First in Man Study Investigating the Biodistribution, the Safety and Optimal Recommended Dose of a New Radiolabelled Monoclonal Antibody Targeting Frizzled Homolog 10

Summary

Advanced synovial sarcoma represents an unmet medical need. The gene encoding frizzled homologue 10 (FZD10), a 7-transmenbrane receptor, member of the Wnt signalling receptor family, is overexpressed in SS and is undetectable in normal human tissues except placenta. OncoTherapy Science Inc. has developed a chimeric humanized monoclonal antibody (mAb) against FZD10, named OTSA101. Non-radiolabeled OTSA101 antibody has only weak antagonistic activity on SS cell growth. However, Yttrium 90-radiolabeled OTSA101 (OTSA101-DTPA-90Y) showed significant antitumor activity following a single intravenous injection in mouse xenograft model. This first in man clinical trial (Phase I) in relapsing SS patients resistant to Doxorubicin and ifosfamide will be divided in 2 parts. In Part 1 (imaging part using OTSA101 radiolabelled with Indium 111 \[111In\]), the biodistribution and tumor uptake of OTSA101-DTPA-111In will be followed using 111In as radiotracer. In Part 2 (therapeutic part with OTSA101 radiolabelled with Yttrium 90 \[90Y\]), the safety and PK profiles of OTSA101-DTPA-90Y will be determined and preliminary efficacy data will be collected. This first in Man study should allow defining the optimal recommended dose of OTSA101-DTPA-90Y. Patients will be followed during 1 year.

Timeline

Start

2011-12

Primary completion

2015-02-03

Completion

2015-06-30

Outcome

Outcome not reported

Stopped (Enrollment): “Too slow accrual.”

