS.
`
`results
`patients
`Seventy-five patients were enrolled at nine sites in the United
`States: 71 were eligible and received treatment between January
`2006 and September 2009. Forty-seven patients (66%)
`discontinued the study due to disease progression determined
`by either PCWG1 criteria or RECIST (Table 1). Of eight
`discontinuations due to AEs, five were caused by irAEs (colitis,
`1; diarrhea, 3; hepatitis, 1). Of seven deaths causing
`discontinuation, one (5 mg/kg group) was due to aspergillosis,
`after 4 months of immunosuppressive therapy required to
`control grade 3 colitis, and was thus considered treatment-
`related. Three patients died from disease progression and one
`
`each from sepsis, pneumonia, and myocardial infarction; these
`deaths were deemed by investigators to be unrelated to
`treatment. The patient who died of sepsis (Clostridium difficile)
`received no immunosuppressives; no autopsy or endoscopy
`was carried out to rule out colitis, but the presentation did not
`include diarrhea above grade 2. Two deaths (10 mg/kg + XRT:
`pneumonia, 1; progression, 1) occurred within 30 days after
`the last ipilimumab dose.
`Patient demographics and baseline disease characteristics are
`listed in Table 2. Of 50 patients in the expanded 10 mg/
`kg ± XRT group, 27 received prior chemotherapy. Of 21
`patients across other cohorts, 6 had prior chemotherapy.
`
`exposure
`There were 71 treated patients; 70 received at least one dose of
`ipilimumab (monotherapy, 29; combination therapy, 41) and
`one received XRT only (3 mg/kg + XRT group). In the 10 mg/
`kg ± XRT group, the median number of ipilimumab doses per
`patient was 3 (range: 1–8), with 22 (44%) patients receiving
`four or more doses. Patients in the 3- and 5-mg/kg cohorts
`received a median of 3.5–4 ipilimumab doses (range: 1–10).
`Of the 41 patients receiving combination therapy, 30, 8, and 3
`had 1, 2, and 3 bone lesions irradiated, respectively.
`Eleven (15%) patients who showed an initial response or
`stable disease by PCWG1 criteria or RECIST and later
`progressed were retreated with the original ipilimumab dose.
`Eight patients (5 mg/kg, 2; 10 mg/kg, 2; 10 mg/kg + XRT, 4)
`received one additional cycle (one cycle: up to four doses once
`every 3 weeks), two (3 mg/kg) received two additional cycles,
`and one (3 mg/kg + XRT) received three additional cycles.
`
`safety
`Thirty-three patients were initially treated with escalating doses
`of ipilimumab at 3–10 mg/kg ± XRT. There were no DLTs
`during the 5-week assessment period. Since the MTD was not
`reached, ipilimumab 10 mg/kg ± XRT cohorts were expanded
`by 38 patients to 50 for phase II evaluation. Results for patients
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`Volume 24 | No. 7 | July 2013
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`doi:10.1093/annonc/mdt107 | 
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`Table 1. Disposition of treated patients as of May 2012a
`
`Characteristic
`
`Discontinued
`Progressive disease
`AE
`irAE
`Death
`Treatment-related
`Unrelated to treatment
`Other
`Lost to follow-up
`Completed scheduled follow-upf
`
`Ipilimumab dose
`3 mg/kg
`−XRT (n = 8)
`8
`6
`2
`1
`0
`0
`0
`0
`0
`0
`
`+XRT (n = 7)
`7
`5
`1
`1
`0
`0
`0
`1e
`0
`0
`
`Annals of Oncology
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`5 mg/kg
`−XRT (n = 6)
`6
`4
`1
`1
`1
`1b
`0
`0
`0
`0
`
`10 mg/kg
`−XRT (n = 16; %)
`13 (91)
`10 (63)
`1 (6)
`1 (6)
`1 (6)
`0
`1 (6)c
`0
`1 (6)
`3 (19)
`
`+XRT (n = 34; %)
`32 (94)
`22 (65)
`3 (9)
`1 (3)
`5 (15)
`0
`5 (15)d
`1 (3)
`1 (3)
`2 (6)
`
`±XRT (n = 50; %)
`45 (90)
`32 (64)
`4 (8)
`2 (4)
`6 (12)
`0
`6 (12)
`1 (2)
`2 (4)
`5 (10)
`
`aFour enrolled patients were not treated; reasons not known.
