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      A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma

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          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d4106767e170">Purpose</h5> <p id="P1">Genetic and preclinical studies have implicated fibroblast growth factor receptor (FGFR) signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor FGFR activity, may be active in ACC. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d4106767e175">Methods</h5> <p id="P2">In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate (ORR) and change in tumor growth rate (TGR). Progression-free survival (PFS), overall survival (OS), metabolic response, biomarker and QOL were secondary endpoints. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d4106767e180">Results</h5> <p id="P3">Of thirty-four evaluable patients, two (6%) had a partial response and 22 (65%) had stable disease &gt;4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on-treatment (p&lt;0.001). Toxicity was moderate; 63% of patients developed grade 3–4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on <sup>18</sup>FDG-PET scans was seen in 3/15 patients but did not correlate with RECIST response. <i>MYB</i> gene translocation was observed and significantly correlated with over-expression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d4106767e191">Conclusion</h5> <p id="P4">Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably to those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine if FGFR signaling is a valid therapeutic target in ACC. </p> </div>

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          Adenoid cystic carcinoma: A review of recent advances, molecular targets, and clinical trials

          Patrick M. Dillon, Samhita Chakraborty, Christopher A. Moskaluk … (2015)
          Abstract Background Adenoid cystic carcinoma (ACC) is a rare tumor of secretory glands. In this study, recent advances in molecular characterization and in therapeutics are reviewed. Methods A search of articles in PubMed and of abstracts from national meetings was performed regarding ACC. Results Recent genetic analyses found that recurrent chromosome 6:9 translocations in ACC generate an MYB:NFIB gene fusion resulting in overexpression of the MYB oncoprotein. Several other frequent mutations are recently published that may be relevant for drug development. Several trials of targeted drugs are reviewed. Some agents delay tumor progression, but tumor responses remain rare. Conclusion ACCs have a characteristic chromosomal translocation, but also frequently pick up additional mutations. Clinical research is limited by the rarity and slow growth of ACC. Several ongoing trials are testing agents that inhibit fibroblast growth factor receptor signaling or other signaling pathways. Novel treatments based on the recently sequenced tumor genome are under development. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. 38: 620–627, 2016
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            A phase 2 trial of bortezomib followed by the addition of doxorubicin at progression in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a trial of the Eastern Cooperative Oncology Group (E1303).

            Barbara Burtness, R C DeConti, Arlene Forastiere … (2011)
            Bortezomib, an inhibitor of the 26S proteasome and NF-κB, may have antitumor activity in adenoid cystic carcinoma (ACC). Preclinical studies have shown synergy between bortezomib and doxorubicin. Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and ejection fraction within normal limits. Patients with stable disease for ≥9 months were excluded. Patients received bortezomib 1.3 mg/m(2) by intravenous (IV) push on Days 1, 4, 8, and 11, every 21 days until progression. Doxorubicin 20 mg/m(2) IV on Days 1 and 8 was added at the time of progression. Twenty-five patients were enrolled, of whom 24 were eligible; the most common distant metastatic sites were the lung (n = 22) and the liver (n = 7). There was no objective response with single-agent bortezomib; best response was stable disease in 15 (71%) of 21 evaluable patients. The median progression-free survival and overall survival were 6.4 months and 21 months, respectively. Of 10 evaluable patients who received bortezomib plus doxorubicin, 1 had a partial response, and 6 had stable disease. The most frequent toxicity with bortezomib was grade 3 sensory neuropathy (16%). With bortezomib plus doxorubicin, serious toxicities seen more than once were grade 3-4 neutropenia (n = 3) and grade 3 anorexia (n = 2). Bortezomib was well tolerated and resulted in disease stabilization in a high percentage of patients but no objective responses. The combination of bortezomib and doxorubicin was also well tolerated and may warrant further investigation in ACC. Copyright © 2011 American Cancer Society.
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              KIT protein expression and analysis of c-kit gene mutation in adenoid cystic carcinoma.

              D V Holst, H Frierson, Christopher Moskaluk … (1999)
              The c-kit proto-oncogene encodes a transmembrane receptor tyrosine kinase (KIT), which is expressed in several normal human tissues, especially mast cells and interstitial cells of Cajal. Expression of KIT has been noted in several types of neoplasms and gene mutation has been shown as a mechanism of c-kit oncogene activation in some tumors. Recently, a single adnexal adenoid cystic carcinoma (ACC) was reported to demonstrate KIT expression, however, examination of KIT expression or c-kit mutation in ACC of salivary glands has not been performed. We examined archival tissue samples from 30 ACC of major and minor salivary glands for KIT protein expression by immunohistochemistry with a polyclonal antibody and c-kit gene mutation by polymerase chain reaction amplification and DNA sequencing. KIT protein expression was noted in 90% of ACCs. An association between the presence of at least 50% KIT positive neoplastic cells and Grade 3 ACC or a solid growth pattern was observed (P < .05). KIT expression in normal or nonneoplastic salivary gland tissue was absent. No c-kit juxtamembrane domain (exon 11) or phosphotransferase domain (exon 17) mutations were found in any of the tumors examined. In conclusion, KIT protein expression is correlated with tumor grade of salivary ACC. However, gene mutation of exon 11 or exon 17 is not a mechanism of c-kit activation in these neoplasms.
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                Author and article information

                Journal
                Title: Clinical Cancer Research
                Abbreviated Title: Clin Cancer Res
                Publisher: American Association for Cancer Research (AACR)
                ISSN (Print): 1078-0432
                ISSN (Electronic): 1557-3265
                Publication date Created: August 01 2017
                Publication date Created: August 01 2017
                Publication date (Print): August 01 2017
                Publication date (Electronic): April 04 2017
                Volume: 23
                Issue: 15
                Pages: 4138-4145
                Article
                DOI: 10.1158/1078-0432.CCR-16-2942
                PMC ID: 5540767
                PubMed ID: 28377480
                SO-VID: cceb7ade-2e82-40ad-9652-ce677b3d7398
                Copyright © © 2017
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