{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T15:20:54Z","timestamp":1780932054020,"version":"3.54.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002839","name":"Charit\u00e9 - Universit\u00e4tsmedizin Berlin","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002839","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cancer Res Clin Oncol"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I\/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Patients (\u2265\u200918\u00a0years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4\u00a0mg\/m<jats:sup>2<\/jats:sup> (day 1, 8, 15, ever 28\u00a0days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400\u00a0mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT 01600573.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400\u00a0mg\/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3\u20134 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5\u00a0months (95% CI 2.0\u20145.0). Due to early progression only 20% of the patients were able to start with maintenance treatment.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00432-023-04647-9","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T11:07:28Z","timestamp":1680260848000},"page":"7637-7649","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pazopanib with Topotecan weekly for patients with platinum-resistant or intermediate-sensitive recurrent ovarian cancer: results of a multicentre, open label phase I\/II study (TOPAZ)"],"prefix":"10.1007","volume":"149","author":[{"given":"Radoslav","family":"Chekerov","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjadina","family":"Arndt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Pietzner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Canzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Wimberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Georg","family":"Strau\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Mahner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linn","family":"Woelber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"de Gregorio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gertraud","family":"Stocker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekkehard","family":"von Abel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Neunhoeffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje Kristina","family":"Belau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Mustea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isil","family":"Yalinkaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Ioana","family":"Braicu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Richter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalid","family":"Sehouli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the NOGGO ovarian cancer study group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,31]]},"reference":[{"issue":"12","key":"4647_CR2","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1080\/17425255.2016.1225038","volume":"12","author":"P Boudou-Rouquette","year":"2016","unstructured":"Boudou-Rouquette P et al (2016) Clinical pharmacology, drug-drug interactions and safety of pazopanib: a review. Expert Opin Drug Metab Toxicol 12(12):1433\u20131444","journal-title":"Expert Opin Drug Metab Toxicol"},{"issue":"2","key":"4647_CR3","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/j.ygyno.2017.01.031","volume":"145","author":"DM Chase","year":"2017","unstructured":"Chase DM, Chaplin DJ, Monk BJ (2017) The development and use of vascular targeted therapy in ovarian cancer. Gynecol Oncol 145(2):393\u2013406","journal-title":"Gynecol Oncol"},{"issue":"12","key":"4647_CR4","first-page":"6869","volume":"35","author":"R Chekerov","year":"2015","unstructured":"Chekerov R et al (2015) Treosulfan in the treatment of advanced ovarian cancer - results of a german multicenter non-interventional study. Anticancer Res 35(12):6869\u20136875","journal-title":"Anticancer Res"},{"issue":"9","key":"4647_CR5","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1016\/S1470-2045(18)30372-3","volume":"19","author":"R Chekerov","year":"2018","unstructured":"Chekerov R et al (2018) Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 19(9):1247\u20131258","journal-title":"Lancet Oncol"},{"key":"4647_CR1","unstructured":"du Bois, A., et al. 2013 AGO-OVAR 12: A randomized placebo-controlled GCIG\/ENGOT-Intergroup Phase III Trial of Standard Frontline Chemotherapy +\/- Nintedanib for Advanced Ovarian Cancer . International Journal of Gynecological Cancer. 238, Supplement 1)."