Use of Off-Label Targeted Therapies in Refractory Sarcomas: Analysis of Pediatric Data from the French Registry Observatoire de l'Utilisation des Thérapies Ciblées dans les Sarcomes

Abstract

Targeted therapies (TT) are used in pediatric patients based on the data from adult literature. In 2008, the French Sarcoma Study Group and the Bone Tumor Group (Groupe Sarcome Français-Groupe d'étude des Tumeurs Osseuses) opened Observatoire de l'Utilisation des Thérapies Ciblées dans les Sarcomes (OUTC'S), a national registry of targeted off-label sarcomas therapies. All patients registered in the OUTC'S database and treated in pediatric oncology units were included in this analysis. We describe TTs using off-label and off clinical trial practices for children with sarcoma. We analyzed TT tolerability and efficacy for 34 patients with osteosarcoma (n = 20), Ewing sarcoma (n = 9), clear cell sarcoma (n = 1), synovialsarcoma (n = 1), epithelioid sarcoma (n = 1), myofibroblastic tumor (n = 1), and desmoid tumor (n = 1) who were registered from six pediatric centers. In total, 38 different TT courses were administered. The median age was 15 years (5–23) and 18.5 years (7–27) at diagnosis and at the time of starting TT, respectively. The decision to initiate TT was taken in a multidisciplinary board in 92% of the cases. TT included sirolimus (alone or in association with other treatments), sunitinib, sorafenib, cetuximab, imatinib, and crizotinib. The median duration of treatment was 109 days (21–515). Of the 34 patients, 6 had a partial response with a median response duration of 3.72 months (2.08–30.8) and 10 had a stabilization of the disease with a median duration of 3.63 months (0.75- 16.89). In our cohort, overall survival and progression-free survival were 8.68 months (95% confidence interval [CI]: 5.85–11.50) and 3.29 months (95% CI: 2.69–3.88), respectively. Grades 3 and 4 toxicities were reported for seven patients (26%) and were most commonly hematological. Patients under 15 years of age did not show severe toxicity. Hence, TT is an acceptable therapeutic option for refractory pediatric sarcomas. It is very important to continue collecting data and develop phase I/II protocols.