`bDue to aspergillosis after prolonged immunosuppressive treatment of grade 3 colitis.
`cDue to disease progression.
`dOne death each due to sepsis (associated with malignant disease), pneumonia, and acute myocardial infarction (after discontinuation for grade 3 acute renal
`failure) and two deaths due to disease progression.
`eReceived XRT, but no ipilimumab.
`fPatients completing all scheduled visits during the initial treatment phase and the 12-month follow-up phase.
`XRT, external-beam radiotherapy; AE, adverse event.
`
`in the combined 10 mg/kg ± XRT group are emphasized in the
`following.
`Treatment-related AEs were common, with the majority
`being grade 1/2 (Table 3). Most of the treatment-related AEs
`were irAEs in each cohort, and the majority of irAEs were
`grade 1/2 (Table 3). Common (≥15%) irAEs of any grade in
`the 10 mg/kg ± XRT group were diarrhea, colitis, rash, and
`pruritus. Other common treatment-treated AEs were fatigue,
`nausea, vomiting, and decreased appetite. Sixteen patients
`(32%) reported irAEs of grade 3/4, most commonly colitis
`(16%, all grade 3), diarrhea (8%, all grade 3), and hepatitis
`(4%, grade 3; 6%, grade 4). There were no reports of bowel
`perforation or neurologic irAEs.
`In the 10 mg/kg ± XRT group, of the 11 (22%) patients
`(12 events) who experienced grade 3 diarrhea/colitis, 8 had
`resolution to <grade 3 within 11 weeks, of whom 7 were
`treated with corticosteroids and/or infliximab; 4 patients
`needed no immunosuppressive therapy. Of the five (10%)
`patients (eight events) with grade 3/4 hepatic irAEs, four had
`resolution to <grade 3 between 3 and 13 weeks, with one
`patient having resolution after 61 weeks; all five were treated
`with corticosteroids and/or mycophenolate mofetil. All skin
`irAEs in this group were grade 1/2, except for one case of grade
`3 pruritus. Endocrine irAEs were noted in nine patients, all of
`which were grade 1/2, and included adrenal insufficiency
`(n = 1), hyperthyroidism (n = 2), hypothyroidism (n = 2),
`hypophysitis (n = 1), and hypopituitarism (n = 3). AEs,
`consisting mainly of fatigue, diarrhea/colitis, and rash/pruritus,
`were observed in both chemotherapy-naive and chemotherapy-
`experienced patients (data not shown). Fourteen (28%) patients
`in the 10 mg/kg ± XRT group discontinued therapy due to
`treatment-related AEs, mostly diarrhea/colitis (Table 3). At the
`database lock of May 2010, 37 (52%) patients across all cohorts
`
`had died (Table 3), due mostly to disease progression (n = 24).
`None of the deaths, except for the one in the 5 mg/kg group
`described above, were treatment-related.
`
`activity
`Activity by both PSA decline and tumor response was observed
`in all cohorts (Figure 2 and Table 4). In the 10 mg/kg ± XRT
`group, the confirmed PSA decline of ≥50% (at any time) was
`reported in eight patients (chemotherapy-naive, 6;
`chemotherapy-experienced, 2). The duration of response was
`3–13+ months. Of the 11 patients who were retreated with
`ipilimumab, 6 had the confirmed PSA decline of ≥50% (at any
`time). One of the 28 tumor-evaluable patients in the 10 mg/
`kg ± XRT group (chemotherapy-naive) achieved confirmed
`complete response with time to response of 2.5 months and
`was censored at 11.3 months. Two patients (10 mg/kg, 1; 10
`mg/kg + XRT, 1) had unconfirmed partial response. Six
`(chemotherapy-naive, 1; chemotherapy-experienced, 5) had
`stable disease lasting between 2.8 and 6.1 months.
`With a median follow-up of 15.7 months (range, 1.1–57.3)
`and 52 deaths reported across all cohorts (n = 71), the median
`OS by the Kaplan–Meier analysis was 17.4 months (95% CI:
`11.5–24.7).