Publications

• Background Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300. doi: 10.3322/caac.20073. Epub 2010 Jul 7.
• Background Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med. 2005 Aug 18;353(7):701-11. doi: 10.1056/NEJMra041866. No abstract available.
• Background Ducimetiere F, Lurkin A, Ranchere-Vince D, Decouvelaere AV, Isaac S, Claret-Tournier C, Suignard Y, Salameire D, Cellier D, Alberti L, Bringuier PP, Blay JY, Ray-Coquard I. [Incidence rate, epidemiology of sarcoma and molecular biology. Preliminary results from EMS study in the Rhone-Alpes region]. Bull Cancer. 2010 Jun;97(6):629-41. doi: 10.1684/bdc.2010.1117. French.
• Background Ladanyi M. Fusions of the SYT and SSX genes in synovial sarcoma. Oncogene. 2001 Sep 10;20(40):5755-62. doi: 10.1038/sj.onc.1204601.
• Background Okcu MF, Munsell M, Treuner J, Mattke A, Pappo A, Cain A, Ferrari A, Casanova M, Ozkan A, Raney B. Synovial sarcoma of childhood and adolescence: a multicenter, multivariate analysis of outcome. J Clin Oncol. 2003 Apr 15;21(8):1602-11. doi: 10.1200/JCO.2003.07.008.
• Background Trassard M, Le Doussal V, Hacene K, Terrier P, Ranchere D, Guillou L, Fiche M, Collin F, Vilain MO, Bertrand G, Jacquemier J, Sastre-Garau X, Bui NB, Bonichon F, Coindre JM. Prognostic factors in localized primary synovial sarcoma: a multicenter study of 128 adult patients. J Clin Oncol. 2001 Jan 15;19(2):525-34. doi: 10.1200/JCO.2001.19.2.525.
• Background Laor T. MR imaging of soft tissue tumors and tumor-like lesions. Pediatr Radiol. 2004 Jan;34(1):24-37. doi: 10.1007/s00247-003-1086-3. Epub 2003 Dec 12.
• Background Lewis JJ, Antonescu CR, Leung DH, Blumberg D, Healey JH, Woodruff JM, Brennan MF. Synovial sarcoma: a multivariate analysis of prognostic factors in 112 patients with primary localized tumors of the extremity. J Clin Oncol. 2000 May;18(10):2087-94. doi: 10.1200/JCO.2000.18.10.2087.
• Background Singer S, Baldini EH, Demetri GD, Fletcher JA, Corson JM. Synovial sarcoma: prognostic significance of tumor size, margin of resection, and mitotic activity for survival. J Clin Oncol. 1996 Apr;14(4):1201-8. doi: 10.1200/JCO.1996.14.4.1201.
• Background Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet. 1997 Dec 6;350(9092):1647-54.
• Background Sleijfer S, Ouali M, van Glabbeke M, Krarup-Hansen A, Rodenhuis S, Le Cesne A, Hogendoorn PC, Verweij J, Blay JY. Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: an exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). Eur J Cancer. 2010 Jan;46(1):72-83. doi: 10.1016/j.ejca.2009.09.022.
• Background Le Cesne A, Blay JY, Judson I, Van Oosterom A, Verweij J, Radford J, Lorigan P, Rodenhuis S, Ray-Coquard I, Bonvalot S, Collin F, Jimeno J, Di Paola E, Van Glabbeke M, Nielsen OS. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol. 2005 Jan 20;23(3):576-84. doi: 10.1200/JCO.2005.01.180.
• Background Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schoffski P, Collin F, Pandite L, Marreaud S, De Brauwer A, van Glabbeke M, Verweij J, Blay JY. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009 Jul 1;27(19):3126-32. doi: 10.1200/JCO.2008.21.3223. Epub 2009 May 18.
• Background Fletcher CD. The evolving classification of soft tissue tumours: an update based on the new WHO classification. Histopathology. 2006 Jan;48(1):3-12. doi: 10.1111/j.1365-2559.2005.02284.x.
• Background Lee YF, John M, Edwards S, Clark J, Flohr P, Maillard K, Edema M, Baker L, Mangham DC, Grimer R, Wooster R, Thomas JM, Fisher C, Judson I, Cooper CS. Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Br J Cancer. 2003 Feb 24;88(4):510-5. doi: 10.1038/sj.bjc.6600766.
• Background Nielsen TO, West RB, Linn SC, Alter O, Knowling MA, O'Connell JX, Zhu S, Fero M, Sherlock G, Pollack JR, Brown PO, Botstein D, van de Rijn M. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet. 2002 Apr 13;359(9314):1301-7. doi: 10.1016/S0140-6736(02)08270-3.
• Background Allander SV, Illei PB, Chen Y, Antonescu CR, Bittner M, Ladanyi M, Meltzer PS. Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation. Am J Pathol. 2002 Nov;161(5):1587-95. doi: 10.1016/S0002-9440(10)64437-9.
• Background Nagayama S, Katagiri T, Tsunoda T, Hosaka T, Nakashima Y, Araki N, Kusuzaki K, Nakayama T, Tsuboyama T, Nakamura T, Imamura M, Nakamura Y, Toguchida J. Genome-wide analysis of gene expression in synovial sarcomas using a cDNA microarray. Cancer Res. 2002 Oct 15;62(20):5859-66.
