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      A randomised, phase II study of intetumumab, an anti- α v-integrin mAb, alone and with dacarbazine in stage IV melanoma

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          Abstract

          Background:

          α v integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti- α v-integrin monoclonal antibody.

          Methods:

          In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1 : 1 : 1 : 1 to 1000 mg m −2 dacarbazine+placebo ( n=32), 1000 mg m −2 dacarbazine+10 mg kg −1 intetumumab ( n=32), 10 mg kg −1 intetumumab ( n=33), or 5 mg kg −1 intetumumab ( n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics.

          Results:

          No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg −1 intetumumab, and 5 mg kg −1 intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab–dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1–2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22–30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16–73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred.

          Conclusion:

          With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.

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          Most cited references25

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          Cancer statistics, 2004.

          Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival rates based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and mortality rates are age standardized to the 2000 US standard million population. A total of 1,368,030 new cancer cases and 563,700 deaths are expected in the United States in 2004. Incidence rates stabilized among men from 1995 through 2000 but continued to increase among females by 0.4% per year from 1987 through 2000. Mortality rates have decreased by 1.5% per year since 1992 among men, but have stabilized from 1998 through 2000 among women. Cancer death rates continued to decrease from the three major cancer sites in men (lung and bronchus, colon and rectum, and prostate) and from female breast and colorectal cancers in women. In analyses by race and ethnicity, African-American men and women have 40% and 20% higher death rates from all cancers combined compared with White men and women, respectively. Cancer incidence and mortality rates are lower in other racial and ethnic groups than in Whites and African Americans for all sites combined and for the four major cancer sites. However, these groups generally have higher rates for stomach, liver, and cervical cancers than do Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden from cancer can be accelerated by applying existing cancer control knowledge into practice among all segments of the population.
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            Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer.

            Sipuleucel-T is an investigational active cellular immunotherapy product designed to stimulate an immune response against prostate cancer. The safety and efficacy of sipuleucel-T was evaluated in 2 identically designed, randomized, double-blind, placebo-controlled trials (D9901 and D9902A) conducted in men with advanced prostate cancer. A total of 225 patients were randomized in D9901 or D9902A to sipuleucel-T (n = 147) or placebo (n = 78), given as 3 intravenous infusions approximately 2 weeks apart. Patients were followed for survival until death or a prespecified cutoff of 36 months after randomization. In the integrated analysis of D9901 and D9902A, patients randomized to sipuleucel-T demonstrated a 33% reduction in the risk of death (hazard ratio, 1.50; 95% confidence interval, 1.10-2.05; P = .011; log-rank). The treatment effect remained strong after performing adjustments for imbalances in baseline prognostic factors, poststudy treatment chemotherapy use, and non-prostate cancer-related deaths. Additional support for the activity of sipuleucel-T is provided by the correlation between a measure of the product's potency, CD54 up-regulation, and overall survival. The most common adverse events associated with treatment were chills, pyrexia, headache, asthenia, dyspnea, vomiting, and tremor. These events were primarily grade 1 and 2, with durations of 1 to 2 days. The integrated results of D9901 and D9902A demonstrate a survival benefit for patients treated with sipuleucel-T compared with those treated with placebo. The generally modest toxicity profile, coupled with the survival benefit, suggests a favorable risk-benefit ratio for sipuleucel-T in patients with advanced prostate cancer.
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              Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials.

              Objective tumor response rates observed in phase II trials for metastatic melanoma have historically not provided a reliable indicator of meaningful survival benefits. To facilitate using overall survival (OS) or progression-free survival (PFS) as an endpoint for future phase II trials, we evaluated historical data from cooperative group phase II trials to attempt to develop benchmarks for OS and PFS as reference points for future phase II trials. Individual-level and trial-level data were obtained for patients enrolled onto 42 phase II trials (70 trial arms) that completed accrual in the years 1975 through 2005 and conducted by Southwest Oncology Group, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, North Central Cancer Treatment Group, and the Clinical Trials Group of the National Cancer Institute of Canada. Univariate and multivariate analyses were performed to identify prognostic variables, and between-trial(-arm) variability in 1-year OS rates and 6-month PFS rates were examined. Statistically significant individual-level and trial-level prognostic factors found in a multivariate survival analysis for OS were performance status, presence of visceral disease, sex, and whether the trial excluded patients with brain metastases. Performance status, sex, and age were statistically significant prognostic factors for PFS. Controlling for these prognostic variables essentially eliminated between-trial variability in 1-year OS rates but not in 6-month PFS rates. Benchmarks are provided for 1-year OS or OS curves that make use of the distribution of prognostic factors of the patients in the phase II trial. A similar benchmark for 6-month PFS is provided, but its use is more problematic because of residual between-trial variation in this endpoint.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                26 July 2011
                12 July 2011
                : 105
                : 3
                : 346-352
                Affiliations
                [1 ]simpleThe Angeles Clinic and Research Institute , 2001 Santa Monica Boulevard, Suite 560W, Santa Monica, CA, USA
                [2 ]simpleNew York University , New York, NY, USA
                [3 ]simpleUniversitätsklinikum Essen , Essen, Germany
                [4 ]simpleUniversity Medical Center , Mainz, Germany
                [5 ]simpleEmory University , Atlanta, GA, USA
                [6 ]simpleKlinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Medizinische Hochschule Hannover , Hannover, Germany
                [7 ]simpleOncology Specialists, S.C. , Park Ridge, IL, USA
                [8 ]simpleUniversitätsklinikum Mannheim , Mannheim, Germany
                [9 ]simpleSeattle Cancer Care Alliance , Seattle, WA, USA
                [10 ]simpleUniversity of Colorado HSC , Aurora, CO, USA
                [11 ]simpleCharité Universitätsmedizin Berlin , Berlin, Germany
                [12 ]simpleElbeklinikum Buxtehude , Buxtehude, Germany
                [13 ]simpleCancer Research UK Clinical Centre , Southampton, UK
                [14 ]simpleRoyal Free Hospital , London, UK
                [15 ]simpleCentocor Oncology Research and Development, Inc. , Malvern, PA, USA
                [16 ]simpleCentocor B.V. , Leiden, The Netherlands
                [17 ]simpleRoyal Marsden Hospital , London, UK
                Author notes
                Article
                bjc2011183
                10.1038/bjc.2011.183
                3172894
                21750555
                976857c6-fe2c-44d3-b6a9-21c041fb4682
                Copyright © 2011 Cancer Research UK
                History
                : 22 September 2010
                : 20 April 2011
                : 02 May 2011
                Categories
                Clinical Study

                Oncology & Radiotherapy
                melanoma,αv integrins,cnto 95,dacarbazine,intetumumab
                Oncology & Radiotherapy
                melanoma, αv integrins, cnto 95, dacarbazine, intetumumab

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