Suzanne George, MD Instructor in Medicine, Harvard Medical School Clinical Director, Center for Sarcoma and Bone Oncology Dana-Farber Cancer Institute Boston, Massachusetts Integrating Novel Approaches to Therapy into the Multidisciplinary Treatment of Sarcomas This program is supported by an educational grant from

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clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Overview of This Presentation  Introduction to soft tissue and bone sarcomas  Treatment of localized disease  Established treatment for advanced disease  GIST as a model for targeted therapy in sarcomas  Targeted therapies in non-GIST sarcomas  Summary  For in-depth information on any of the issues covered in this presentation, please review the relevant content on the Clinical Care Options Web site: clinicaloptions.com/oncology

Introduction

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Sarcomas: Background and Incidence 1. NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma v Jemal A, et al. Ca Cancer J Clin. 2008;58:  Sarcomas are a diverse group of rare, mesenchymally derived tumors –> 50 histologic subtypes with varying behavior, prognosis, and response to treatment –15% of childhood cancers; 1% of adult malignancies [1] –< 1% of malignant tumors are sarcomas [2] –~ 12,700 new cases annually with ~ 5000 deaths [2] –Incidence likely underestimated –GIST added to tumor registry databases in 2001, represents ~ 5000 new cases annually [1] –Tumors typically reported by site of origin vs tissue of origin (mesenchymal)

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Risk Factors for Sarcomas  Most sarcomas arise without known predisposing factors or specific etiology –Sarcomas do not arise in preexisting benign tumors  Trauma  Chemicals –Dioxin, vinyl chloride, herbicides  Therapeutic irradiation [1]  Viral infection –Kaposi’s sarcoma  Immune disorders –Leiomyosarcoma in childhood AIDS –Postmastectomy angiosarcoma  Genetics –Neurofibromatosis –Li-Fraumeni syndrome [2] –Retinoblastoma [3] 1. Cormier JN, et al. CA Cancer J Clin. 2004;54: Strong LC, et al. Am J Epidemiol. 1992;135: Wong FL, et al. JAMA. 1997;278:

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Soft Tissue Sarcomas  Adult sarcomas are more common in soft tissue than bone –~ 50% in extremities, ~ 40% in trunk/retroperitoneum, ~ 10% head/neck [1] 1. National Cancer Institute, Treatment PDQ: Adult Soft Tissue Sarcoma. 2. Toro JR, et al. Int J Cancer. 2006;119: Incidence of Soft Tissue Sarcoma Subtypes ( ) [2] Histologic Subtype% Leiomyosarcoma 23.9 “Malignant fibrous histiocytoma” 17.1 Liposarcoma 11.5 Dermatofibrosarcoma 10.5 Rhabdomyosarcoma 4.6 Angiosarcoma 4.1

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Sarcomas: Management  Multidisciplinary approach recommended due to rarity and heterogeneity –Pathologists, radiologists, oncologists, sarcoma-experienced surgeons –Treatment at specialized sarcoma centers lowers rates of recurrence and improves OS [1]  Pretreatment biopsy critical –Treatment choice depends on histology and grade  Poor prognostic factors –Age > 60 years –Tumor > 5 cm –High-grade histology [2] 1. Ray-Coquard I, et al. Ann Oncol. 2004;15: National Cancer Institute, Treatment PDQ: Adult Soft Tissue Sarcoma.

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas 0.5 Kattan MW, et al. J Clin Oncol. 2002;20: Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. 1.Draw lines from prognostic variable axes to points axis 2.Add prognostic points for each variable to determine total points 3.Determine survival probability by drawing line from total points axis to survival probability axes Nomogram Predicts Risk of Death  Nomogram developed from prospective analysis of 2136 sarcoma patients treated from –Predicts risk of sarcoma-specific death at 12 yrs postsurgery Points Size (cm) Depth Site Histology Age (yrs) Total Points 12-yr Low Gr. SSD 12-yr High Gr. SSD ≤ 5 > 10 Deep Superficial Lower extremityHead/neckThoracic/trunk Upper extremityVisceralRetro/intra-abdominal Lipo Leiomyo Synovial FibroMFHOtherMPNT