`
`discussion
`Ipilimumab is a cancer immunotherapy that has been shown
`to improve OS in patients with metastatic melanoma [25, 26],
`with 19%–36% of patients having long-term (4-year) OS
`[27–29]. As an immunotherapy, ipilimumab exerts its effect on
`the immune system instead of directly on the tumor as occurs
`for chemotherapy. In this study, we made a systematic
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` | Slovin et al.
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`Volume 24 | No. 7 | July 2013
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`Annals of Oncology
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`Table 2. Baseline Characteristics
`
`Characteristic
`
`Age (years)
`Median
`Range
`Race
`Asian
`Black
`White
`ECOG performance status
`0
`1
`2
`Not reported
`Time from diagnosis (months)
`Median
`Range
`Selected tumor lesionsa
`Lymph node
`Liver
`Lung
`Bone lesions (no.)
`Median
`Range
`Hemoglobin decreased
`Grade 0–1
`Grade 2–3
`Not reported
`Alkaline phosphatase increased
`Grade 0–1
`Grade 2–3
`Grade 4
`Not reported
`Serum PSA (ng/ml)
`Median
`Range
`Selected prior therapyb
`Surgery
`Radiotherapy
`Goserelin
`Leuprolide
`Bicalutamide
`Flutamide
`Nilutamide
`Chemotherapyc
`
`original articles
`
`Ipilimumab dose
`3 mg/kg
`−XRT (n = 8)
`
`+XRT (n = 7)
`
`5 mg/kg
`−XRT (n = 6)
`
`10 mg/kg
`−XRT (n = 16; %)
`
`+XRT (n = 34; %)
`
`±XRT (n = 50; %)
`
`69
`55–78
`
`68
`54–81
`
`57
`51–68
`
`0
`0
`8
`
`5
`3
`0
`0
`
`0
`1
`6
`
`4
`2
`1
`0
`
`79
`41–135
`
`61
`20–198
`
`3
`0
`0
`
`4
`1–11
`
`7
`0
`1
`
`8
`0
`0
`0
`
`2
`1
`0
`
`6
`2–11
`
`4
`2
`1
`
`5
`1
`0
`1
`
`0
`0
`6
`
`5
`1
`0
`0
`
`34
`10–98
`
`2
`0
`2
`
`5
`2–10
`
`6
`0
`0
`
`6
`0
`0
`0
`
`91
`7–449
`
`47
`14–197
`
`38
`3–111
`
`7
`8
`1
`7
`6
`0
`4
`0
`
`5
`4
`2
`7
`5
`1
`1
`4
`
`6
`5
`0
`6
`6
`0
`0
`2
`
`65
`53–76
`
`0
`0
`16 (100)
`
`10 (63)
`6 (37)
`0
`0
`
`60
`22–204
`
`7 (44)
`2 (13)
`0
`
`2.5
`1–12
`
`15 (94)
`1 (6)
`0
`
`13 (81)
`3 (19)
`0
`0
`
`132
`13–2581
`
`16 (100)
`9 (56)
`3 (19)
`14 (88)
`15 (94)
`3 (19)
`3 (19)
`6 (38)
`
`66
`50–83
`
`1 (3)
`3 (9)
`30 (88)
`
`9 (27)
`22 (65)
`0
`3 (9)
`
`67
`10–239
`
`20 (59)
`5 (15)
`6 (18)
`
`8
`1–15
`
`25 (74)
`5 (15)
`4 (12)
`
`25 (74)
`5 (15)
`1 (3)
`3 (9)
`
`120
`8–1314
`
`28 (82)
`20 (59)
`13 (38)
`28 (82)
`29 (85)
`3 (9)
`9 (27)
`21 (62)
`
`65
`50–83
`
`1 (2)
`3 (6)
`46 (92)
`
`19 (38)
`28 (56)
`0
`3 (6)
`
`65
`10–239
`
`27 (54)
`7 (14)
`6 (12)
`
`6
`1–15
`
`40 (80)
`6 (12)
`4 (8)
`
`38 (76)
`8 (16)
`1 (2)
`3 (6)
`
`133
`8–2581
`
`44 (88)
`29 (58)
`16 (32)
`42 (84)
`45 (90)
`6 (12)
`12 (24)
`27 (54)
`
`aReported in ≥10% of patients. Patients may have had lesions at more than one site.