},{"issue":"30","key":"4647_CR6","doi-asserted-by":"publisher","first-page":"3374","DOI":"10.1200\/JCO.2014.55.7348","volume":"32","author":"A du Bois","year":"2014","unstructured":"du Bois A et al (2014) Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 32(30):3374\u20133382","journal-title":"J Clin Oncol"},{"issue":"6","key":"4647_CR7","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1002\/cncr.24149","volume":"115","author":"A du Bois","year":"2009","unstructured":"du Bois A et al (2009) Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d\u2019Investigateurs Nationaux Pour les Etudes des Cancers de l\u2019Ovaire (GINECO). Cancer 115(6):1234\u20131244","journal-title":"Cancer"},{"issue":"5","key":"4647_CR8","first-page":"672","volume":"30","author":"N Colombo","year":"2019","unstructured":"Colombo N et al (2019) ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Int J Gynecol Cancer 30(5):672\u2013705","journal-title":"Int J Gynecol Cancer"},{"issue":"7","key":"4647_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3310\/hta19070","volume":"19","author":"SJ Edwards","year":"2015","unstructured":"Edwards SJ et al (2015) Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced recurrent or refractory ovarian cancer: a systematic review and economic evaluation. Health Technol Assess 19(7):1\u2013480","journal-title":"Health Technol Assess"},{"issue":"1","key":"4647_CR10","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.ygyno.2010.05.033","volume":"119","author":"M Friedlander","year":"2010","unstructured":"Friedlander M et al (2010) A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol 119(1):32\u201337","journal-title":"Gynecol Oncol"},{"issue":"1","key":"4647_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ygyno.2004.07.011","volume":"95","author":"AN Gordon","year":"2004","unstructured":"Gordon AN et al (2004) Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol 95(1):1\u20138","journal-title":"Gynecol Oncol"},{"issue":"6","key":"4647_CR12","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1634\/theoncologist.2009-0274","volume":"15","author":"P Hamberg","year":"2010","unstructured":"Hamberg P, Verweij J, Sleijfer S (2010) (Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. Oncologist 15(6):539\u2013547","journal-title":"Oncologist"},{"issue":"10","key":"4647_CR13","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1093\/annonc\/mds203","volume":"23","author":"LC Hanker","year":"2012","unstructured":"Hanker LC et al (2012) The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane\/platinum-based therapy. Ann Oncol 23(10):2605\u20132612","journal-title":"Ann Oncol"},{"issue":"12","key":"4647_CR14","doi-asserted-by":"publisher","first-page":"4220","DOI":"10.1158\/1078-0432.CCR-08-2740","volume":"15","author":"HI Hurwitz","year":"2009","unstructured":"Hurwitz HI et al (2009) Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 15(12):4220\u20134227","journal-title":"Clin Cancer Res"},{"issue":"3","key":"4647_CR15","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.ygyno.2022.06.022","volume":"166","author":"F Joly","year":"2022","unstructured":"Joly F et al (2022) Paclitaxel with or without pazopanib for ovarian cancer relapsing during bevacizumab maintenance therapy: the GINECO randomized phase II TAPAZ study. Gynecol Oncol 166(3):389\u2013396","journal-title":"Gynecol Oncol"},{"issue":"10023","key":"4647_CR16","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1016\/S0140-6736(15)01167-8","volume":"387","author":"JA Ledermann","year":"2016","unstructured":"Ledermann JA et al (2016) Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 387(10023):1066\u20131074","journal-title":"Lancet"},{"key":"4647_CR17","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/171425","volume":"2010","author":"M Markman","year":"2010","unstructured":"Markman M et al (2010) Epithelial ovarian cancer: focus on targeted therapy. J Oncol 2010:171425","journal-title":"J Oncol"},{"issue":"4","key":"4647_CR18","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1158\/1535-7163.MCT-09-0967","volume":"9","author":"WM Merritt","year":"2010","unstructured":"Merritt WM et al (2010) Bridging the gap between cytotoxic and biologic therapy with metronomic topotecan and pazopanib in ovarian cancer. Mol Cancer Ther 9(4):985\u2013995","journal-title":"Mol Cancer Ther"},{"issue":"8","key":"4647_CR19","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/S1470-2045(14)70244-X","volume":"15","author":"BJ Monk","year":"2014","unstructured":"Monk BJ et al (2014) Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15(8):799\u2013808","journal-title":"Lancet Oncol"},{"issue":"5","key":"4647_CR20","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/S1470-2045(15)70115-4","volume":"16","author":"S Pignata","year":"2015","unstructured":"Pignata S et al (2015) Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial. Lancet Oncol 16(5):561\u2013568","journal-title":"Lancet Oncol"},{"issue":"13","key":"4647_CR21","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1200\/JCO.2013.51.4489","volume":"32","author":"E Pujade-Lauraine","year":"2014","unstructured":"Pujade-Lauraine E et al (2014) Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol 32(13):1302\u20131308","journal-title":"J Clin Oncol"},{"issue":"3","key":"4647_CR22","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.critrevonc.2010.02.012","volume":"77","author":"FA Schutz","year":"2011","unstructured":"Schutz FA, Choueiri TK, Sternberg CN (2011) Pazopanib: clinical development of a potent anti-angiogenic drug. Crit Rev Oncol Hematol 77(3):163\u2013171","journal-title":"Crit