• Background Ray-Coquard I, Le Cesne A, Whelan JS, Schoffski P, Bui BN, Verweij J, Marreaud S, van Glabbeke M, Hogendoorn P, Blay JY. A phase II study of gefitinib for patients with advanced HER-1 expressing synovial sarcoma refractory to doxorubicin-containing regimens. Oncologist. 2008 Apr;13(4):467-73. doi: 10.1634/theoncologist.2008-0065.
• Background Koike J, Takagi A, Miwa T, Hirai M, Terada M, Katoh M. Molecular cloning of Frizzled-10, a novel member of the Frizzled gene family. Biochem Biophys Res Commun. 1999 Aug 19;262(1):39-43. doi: 10.1006/bbrc.1999.1161.
• Background Hanaoka H, Katagiri T, Fukukawa C, Yoshioka H, Yamamoto S, Iida Y, Higuchi T, Oriuchi N, Paudyal B, Paudyal P, Nakamura Y, Endo K. Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10: therapeutic efficacy largely depends on radiosensitivity. Ann Nucl Med. 2009 Jul;23(5):479-85. doi: 10.1007/s12149-009-0265-1. Epub 2009 May 2.
• Background Nagayama S, Fukukawa C, Katagiri T, Okamoto T, Aoyama T, Oyaizu N, Imamura M, Toguchida J, Nakamura Y. Therapeutic potential of antibodies against FZD 10, a cell-surface protein, for synovial sarcomas. Oncogene. 2005 Sep 15;24(41):6201-12. doi: 10.1038/sj.onc.1208780.
• Background Fukukawa C, Hanaoka H, Nagayama S, Tsunoda T, Toguchida J, Endo K, Nakamura Y, Katagiri T. Radioimmunotherapy of human synovial sarcoma using a monoclonal antibody against FZD10. Cancer Sci. 2008 Feb;99(2):432-40. doi: 10.1111/j.1349-7006.2007.00701.x.
• Background Theuer CP, Leigh BR, Multani PS, Allen RS, Liang BC. Radioimmunotherapy of non-Hodgkin's lymphoma: clinical development of the Zevalin regimen. Biotechnol Annu Rev. 2004;10:265-95. doi: 10.1016/S1387-2656(04)10011-2.
• Background Cheson BD. Radioimmunotherapy of non-Hodgkin lymphomas. Blood. 2003 Jan 15;101(2):391-8. doi: 10.1182/blood-2002-06-1793. Epub 2002 Sep 19.
• Background Jain S, Xu R, Prieto VG, Lee P. Molecular classification of soft tissue sarcomas and its clinical applications. Int J Clin Exp Pathol. 2010 Apr 23;3(4):416-28.
• Background Goldenberg DM. Advancing role of radiolabeled antibodies in the therapy of cancer. Cancer Immunol Immunother. 2003 May;52(5):281-96. doi: 10.1007/s00262-002-0348-5. Epub 2003 Mar 11.
• Background Verhaar-Langereis MJ, Zonnenberg BA, de Klerk JM, Blijham GH. Radioimmunodiagnosis and therapy. Cancer Treat Rev. 2000 Feb;26(1):3-10. doi: 10.1053/ctrv.1999.0146.
• Background Pinkas L, Robins PD, Forstrom LA, Mahoney DW, Mullan BP. Clinical experience with radiolabelled monoclonal antibodies in the detection of colorectal and ovarian carcinoma recurrence and review of the literature. Nucl Med Commun. 1999 Aug;20(8):689-96. doi: 10.1097/00006231-199908000-00002.
• Background Sodee DB, Malguria N, Faulhaber P, Resnick MI, Albert J, Bakale G. Multicenter ProstaScint imaging findings in 2154 patients with prostate cancer. The ProstaScint Imaging Centers. Urology. 2000 Dec 20;56(6):988-93. doi: 10.1016/s0090-4295(00)00824-4.
• Background Tsai SW, Sun Y, Williams LE, Raubitschek AA, Wu AM, Shively JE. Biodistribution and radioimmunotherapy of human breast cancer xenografts with radiometal-labeled DOTA conjugated anti-HER2/neu antibody 4D5. Bioconjug Chem. 2000 May-Jun;11(3):327-34. doi: 10.1021/bc9901292.
• Background Milowsky MI, Nanus DM, Kostakoglu L, Vallabhajosula S, Goldsmith SJ, Bander NH. Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer. J Clin Oncol. 2004 Jul 1;22(13):2522-31. doi: 10.1200/JCO.2004.09.154. Epub 2004 Jun 1.
• Background Tempero M, Leichner P, Baranowska-Kortylewicz J, Harrison K, Augustine S, Schlom J, Anderson J, Wisecarver J, Colcher D. High-dose therapy with 90Yttrium-labeled monoclonal antibody CC49: a phase I trial. Clin Cancer Res. 2000 Aug;6(8):3095-102.
• Background Richman CM, DeNardo SJ, O'Donnell RT, Goldstein DS, Shen S, Kukis DL, Kroger LA, Yuan A, Boniface GR, Griffith IJ, DeNardo GL. Dosimetry-based therapy in metastatic breast cancer patients using 90Y monoclonal antibody 170H.82 with autologous stem cell support and cyclosporin A. Clin Cancer Res. 1999 Oct;5(10 Suppl):3243s-3248s.