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas : Conventional Treatment Sarcomas: Conventional Treatment  Surgical resection with wide margins is standard therapy for patients with localized sarcomas  Postoperative radiotherapy recommended for high- or intermediate-grade tumors and those tumors with close or positive margins [1] –External-beam therapy, brachytherapy, or intensity- modulated radiotherapy Distant metastases remain problematic for ~ 50% of sarcoma patients [2] 1. Clark MA, et al. N Engl J Med. 2005;353: Wunder JS, et al. Lancet Oncol. 2007;8:

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Chemotherapy for Localized Sarcomas  Chemotherapy, in addition to local therapy, is standard of care for rhabdomyosarcoma, osteosarcoma, and Ewing’s sarcoma –These subtypes most common in children and young adults but can be seen throughout the age spectrum –Cure rates dramatically increased vs local therapy (up to 75% DFS at Yr 5) [1]  More frequent administration (Q2W vs Q3W) may improve EFS in patients with localized Ewing’s sarcoma [2] –Particularly in pts younger than 17 yrs of age 1. Wunder JS, et al. Lancet Oncol. 2007;8: Womer R, et al. ASCO Abstract Reprinted with permission. P =.023 EFS (%) Years Regimen Standard Intensive

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Chemotherapy for Localized Sarcomas  Chemotherapy not well defined for sarcomas other than rhabdomyosarcoma, osteosarcoma, and Ewing’s sarcoma  Meta-analysis of 14 trials in common types of adult STS showed no significant OS benefit to doxorubicin-containing adjuvant chemotherapy despite RFS benefit –Subgroup analysis of meta-analysis revealed significant OS benefit in patients with sarcomas in extremities (P =.029) [1]  Phase III randomized study (N = 350) in resected, nonmetastatic STS showed no OS benefit to adjuvant chemotherapy and similar RFS in both arms [2] 1. Sarcoma Meta-Analysis Collaboration. Lancet. 1997;350: Woll PJ, et al. ASCO Abstract

Advanced Sarcomas

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Treatment of Advanced Sarcomas  Standard first-line approach: doxorubicin/ifosfamide –“Dismal” response rates: 10% to 25% [1] –Substantial toxicities: cardiotoxicity, myelosuppression –Combined administration not superior to sequential dosing –Dose escalation and intensification do not improve survival  No consensus on second-line treatment, but several chemotherapeutic agents appear promising [2] 1. Ordóñez JL, et al. Semin Diagn Pathol. 2008;25: Kopp HG, et al. Am J Clin Dermatol. 2008;9:

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas New Agents for Advanced Sarcomas Gemcitabine-Based Regimens  Gemcitabine as single agent shows modest activity [1]  Gemcitabine plus docetaxel –Leiomyosarcoma and HGUPS respond better than other sarcoma histologies [2,3] –Pts with ECOG PS 0 respond better than pts with PS 1  Phase II studies of gemcitabine/docetaxel yielded inconsistent results 1. Patel SR, et al. J Clin Oncol. 2001;19: Hensley ML, et al. J Clin Oncol. 2002;20: Maki RG, et al. J Clin Oncol. 2007;25: Duffaud F, et al. ASCO Abstract Phase II StudyNORR, %CR, % Median PFS, Mos OS Hensley* [2] Median: 17.9 mos SARC †[3] Median: 17.9 mos Duffaud* [4] % at 6 mos *Leiomyosarcoma. † Various types of STS.

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Trabectedin in Advanced Sarcomas  Trabectedin binds selectively to the minor groove of DNA [1] –Most active in G1 phase, thus blocking cell cycle at G2/M phase [2] –Approved in Europe for patients with advanced STS who failed or are not candidates for anthracycline- and ifosfamide-based chemotherapy [2]  Main grade 3/4 toxicities: elevated transaminases (reversible), neutropenia [3] 1. D’Incalci M, et al. The Oncologist. 2002;7: Ordóñez JL, et al. Semin Diagn Pathol. 2008;25: Le Cesne A, et al. J Clin Oncol. 2005;23: Grosso F, et al. Lancet Oncol. 2007;8: StudyNSTS SubtypeORR, %6-Mo PFS, % Phase II [3] % leiomyosarcoma; 59% other STS 829 Retrospective analysis [4] 51Myxoid liposarcoma5188