`bReported in ≥ 10% of patients. Patients may have received more than one therapy.
`cDocetaxel.
`XRT, external-beam radiotherapy; ECOG, Eastern Cooperative Oncology Group; PSA, prostate-specific antigen.
`
`evaluation of the safety and antitumor activity of ipilimumab
`as monotherapy or in combination with radiotherapy in
`mCRPC patients.
`Patients in all cohorts, including 10 mg/kg with or without
`radiotherapy, experienced frequent (all grades, 80%; grade 3/4,
`
`32%), but not unexpected, irAEs consisting mainly of diarrhea/
`colitis and rash/pruritus. Although no DLTs were noted within
`the 5-week assessment period, grade 3/4 AEs occurring beyond
`the DLT window were frequent and mostly immune-related,
`with some events having a long duration. These irAEs were
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`Volume 24 | No. 7 | July 2013
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`doi:10.1093/annonc/mdt107 | 
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`

`
`original articles
`
`Table 3. Safety
`
`Annals of Oncology
`
`Ipilimumab dose
`10 mg/kg
`5 mg/kg
`3 mg/kg
`−XRT (n = 8; %) +XRT (n = 7; %) −XRT (n = 6; %) −XRT (n = 16; %) +XRT (n = 34; %) ±XRT (n = 50; %)
`
`Downloaded from
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` at Infotrieve on June 25, 2014
`
`6 (86)
`4 (57)
`3
`1
`1
`0
`3
`3
`3
`2
`
`3 (43)
`3 (43)
`1
`0
`2
`1
`
`6
`5
`6
`5
`2
`2
`0
`
`6
`0
`1
`1
`0
`
`3
`3
`3
`0
`0
`3
`0
`
`5 (83)
`5 (83)
`3
`2
`2
`1
`3
`2
`1
`0
`
`3 (50)
`3 (50)
`1
`0
`1
`0
`
`5
`3
`4
`4
`2
`2
`3
`
`5
`0
`0
`0
`1
`
`2
`2
`2
`0
`0
`4
`0
`
`16 (100)
`16 (100)
`13 (81)
`9 (56)
`7 (44)
`6 (38)
`8 (50)
`3 (19)
`2 (13)
`2 (13)
`
`10 (63)
`10 (63)
`6 (38)
`3 (19)
`2 (13)
`0
`
`15 (100)
`12 (80)
`12 (80)
`7 (47)
`7 (47)
`6 (40)
`4 (27)
`
`15 (100)
`1 (7)
`2 (13)
`1 (7)
`2 (13)
`
`6 (38)
`6 (38)
`3 (19)
`3 (19)
`0
`7 (44)
`0
`
`29 (85)
`24 (71)
`14 (41)
`7 (21)
`4 (12)
`4 (12)
`17 (50)
`9 (27)
`9 (27)
`7 (21)
`
`13 (38)
`6 (18)
`2 (6)
`2 (6)
`2 (6)
`3 (9)
`
`34 (100)
`31 (91)
`28 (82)
`21 (62)
`10 (29)
`8 (24)
`4 (12)
`
`34 (100)
`6 (18)
`3 (9)
`5 (15)
`1 (3)
`
`8 (24)
`5 (15)
`3 (9)
`1 (3)
`1 (3)
`18 (53)
`2 (6)
`
`45 (90)
`40 (80)
`27 (54)
`16 (32)
`11 (22)
`10 (20)
`25 (50)
`12 (24)
`11 (22)
`9 (18)
`
`23 (46)
`16 (32)
`8 (16)
`5 (10)
`4 (8)
`3 (6)
`
`49 (100)
`43 (88)
`40 (82)
`28 (57)
`17 (35)
`14 (29)
`8 (16)
`
`49 (100)
`7 (14)
`5 (10)
`6 (12)
`3 (6)
`
`14 (28)
`11 (22)
`6 (12)
`4 (8)
`1(2)
`25 (50)
`2 (4)
`
`8 (100)
`6 (75)
`4
`1
`1
`2
`6
`3
`2
`2
`
`2 (25)
`1 (13)
`1
`0
`0
`0
`
`AEs, any gradea
`Any treatment-related
`Any immune-related
`Diarrhea
`Rash
`Colitis
`Pruritus
`Fatigue
`Nausea
`Decreased appetite
`Vomiting
`AEs, grade 3/4b
`Any treatment-related
`Any immune-related
`Colitis
`Hepatitis
`Diarrhea
`Fatigue
`Laboratory abnormalities, any gradea,c
`8
`Evaluable patients
`7
`Lymphopenia
`7
`Hemoglobin decreased
`3
`Alkaline phosphatase increased
`0
`Alanine aminotransferase increased
`Aspartate aminotransferase increased 0
`Amylase increased
`2
`Laboratory abnormalities, grade 3/4b,c
`8
`Evaluable patients
`0
`Hemoglobin decreased
`0
`Lymphopenia
`0
`Alkaline phosphatase increased
`0
`Alanine aminotransferase increased
`AEs leading to study therapy discontinuation
`Any treatment-related AEs
`2
`Any irAEs
`2
`Diarrhea/colitis
`2
`Hepatitis
`0
`Diarrhea/colitis/hepatitis
`0
`Death
`5
`Within 30 days after last dose
`0
`