Rev Oncol Hematol"},{"issue":"19","key":"4647_CR23","doi-asserted-by":"publisher","first-page":"3176","DOI":"10.1200\/JCO.2007.15.1258","volume":"26","author":"J Sehouli","year":"2008","unstructured":"Sehouli J et al (2008) Nonplatinum topotecan combinations versus topotecan alone for recurrent ovarian cancer: results of a phase III study of the north-eastern german society of gynecological oncology ovarian cancer study group. J Clin Oncol 26(19):3176\u20133182","journal-title":"J Clin Oncol"},{"issue":"2","key":"4647_CR24","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1200\/JCO.2009.27.8911","volume":"29","author":"J Sehouli","year":"2011","unstructured":"Sehouli J et al (2011) Topotecan weekly versus conventional 5-day schedule in patients with platinum-resistant ovarian cancer: a randomized multicenter phase ii trial of the north-eastern German society of gynecological oncology ovarian cancer study group. J Clin Oncol 29(2):242\u2013248","journal-title":"J Clin Oncol"},{"issue":"3","key":"4647_CR25","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209\u2013249","journal-title":"CA Cancer J Clin"},{"issue":"9829","key":"4647_CR26","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1016\/S0140-6736(12)60651-5","volume":"379","author":"WT van der Graaf","year":"2012","unstructured":"van der Graaf WT et al (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379(9829):1879\u20131886","journal-title":"Lancet"},{"issue":"2","key":"4647_CR27","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.ygyno.2019.08.024","volume":"155","author":"I Vergote","year":"2019","unstructured":"Vergote I et al (2019) Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer. Gynecol Oncol 155(2):186\u2013191","journal-title":"Gynecol Oncol"},{"issue":"4","key":"4647_CR28","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1093\/annonc\/mdw663","volume":"28","author":"MK Wilson","year":"2017","unstructured":"Wilson MK et al (2017) Fifth ovarian cancer consensus conference of the gynecologic cancer intergroup: recurrent disease. Ann Oncol 28(4):727\u2013732","journal-title":"Ann Oncol"}],"container-title":["Journal of Cancer Research and Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-023-04647-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00432-023-04647-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-023-04647-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T17:42:08Z","timestamp":1690479728000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00432-023-04647-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,31]]},"references-count":28,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,8]]}},"alternative-id":["4647"],"URL":"https:\/\/doi.org\/10.1007\/s00432-023-04647-9","relation":{},"ISSN":["0171-5216","1432-1335"],"issn-type":[{"value":"0171-5216","type":"print"},{"value":"1432-1335","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,31]]},"assertion":[{"value":"23 December 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 February 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"We declare the following potential <i>conflicts of interest<\/i>. Employment: none of the authors. Stock or other Ownership: none of the authors. Honoraria: Roche, Eisai, Novartis, MSD, Seagen, GSK, Astra Zeneca, Pfizer, Lumenis, TEVA, pomedicis, Omniamed, PharmaMar, Vifor Pharma, Hexal AG, Lilly (RC, KP, UC, PW, SM, LW, NdG, GS, EvA, AM, EIB, JS). Consulting or advisory role: AstraZeneca, Roche, GSK, Clovis, Eisai, MSD, Seagen, Tesaro, Merck, Novocure, Olympus, Sensor Kinesis, Nykode, Myriad, Daichy (KP, PW, UC, SM, LW, NdG, AM, TN, EIB, JS). Research funding: Roche, GSK, AstraZeneca, Amgen, Novartis, Lilly, Bayer, Medac, Clovis, PharmaMar, Tesaro, Novocure (RC, KP, PW, SM, LW, NdG, GS, AKB, AM, TN, EIB, JS). Patents, Rolayties or Intellectual property: none of the authors. Expert Testimony: none of the authors. Travel, Accomodation, Expenses: Medac, Roche, GSK, AstraZeneca, Lilly (RC, KP, PW, SM, LW, NdG, AM, EIB, JS). Other relationship: none of the authors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"The study was conducted according to the Declaration of Helsinki (1996), the International Conference on Harmonization Good Clinical Practice recommendations, and provisions of the German Medicines Act. The Ethical review committee\u2014Ethikkommission des Landes Berlin, reference number 11\/0570 ZS EK, approved the study protocol; final study approval by the German federal authority\u2014Bundesinstitut f\u00fcr Arzneimittel und Medizinprodukte (BfArM), reference number 61\u20133910-4037860, was granted on 04.04.2012. All amendments and other relevant study documentation were voted by the ethics committee and approved by the German federal authority BfArM: amendment 1 approved on 31.10.2012, amendment 2 approved on 27.05.2013, amendment 3 approved on 26.03.2014, amendment 4 approved on 09.03.2015 and amendment 5 approved on 13.04.2016.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All patients provided written informed consent before study start.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}