Gastrointestinal Stromal Tumors

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas GIST: A Model for Targeted Therapies in Sarcoma  GISTs are the most common mesenchymal tumors of the gastrointestinal tract  Annual incidence is ~ new cases in the US  60% gastric; 30% small bowel; 5% colon/rectum; 5% other  Majority of GISTs are defined by gain of function mutation in the transmembrane tyrosine kinase receptor, KIT Emory TS, Sobin LH, Lukes L. Am J Surg Pathol 1999;23:

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas c-KIT PDGFR VEGFR Abl JAK Src Raf MAPK MEKERKRas PI3-K AKT Raf MAPK MEKERKRas PI3-K AKT Tumor CellEndothelial Cell Proliferation/Survival Metastasis Angiogenesis Transcription STAT Sunitinib SorafenibImatinib Tyrosine Kinase Inhibitors: Mechanism of Action

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Imatinib in GIST  Imatinib, selective TKI (KIT, PDGFR), approved for treatment of KIT positive advanced/metastatic GIST –Clinical benefit rate: 85% –Median PFS  Recently approved, 12.08, for adjuvant therapy based on randomized phase III ACOSOG Z9001 study (N = 644) of resected, KIT + GIST [1] –Results showed significant improvement in 12-mo RFS rate: 97% vs 83% with placebo (P <.001) 1. DeMatteo R, et al. ASCO Abstract Placebo Imatinib Patients (%) Grade

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Sunitinib in GIST  Sunitinib a novel, broad spectrum TKI affecting FLT3, PDGFR, and VEGFR pathways –All relevant to GIST pathogenesis [1] –Approved for imatinib- resistant, progressive GIST based on TTP results from randomized phase III study (N = 312) [2] 1. Hopkins TG, et al. Eur J Cancer Society. 2008;34: Demetri GD, et al. Lancet. 2006;368: Reprinted from The Lancet with permission from Elsevier. Sunitinib Median TTP: 27.3 wks Placebo Median TTP: 6.4 wks P <.0001 Tumor Progression Free (%) Weeks

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas New TKIs in GIST  Sorafenib  Nilotinib  Dasatinib

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas HSP Inhibition in Sarcomas  HSPs are molecular chaperones –Maintain stability and subcellular localization of proteins, including some critical to cancer cell proliferation Damaged Cell and Tumor Cell: HSP 90- centered chaperone machine Stabilization of Client Proteins HSP 90 Inhibitors Evading Apoptosis (IGF-1R, AKT) Self-Sufficiency in Growth Signals (HER2, KIT, MET) Tissue Invasion an Metastasis (MMP2) Limitless Replicative Potential (telomerase) Insensitivity to Anti-Growth Signals (CDK4, 6, cyclin D) Sustained Angiogenesis (HIF, MET, VEGF)

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas HSP Trials in Sarcomas  Phase I dose-escalation trial of HSP inhibitor retaspimycin (IPI-504) in patients with pretreated GIST (n = 36) and other sarcomas (n = 11) [1] –Disease-control rate: 70% in GIST, 45% in other sarcomas –Dose-limiting grade 3 toxicities: lipase elevation, headache, fatigue, nausea  Phase III study will evaluate retaspimycin in patients with metastatic and/or unresectable GIST (planned N = 195) who failed TKIs (at least imatinib and sunitinib) [2] 1. Wagner AJ, et al. ASCO Abstract ClinicalTrials.gov. NCT

Targeted Therapies in Non-GIST Sarcomas

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Targeting Protein Translation: mTOR Inhibitors  mTOR is a serine/threonine kinase downstream effector of the PI3K/Akt pathway –Common point in regulation of cell nutritional status and growth factor stimulation  mTOR kinase regulates mRNA translation by phosphorylation of 2 critical substrates, eIF4E and S6k  mTOR inhibitors –Rapamycin, temsirolimus, everolimus, deforolimus (now called ridaforolimus) –In preclinical models, induce apoptosis, inhibit angiogenesis mTOR Witzig T, et al. J Clin Oncol. 2005;23: Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Activated Ras PI3K P S6 PIP2 PTEN ILKPDK1 AktpAktppAkt pTSC2 + TSC1 TSC1/TSC2 Rheb.GTPRheb.GDP mTOR inhibitor + FKBP12 mTOR inhibitor, FKBP12 PI3K p70S6k P p70S6k Protein S6 eIF4E.4EBP-1 complex P 4E-BP1 + eIF4E Downstream events: proliferation, angiogenesis Receptor tyrosine kinase (eg, VEGFR, IGF-1R) ATP Glucose