`aListed were those AEs or laboratory abnormalities that occurred in ≥15% of patients in the 10 mg/kg ± XRT group.
`bListed were those AEs or laboratory abnormalities that occurred in ≥5% of patients in the 10 mg/kg ± XRT group. All but three cases of hepatitis in the 10
`mg/kg cohort were grade 3.
`cCalculated from laboratory values.
`XRT, external-beam radiotherapy; AEs, adverse events.
`
`generally managed with corticosteroids, endocrine hormone
`replacement therapy (e.g. hydrocortisone, levothyroxine), and
`supportive care. Five patients (5 mg/kg, 2; 10 mg/kg, 3)
`received additional immunosuppressives, including infliximab,
`tacrolimus, and mycophenolate mofetil. Early recognition and
`immediate intervention of irAEs, particularly diarrhea and
`colitis, are critical to their management but are not always
`
`adequate as seen in the patient with grade 3 colitis in this trial
`who died from aspergillosis after a 4-month
`immunosuppressive regimen.
`Ipilimumab 10 mg/kg was the highest dose tested in this
`study and, since it showed a generally manageable safety
`profile, the 10 mg/kg ± XRT group was expanded to include 50
`mCRPC patients. Clinical activity was assessed by both
`
` | Slovin et al.
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`Volume 24 | No. 7 | July 2013
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`
`Annals of Oncology
`
`original articles
`
`Figure 2. Waterfall plots of percent change in PSA from baseline. The greatest change at any time up to and including day 85 for patients (n = 65) across
`all cohorts (A) and for patients (n = 45) in the 10 mg/kg ± XRT group (B). The greatest change at any time during the entire study period for patients
`(n = 66) across all cohorts (C) and for patients (n = 46) in the 10 mg/kg ± XRT group (D). The number of patients with ≥50% PSA decline is higher in this
`figure than in Table 4 because the figure includes all declines, regardless of confirmation, and the table includes only confirmed declines.
`
`PCWG1 and RECIST guidelines. Among patients receiving 10
`mg/kg ± XRT, there were PSA changes, irrespective of prior
`exposure to chemotherapy. These PSA data, taken together
`with the observation that, of 28 tumor-evaluable patients
`receiving 10 mg/kg ± XRT, 1 achieved complete response and 6
`had stable disease, suggest potential clinical antitumor activity
`with disease control at ipilimumab 10 mg/kg. PSA declines
`further suggest a direct antitumor effect of ipilimumab in
`contrast to other biologics such as sipuleucel-T, which showed
`survival benefit in the absence of changes in PSA or
`progression in phase III trials [2].
`Several lines of evidence suggest that ipilimumab 10 mg/
`kg ± XRT merits further evaluation in phase III trials of
`mCRPC. First, preclinical data and two recent case reports in
`metastatic melanoma showed synergistic antitumor activity
`between CTLA-4 blockade and radiotherapy [38–41]. Second,
`data from a dose-ranging phase II study in melanoma patients
`
`have further described the benefit/risk profile of ipilimumab
`10 mg/kg [18], and long-term (4-year) OS has been seen in
`19%–36% of melanoma patients treated with ipilimumab
`[27–29]. Third, ipilimumab 10 mg/kg ± XRT appeared to show
`activity in mCRPC patients, irrespective of prior chemotherapy
`exposure, with AEs that were managed by proactive
`intervention according to treatment guidelines (this study).