Keywords

targeted therapies - sarcomas - pediatric

• References

• 1 ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25 (Suppl. 03) iii113-iii123
• 2 Ladenstein R, Pötschger U, Le Deley MC , et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 2010; 28 (20) 3284-3291
• 3 Pakos EE, Nearchou AD, Grimer RJ , et al. Prognostic factors and outcomes for osteosarcoma: an international collaboration. Eur J Cancer 2009; 45 (13) 2367-2375
• 4 Oberlin O, Deley MCL, Bui BNG , et al; French Society of Paediatric Oncology. Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 2001; 85 (11) 1646-1654
• 5 Le Deley MC, Guinebretière JM, Gentet JC , et al; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer 2007; 43 (4) 752-761
• 6 Stahl M, Ranft A, Paulussen M , et al. Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Pediatr Blood Cancer 2011; 57 (4) 549-553
• 7 Marec-Bérard P, Chotel F, Claude L. PNET/. Ewing tumours: current treatments and future perspectives [in French]. Bull Cancer 2010; 97 (6) 707-713
• 8 Piperno-Neumann S. Diagnosis and treatment of primary osteosarcoma in 2009 [in French]. Bull Cancer 2010; 97 (6) 715-721
• 9 Gaspar N, Di Giannatale A, Geoerger B , et al. Bone sarcomas: from biology to targeted therapies. Sarcoma 2012; 2012: 301975 DOI: 10.1155/2012/301975.
• 10 Sampson VB, Gorlick R, Kamara D, Anders Kolb E. A review of targeted therapies evaluated by the pediatric preclinical testing program for osteosarcoma. Front Oncol 2013; 3: 132 DOI: 10.3389/fonc.2013.00132.
• 11 Somaiah N, von Mehren M. New drugs and combinations for the treatment of soft-tissue sarcoma: a review. Cancer Manag Res 2012; 4: 397-411
• 12 Kelleher FC, Thomas DM. Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours. Clin Sarcoma Res 2012; 2 (1) 6 DOI: 10.1186/2045-3329-2-6.
• 13 Blay JY. Updating progress in sarcoma therapy with mTOR inhibitors. Ann Oncol 2011; 22 (2) 280-287
• 14 Asmane I, Watkin E, Alberti L , et al. Insulin-like growth factor type 1 receptor (IGF-1R) exclusive nuclear staining: a predictive biomarker for IGF-1R monoclonal antibody (Ab) therapy in sarcomas. Eur J Cancer 2012; 48 (16) 3027-3035
• 15 Zheng H, Shen H, Oprea I , et al. β-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma. Proc Natl Acad Sci U S A 2012; 109 (50) 20620-20625
• 16 Kang MH, Reynolds CP, Maris JM , et al. Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program. Pediatr Blood Cancer 2014; 61 (8) 1486-1489
• 17 Subbiah V, Brown RE, Jiang Y , et al. Morphoproteomic profiling of the mammalian target of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor (EWS/WT1), Ewing's sarcoma (EWS/FLI1) and Wilms' tumor(WT1). PLoS One 2013; 8 (7) e68985 DOI: 10.1371/journal.pone.0068985.
• 18 Maris JM, Courtright J, Houghton PJ , et al. Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program. Pediatr Blood Cancer 2008; 51 (1) 42-48
• 19 Mateo-Lozano S, Tirado OM, Notario V. Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing's sarcoma cell proliferation. Oncogene 2003; 22 (58) 9282-9287
• 20 Garnett MJ, Edelman EJ, Heidorn SJ , et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 2012; 483 (7391): 570-575
• 21 Ray-Coquard I, Italiano A, Bompas E , et al; French Sarcoma Group (GSF/GETO). Sorafenib for patients with advanced angiosarcoma: a phase II Trial from the French Sarcoma Group (GSF/GETO). Oncologist 2012; 17 (2) 260-266
• 22 Grignani G, Palmerini E, Dileo P , et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol 2012; 23 (2) 508-516
• 23 Sleijfer S, Ray-Coquard I, Papai Z , et al. 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; 27 (19) 3126-3132
• 24 Schuetze SM, Zhao L, Chugh R , et al. Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma. Eur J Cancer 2012; 48 (9) 1347-1353
• 25 Malempati S, Weigel B, Ingle AM , et al. Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 2012; 30 (3) 256-262
• 26 DuBois SG, Shusterman S, Reid JM , et al. Tolerability and pharmacokinetic profile of a sunitinib powder formulation in pediatric patients with refractory solid tumors: a Children's Oncology Group study. Cancer Chemother Pharmacol 2012; 69 (4) 1021-1027
• 27 Penel N, Le Cesne A, Bui BN , et al. Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up. Ann Oncol 2011; 22 (2) 452-457
• 28 Demetri GD, Chawla SP, Ray-Coquard I , et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol 2013; 31 (19) 2485-2492
• 29 Van Glabbeke M, Verweij J, Judson I, Nielsen OS ; EORTC Soft Tissue and Bone Sarcoma Group. Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer 2002; 38 (4) 543-549
• 30 CTCAE Files. Available at http://evs.nci.nih.gov/ftp1/CTCAE/About.html . Accessed April 25, 2012
• 31 Eberst L, Cropet C, Le Cesne A , et al. The off-label use of targeted therapies in sarcomas: the OUTC'S program. BMC Cancer 2014; 14: 870 DOI: 10.1186/1471-2407-14-870.
• 32 Chawla SP, Staddon AP, Baker LH , et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol 2012; 30 (1) 78-84
• 33 Gore L, Trippett TM, Katzenstein HM , et al; Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC). A multicenter, first-in-pediatrics, phase 1, pharmacokinetic and pharmacodynamic study of ridaforolimus in patients with refractory solid tumors. Clin Cancer Res 2013; 19 (13) 3649-3658
• 34 Yoo C, Lee J, Rha SY , et al. Multicenter phase II study of everolimus in patients with metastatic or recurrent bone and soft-tissue sarcomas after failure of anthracycline and ifosfamide. Invest New Drugs 2013; 31 (6) 1602-1608
• 35 Martin-Liberal J, Gil-Martín M, Sáinz-Jaspeado M , et al. Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours. Br J Cancer 2014; 111 (5) 858-865
• 36 Bagatell R, Norris R, Ingle AM , et al. Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children's Oncology Group Study. Pediatr Blood Cancer 2014; 61 (5) 833-839
• 37 Quek R, Wang Q, Morgan JA , et al. Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin Cancer Res 2011; 17 (4) 871-879
• 38 George S, Merriam P, Maki RG , et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol 2009; 27 (19) 3154-3160
• 39 von Mehren M, Benjamin RS, Bui MM , et al. Soft tissue sarcoma, version 2.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw 2012; 10 (8) 951-960
• 40 Gounder MM, Lefkowitz RA, Keohan ML , et al. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res 2011; 17 (12) 4082-4090
• 41 Navid F, Baker SD, McCarville MB , et al. Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors. Clin Cancer Res 2013; 19 (1) 236-246
• 42 Widemann BC, Kim A, Fox E , et al. A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children's Oncology Group Phase I Consortium report. Clin Cancer Res 2012; 18 (21) 6011-6022
• 43 Maki RG, D'Adamo DR, Keohan ML , et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol 2009; 27 (19) 3133-3140
• 44 Dubois SG, Shusterman S, Ingle AM , et al. Phase I and pharmacokinetic study of sunitinib in pediatric patients with refractory solid tumors: a children's oncology group study. Clin Cancer Res 2011; 17 (15) 5113-5122