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Deforolimus* for Advanced Sarcomas  Phase II trial of mTOR inhibitor in patients with pretreated, advanced STS or bone sarcomas (N = 212) [1] –Dose: 12.5 mg, IV Days 1-5, every 2 weeks –Clinical benefit (response or SD for ≥ 16 weeks): 29% –5 pts achieved a PR (4 bone sarcoma, 1 MFH)  Phase III SUCCEED trial currently evaluating maintenance oral deforolimus* in pts with metastatic STS or bone sarcoma [2] *Deforolimus: now known as ridaforolimus 1. Chawla SP, et al. ASCO Abstract ClinicalTrials.gov. NCT

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Pts with metastatic STS or bone sarcoma, aged ≥ 13 yrs, with ECOG PS 0 or 1 (N = 650 planned) Continue treatment until PD Placebo Deforolimus* 40 mg, orally Days 1-5 weekly SUCCEED: Phase III Deforolimus* for Advanced Sarcomas  Primary endpoint: PFS  Secondary endpoints: OS, response rate, cancer-related symptoms, safety *Now known as ridaforolimus

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Targeting VEGF in Sarcomas: Bevacizumab + Doxorubicin  In phase II trial of anti-VEGF antibody bevacizumab added to doxorubicin in phase II trial in pts with metastatic STS (N = 17) vs previous studies of single-agent doxorubicin [1] –No improvement in response rates –Disease control rate 76% (2 PR, 11 SD ≥ 12 wks) –12% ORR with ≥ grade 2 cardiotoxicity in 35% 1. D’Adamo DR, et al. J Clin Oncol. 2005;23:

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Targeting VEGF: Gemcitabine, Docetaxel + Bevacizumab  PhaseI/II study of untreated, advanced STS (N = 27) [1] –Phase II dose (every 2 wks) –Gemcitabine 1500 mg/m 2 –Docetaxel 50 mg/m 2 –Bevacizumab 5 mg/kg IV –44% ORR and 80% disease-control rate –3 CR (1 MFH, 2 angiosarcoma); 5 PR (2 leiomyosarcoma, 1 MFH, 1 liposarcoma, 1 undifferentiated sarcoma)  HOWEVER, difficult to discern contribution of bevacizumab from contributions of gemcitabine/docetaxel which are known to be active in sarcoma [2] 1. Verschraegen CF, et al. ASCO Abstract Hensley ML, et al. J Clin Oncol. 2002;20:

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Temozolomide and Bevacizumab in Hemangiopericytoma/SFT  MDACC retrospective review from May Dec 2007 –N = 17; median age: 50 yrs (range: 44-75) –Treatment regimen (28-day cycle) –Temozolomide 150 mg/m 2 Days 1-7, –Bevacizumab 5 mg/kg Days 8, 22 –Response rate (14 evaluable pts): 79% PR, 14% SD –Median PFS: 10.3 mos –Adverse events ≥ grade 2 –Neutropenia (1), thrombocytopenia (2), infection (1), renal insufficiency (1) Park MS, et al. ASCO Abstract 10512

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas CTEP 7060: Phase II Sorafenib for Non-GIST Sarcomas  Multi-institutional trial, with 6 histologies analyzed –Starting dose 400 mg, orally twice daily for 4 weeks –Median cycles: 2 (range: )  Adverse events ≥ grade 3 –3 DVT/PE –2 CNS bleeding –1 cardiomyopathy –3 GI bleeding or perforation –1 hemoptysis HistologynResponses Median TTP, Mos Angiosarcoma 371 CR, 4 PRs5.5 ± 0.8 Leiomyosarcoma 372 PRs5.2 ± 0.7 Sarcoma, NOS ± 0.6 MPNST 142 MRs MFH 13-- Synovial sarcoma 131 MR Maki RG, et al. ASCO Abstract D’Adamo DR, et al. ASCO Abstract

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Phase II Sunitinib for Non-GIST Sarcomas  Multicenter, 2-arm study of sunitinib 37.5 mg/day continuous dosing –Arm A: vascular connective tissue neoplasms (n = 21) –Leiomyosarcoma, chordoma, angiosarcoma, hemangiopericytoma/SFT –Arm B: high-grade pleomorphic sarcoma (n = 21) –Sarcoma NOS/MFH/undifferentiated sarcoma, synovial sarcoma, liposarcoma Keohan ML, et al. ASCO Abstract OutcomeArm AArm B PR, % 05 SD ≥ 8 wks, % 3830 Median PFS, wks (range) 8 (6-54)8 (2-53)