`Finally, recent phase I studies in mCRPC showed the
`combination of ipilimumab (1–10 mg/kg) and the granulocyte-
`macrophage colony-stimulating factor-transduced allogeneic
`prostate cancer cells vaccine (GVAX) or PSA-targeted poxviral
`vaccine to be safe and tolerable with PSA declines relative to
`baseline [47, 48], supporting the view that ipilimumab has
`potential as a component of combination approaches for the
`treatment of mCRPC. Two confirmatory phase III trials of
`ipilimumab 10 mg/kg in mCRPC are underway. One trial
`(NCT01057810) is evaluating ipilimumab as monotherapy in
`
`Volume 24 | No. 7 | July 2013
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`doi:10.1093/annonc/mdt107 | 
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`
`original articles
`
`Table 4. PSA decline and tumor responsea
`
`Annals of Oncology
`
`Characteristics
`
`PSA-evaluable patients
`PSA decline by day 85
`PSA decline at any time
`Tumor-evaluable patients
`Complete response
`Partial response
`Partial response
`(unconfirmed)
`Stable disease
`Progressive disease
`Unknown
`
`Ipilimumab dose
`3 mg/kg
`−XRT
`(n = 8)
`8
`1
`2
`1
`0
`0
`0
`
`1
`0
`0
`
`+XRT
`(n = 7)
`6
`0
`2
`2
`0
`0
`0
`
`1
`1
`0
`
`5 mg/kg
`−XRT
`(n = 6)
`6
`1
`1
`1
`0
`0
`0
`
`1
`0
`0
`
`10 mg/kg
`−XRT
`(n = 16; %)
`16 (100)
`3 (19)
`4 (25)
`8 (100)
`1 (13)
`0
`1
`
`1 (13)
`3 (38)
`2 (25)
`
`+XRT
`(n = 34; %)
`34 (100)
`4 (12)
`4 (12)
`20 (100)
`0
`0
`1
`
`5 (25)
`5 (25)
`9 (45)
`
`±XRT
`(n = 50; %)
`50 (100)
`7 (14)
`8 (16)
`28 (100)
`1 (4)
`0
`2 (4)
`
`6 (21)
`8 (29)
`11 (40)
`
`aPSA decline of ≥50% from baseline (day 85 and at any time) and tumor response (at any time) were confirmed by a second assessment at least 28 days
`after the initial assessment.
`XRT, external-beam radiotherapy; PSA, prostate-specific antigen.
`
`patients who received no prior chemotherapy, and the other
`(NCT00861614) is evaluating ipilimumab and bone-directed
`XRT in patients who had prior chemotherapy.
`
`acknowledgements
`We thank patients and investigators for their participation in
`the trial. We also thank Motasim Billah, PhD, of Bristol-Myers
`Squibb for writing and editorial support.
`
`funding
`This work was supported by Bristol-Myers Squibb (no grant
`number) and NIH grant P50 CA092629 (PI: Howard I. Scher,
`MD).
`
`disclosure
`Employed by Bristol-Myers Squibb (BMS) and own BMS stock:
`KC, PG, and MBM; consultant or advisory role with BMS: CSH
`and HIS; research funding from BMS: HIS and TMB; honoraria
`from ECG and IMER and research funding from Progenics Bio
`Pharma, Inc: SFS; research funding from Medarex: CSH;
`consultant or advisory role with Roche, honoraria from Roche,
`and research funding from Roche and Genentech: OH;
`consultant or advisory role with Dendreon: HIS. All remaining
`authors have declared no conflicts of interest.
`
`references
`1. Slovin SF. Emerging role of immunotherapy in the management of prostate
`cancer. Oncology (Williston Park) 2007; 21: 326–333.
`2. Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for
`castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–422.
`3. Tannock IF, de WR, Berry WR et al. Docetaxel plus prednisone or mi