• Background Pai-Scherf LH, Carrasquillo JA, Paik C, Gansow O, Whatley M, Pearson D, Webber K, Hamilton M, Allegra C, Brechbiel M, Willingham MC, Pastan I. Imaging and phase I study of 111In- and 90Y-labeled anti-LewisY monoclonal antibody B3. Clin Cancer Res. 2000 May;6(5):1720-30.
• Background Pless M, Waldherr C, Maecke H, Buitrago C, Herrmann R, Mueller-Brand J. Targeted radiotherapy for small cell lung cancer using 90Yttrium-DOTATOC, an Yttrium-labelled somatostatin analogue: a pilot trial. Lung Cancer. 2004 Sep;45(3):365-71. doi: 10.1016/j.lungcan.2004.02.020.
• Background Forrer F, Riedweg I, Maecke HR, Mueller-Brand J. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q J Nucl Med Mol Imaging. 2008 Dec;52(4):334-40. Epub 2008 May 16.
• Background Tubiana M, Koscielny S. On clonogenic tumour cells and metastasis-forming cells. Nat Rev Cancer. 2008 Dec;8(12):990; author reply 990. doi: 10.1038/nrc2419-c1. No abstract available.
• Background Betts AM, Clark TH, Yang J, Treadway JL, Li M, Giovanelli MA, Abdiche Y, Stone DM, Paralkar VM. The application of target information and preclinical pharmacokinetic/pharmacodynamic modeling in predicting clinical doses of a Dickkopf-1 antibody for osteoporosis. J Pharmacol Exp Ther. 2010 Apr;333(1):2-13. doi: 10.1124/jpet.109.164129. Epub 2010 Jan 20.
• Background Leveque D, Wisniewski S, Jehl F. Pharmacokinetics of therapeutic monoclonal antibodies used in oncology. Anticancer Res. 2005 May-Jun;25(3c):2327-43.
• Background Kelly MP, Lee FT, Smyth FE, Brechbiel MW, Scott AM. Enhanced efficacy of 90Y-radiolabeled anti-Lewis Y humanized monoclonal antibody hu3S193 and paclitaxel combined-modality radioimmunotherapy in a breast cancer model. J Nucl Med. 2006 Apr;47(4):716-25.
• Background Knox SJ, Goris ML, Trisler K, Negrin R, Davis T, Liles TM, Grillo-Lopez A, Chinn P, Varns C, Ning SC, Fowler S, Deb N, Becker M, Marquez C, Levy R. Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma. Clin Cancer Res. 1996 Mar;2(3):457-70.
• Background Nademanee A, Forman S, Molina A, Fung H, Smith D, Dagis A, Kwok C, Yamauchi D, Anderson AL, Falk P, Krishnan A, Kirschbaum M, Kogut N, Nakamura R, O'donnell M, Parker P, Popplewell L, Pullarkat V, Rodriguez R, Sahebi F, Smith E, Snyder D, Stein A, Spielberger R, Zain J, White C, Raubitschek A. A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood. 2005 Oct 15;106(8):2896-902. doi: 10.1182/blood-2005-03-1310. Epub 2005 Jul 7.
• Background Lhommel R, van Elmbt L, Goffette P, Van den Eynde M, Jamar F, Pauwels S, Walrand S. Feasibility of 90Y TOF PET-based dosimetry in liver metastasis therapy using SIR-Spheres. Eur J Nucl Med Mol Imaging. 2010 Aug;37(9):1654-62. doi: 10.1007/s00259-010-1470-9. Epub 2010 Apr 27.
• Background Baechler S, Hobbs RF, Jacene HA, Bochud FO, Wahl RL, Sgouros G. Predicting hematologic toxicity in patients undergoing radioimmunotherapy with 90Y-ibritumomab tiuxetan or 131I-tositumomab. J Nucl Med. 2010 Dec;51(12):1878-84. doi: 10.2967/jnumed.110.079947.
• Background Minarik D, Sjogreen-Gleisner K, Linden O, Wingardh K, Tennvall J, Strand SE, Ljungberg M. 90Y Bremsstrahlung imaging for absorbed-dose assessment in high-dose radioimmunotherapy. J Nucl Med. 2010 Dec;51(12):1974-8. doi: 10.2967/jnumed.110.079897. Epub 2010 Nov 15.
• Background Rault E, Staelens S, Van Holen R, De Beenhouwer J, Vandenberghe S. Fast simulation of yttrium-90 bremsstrahlung photons with GATE. Med Phys. 2010 Jun;37(6):2943-50. doi: 10.1118/1.3431998.
• Background Walrand S, Flux GD, Konijnenberg MW, Valkema R, Krenning EP, Lhommel R, Pauwels S, Jamar F. Dosimetry of yttrium-labelled radiopharmaceuticals for internal therapy: 86Y or 90Y imaging? Eur J Nucl Med Mol Imaging. 2011 May;38 Suppl 1:S57-68. doi: 10.1007/s00259-011-1771-7. Epub 2011 Mar 11.
• Background Shen D, Fritz T, Wu GL, Kulik B, Palestrant D, Unger E. Block co-polymeric magnetic resonance contrast agents. Invest Radiol. 1994 Jun;29 Suppl 2:S217-9. doi: 10.1097/00004424-199406001-00072. No abstract available.
• Giraudet AL, Cassier PA, Iwao-Fukukawa C, Garin G, Badel JN, Kryza D, Chabaud S, Gilles-Afchain L, Clapisson G, Desuzinges C, Sarrut D, Halty A, Italiano A, Mori M, Tsunoda T, Katagiri T, Nakamura Y, Alberti L, Cropet C, Baconnier S, Berge-Montamat S, Perol D, Blay JY. A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients. BMC Cancer. 2018 Jun 8;18(1):646. doi: 10.1186/s12885-018-4544-x.

Drugs

Indications