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Sorafenib in Sarcoma  Sorafenib, a multitargeted TKI affecting RAF, PDGFR, VEGFR, and other kinase pathways Subtype-specific activity of TKIs in sarcomas emphasizes importance of histology-specific clinical trials 1. Ryan CW, et al. ASCO Abstract Maki RA, et al. ASCO Abstract Phase II Study Sarcoma SubtypeN ORR, % Survival Outcome Other Outcome SWOG 0505 [1] Vascular sarcoma806-mo PFS: 38%SD: 75% Grade 3/4 leiomyosarcoma 2006-mo PFS: 39%SD: 45% Grade 3/4 liposarcoma1006-mo PFS: 20%SD: 20% CTEP 7060 [2] Angiosarcoma Median OS: 13.7 mos Median TTP: 5.5 mos Leiomyosarcoma375.4 Median TTP: 5.2 mos

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Inhibiting IGF-1R in Sarcomas  Inhibition of IGF-1R promising approach to sarcoma treatment [1] –IGF-1R interaction triggers downstream pathway activation, including mTOR and PI3K pathways –Preclinical data suggested significant inhibition of growth in EWS, RMS in response to IGF-1R inhibition 1. Ordóñez JL, et al. Semin Diagn Pathol. 2008;25:

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Inhibiting IGF-1R in Sarcomas  Phase I study of anti–IGF-1R antibody CP-751,871 in advanced sarcoma patients (N = 24) –1 PR (Ewing’s sarcoma) –9 pts achieved SD ≥ 3 ms; 5 among 11 Ewing’s sarcoma pts  Several phase II studies of IGF-1R monoclonal antibodies under way in sarcomas Olmos D, et al. ASCO Abstract

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Summary  Sarcomas are a diverse group of rare mesenchymally derived tumors –Most risk factors or specific etiologies unknown –More common in soft tissue than bone –Poor prognosis conferred by age > 60 yrs, tumor > 5 cm, and high-grade histology  Multidisciplinary management approach recommended  Sarcoma-specific death postsurgery can be predicted using nomogram

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Summary  GIST is a distinct entity that has served as a paradigm for targeted therapy  Conventional treatment for non-GIST sarcomas –Low-grade STS: surgery alone –High- or intermediate-grade tumors: surgery + radiotherapy –Adjuvant chemotherapy only appropriate for rhabdomyosarcoma, osteosarcoma, and Ewing’s sarcoma –No consensus on second-line therapy

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Summary  New agents –Gemcitabine-based regimens have activity in STS –Trabectedin most effective in myxoid liposarcoma, also demonstrates benefit in leiomyosarcoma, liposarcoma, and synovial sarcoma  Targeted agents –TKIs imatinib and sunitinib approved for advanced GIST –Sorafenib (TKI) efficacy varies by subtype –HSP inhibitor retaspimycin promising in phase I results –Deforolimus (mTOR inhibitor, now called ridaforolimus) active in phase II results –Bevacizumab (VEGF inhibitor) possibly active in combinations –IGF-1R inhibition promising

clinicaloptions.com/oncology Integrating Novel Approaches Into Multidisciplinary Treatment of Sarcomas Agent/RegimenConditionTrial Identifier Pazopanib Metastatic STS, relapsed or refractory NCT NCT Deforolimus (now known as ridaforolimus) Metastatic STS, metastatic bone sarcomas NCT Trabectedin Recurrent or persistent STS NCT NCT AVE8062 Advanced STSNCT PegIFN alfa-2b + chemo and surgery SarcomaNCT Imatinib mesylate maintenance vs interruption Advanced GISTNCT Nilotinib vs Imatinib GISTNCT IPI-504 (retaspimycin) GIST in imatinib and sunitinib failureNCT Zoledronic acid + chemotherapy High-grade osteosarcomaNCT Zoledronic acid vs chemo vs sequential administration High-grade osteosarcomaNCT Bevacizumab + chemotherapy Osteosarcoma, MFH of boneNCT ClinicalTrials.gov Phase III Clinical Trials of Novel Agents in Sarcomas

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