Iscador® P (Mistletoe) Immunotherapy for Recurrent Resectable Osteogenic Sarcoma

Summary

This will be a phase II, single arm study of osteosarcoma patients with fully resected pulmonary metastases. The MTD corresponds to the dosage recommendations of the manufacturer of Iscador® P which is licensed in Sweden, New Zealand, South Korea, Germany and Switzerland for the treatment of solid tumors and precancerous lesions. The study population includes patients with relapse of osteosarcoma in the lung following surgical resection of all gross disease (2nd or greater CR). Following completion of final thoracotomy, they will be treated with Iscador® P at concentrations up to the MTD with surveillance imaging via CT scan to monitor for relapsed disease.

Timeline

Start

2024-05-14

Primary completion

2027-05-11

Completion

2027-05-11

Publications

• Background Boye K, Longhi A, Guren T, Lorenz S, Naess S, Pierini M, Taksdal I, Lobmaier I, Cesari M, Paioli A, Londalen AM, Setola E, Hompland I, Meza-Zepeda LA, Sundby Hall K, Palmerini E. Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial. Cancer Immunol Immunother. 2021 Sep;70(9):2617-2624. doi: 10.1007/s00262-021-02876-w. Epub 2021 Feb 12.
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• Background Bussing A, Stumpf C, Troger W, Schietzel M. Course of mitogen-stimulated T lymphocytes in cancer patients treated with Viscum album extracts. Anticancer Res. 2007 Jul-Aug;27(4C):2903-10.
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• Background Gabius HJ, Gabius S, Joshi SS, Koch B, Schroeder M, Manzke WM, Westerhausen M. From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe? Planta Med. 1994 Feb;60(1):2-7. doi: 10.1055/s-2006-959396.
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• Background Horneber MA, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Database Syst Rev. 2008 Apr 16;2008(2):CD003297. doi: 10.1002/14651858.CD003297.pub2.
• Background Heinzerling L, von Baehr V, Liebenthal C, von Baehr R, Volk HD. Immunologic effector mechanisms of a standardized mistletoe extract on the function of human monocytes and lymphocytes in vitro, ex vivo, and in vivo. J Clin Immunol. 2006 Jul;26(4):347-59. doi: 10.1007/s10875-006-9023-5. Epub 2006 May 17.
• Background Jung ML, Baudino S, Ribereau-Gayon G, Beck JP. Characterization of cytotoxic proteins from mistletoe (Viscum album L.). Cancer Lett. 1990 May 30;51(2):103-8. doi: 10.1016/0304-3835(90)90044-x.
• Background Klein R, Classen K, Berg PA, Ludtke R, Werner M, Huber R. In vivo-induction of antibodies to mistletoe lectin-1 and viscotoxin by exposure to aqueous mistletoe extracts: a randomised double-blinded placebo controlled phase I study in healthy individuals. Eur J Med Res. 2002 Apr 30;7(4):155-63.
• Background Klein R et al. Effects of mistletoe extracts on immunocompetent cells in vitro and in vivo and their relevance for the therapy of tumor diseases and other clinical entities. In Scheer R et al.(Ed): Forschritte in der Mistletherapie. KVC Verlag, Essen, 207-221. 2005
• Background Lagmay JP, Krailo MD, Dang H, Kim A, Hawkins DS, Beaty O 3rd, Widemann BC, Zwerdling T, Bomgaars L, Langevin AM, Grier HE, Weigel B, Blaney SM, Gorlick R, Janeway KA. Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children's Cancer Group, Pediatric Oncology Group, and Children's Oncology Group: Learning From the Past to Move Forward. J Clin Oncol. 2016 Sep 1;34(25):3031-8. doi: 10.1200/JCO.2015.65.5381. Epub 2016 Jul 11.
• Background Loef M, Walach H. Quality of life in cancer patients treated with mistletoe: a systematic review and meta-analysis. BMC Complement Med Ther. 2020 Jul 20;20(1):227. doi: 10.1186/s12906-020-03013-3.
• Background Longhi A, Errani C, De Paolis M, Mercuri M, Bacci G. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev. 2006 Oct;32(6):423-36. doi: 10.1016/j.ctrv.2006.05.005. Epub 2006 Jul 24.
• Background Longhi A, Reif M, Mariani E, Ferrari S. A Randomized Study on Postrelapse Disease-Free Survival with Adjuvant Mistletoe versus Oral Etoposide in Osteosarcoma Patients. Evid Based Complement Alternat Med. 2014;2014:210198. doi: 10.1155/2014/210198. Epub 2014 Mar 31.
• Background Longhi A, Cesari M, Serra M, Mariani E. Long-Term Follow-up of a Randomized Study of Oral Etoposide versus Viscum album Fermentatum Pini as Maintenance Therapy in Osteosarcoma Patients in Complete Surgical Remission after Second Relapse. Sarcoma. 2020 Apr 26;2020:8260730. doi: 10.1155/2020/8260730. eCollection 2020.
• Background Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, Ferguson WS, Gebhardt MC, Goorin AM, Harris M, Kleinerman E, Link MP, Nadel H, Nieder M, Siegal GP, Weiner MA, Wells RJ, Womer RB, Grier HE; Children's Oncology Group. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group. J Clin Oncol. 2008 Feb 1;26(4):633-8. doi: 10.1200/JCO.2008.14.0095.
• Background Olsnes S, Stirpe F, Sandvig K, Pihl A. Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe). J Biol Chem. 1982 Nov 25;257(22):13263-70.
• Background Ostermann T, Appelbaum S, Poier D, Boehm K, Raak C, Bussing A. A Systematic Review and Meta-Analysis on the Survival of Cancer Patients Treated with a Fermented Viscum album L. Extract (Iscador): An Update of Findings. Complement Med Res. 2020;27(4):260-271. doi: 10.1159/000505202. Epub 2020 Jan 10.
• Background Podlech O, Harter PN, Mittelbronn M, Poschel S, Naumann U. Fermented mistletoe extract as a multimodal antitumoral agent in gliomas. Evid Based Complement Alternat Med. 2012;2012:501796. doi: 10.1155/2012/501796. Epub 2012 Oct 22.
• Background Schoffski P, Breidenbach I, Krauter J, Bolte O, Stadler M, Ganser A, Wilhelm-Ogunbiyi K, Lentzen H. Weekly 24 h infusion of aviscumine (rViscumin): a phase I study in patients with solid tumours. Eur J Cancer. 2005 Jul;41(10):1431-8. doi: 10.1016/j.ejca.2005.03.019.
• Background Stammer RM, Kleinsimon S, Rolff J, Jager S, Eggert A, Seifert G, Delebinski CI. Synergistic Antitumour Properties of viscumTT in Alveolar Rhabdomyosarcoma. J Immunol Res. 2017;2017:4874280. doi: 10.1155/2017/4874280. Epub 2017 Jul 16.
• Background Stein GM, Stettin A, Schultze J, Berg PA. Induction of anti-mistletoe lectin antibodies in relation to different mistletoe-extracts. Anticancer Drugs. 1997 Apr;8 Suppl 1:S57-9. doi: 10.1097/00001813-199704001-00013.
• Background Stirpe F, Sandvig K, Olsnes S, Pihl A. Action of viscumin, a toxic lectin from mistletoe, on cells in culture. J Biol Chem. 1982 Nov 25;257(22):13271-7.
• Background Timoshenko AV, Cherenkevich SN, Gabius HJ. Viscum album agglutinin-induced aggregation of blood cells and the lectin effects on neutrophil function. Biomed Pharmacother. 1995;49(3):153-8. doi: 10.1016/0753-3322(96)82609-6.
• Background Twardziok M, Kleinsimon S, Rolff J, Jager S, Eggert A, Seifert G, Delebinski CI. Multiple Active Compounds from Viscum album L. Synergistically Converge to Promote Apoptosis in Ewing Sarcoma. PLoS One. 2016 Sep 2;11(9):e0159749. doi: 10.1371/journal.pone.0159749. eCollection 2016.
• Background Wedekind MF, Wagner LM, Cripe TP. Immunotherapy for osteosarcoma: Where do we go from here? Pediatr Blood Cancer. 2018 Sep;65(9):e27227. doi: 10.1002/pbc.27227. Epub 2018 Jun 19.
• Background Weissenstein U, Kunz M, Urech K, Regueiro U, Baumgartner S. Interaction of a standardized mistletoe (Viscum album) preparation with antitumor effects of Trastuzumab in vitro. BMC Complement Altern Med. 2016 Aug 4;16:271. doi: 10.1186/s12906-016-1246-2.
• Background U.S. Department of Health and Human Services, Food and Drug Administration,Office of the Commissioner, Good Clinical Practice Program (2008). Guidance for Sponsors, Clinical Investigators, and IRBs Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials. From: https://www.fda.gov/media/75138/download. Accessed 7/22/20.
• Background Iscador AG, "ISCADOR in Cancer Therapy: Scientific Information and Study Results", www.iscador.com
• Background Iscador AG, "Iscador®P Investigational Medicinal Product Dossier (IMPD)" March, 2020 https://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq#_55. Accessed 12/30/19

Drugs

Indications