Soft Tissue Sarcoma Chemotherapy: Past, Present, Future

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1 Soft Tissue Sarcoma Chemotherapy: Past, Present, Future Warren Chow, M.D. Division of Medical Oncology UCSF 7th Annual Clinical Cancer Update January 25, 2008

2 Disclosure Statement Research funding from: Pfizer Pharmaceuticals Ariad Pharmaceuticals Food and Drug Administration FDA Orphan Products Development Grants Program Arqule, Inc. Eli Lilly Pharmaceuticals Sarcoma Alliance for Research thru Collaboration

3 Sarcoma Introduction Cancer of the connective tissue Soft-tissue sarcomas: Estimated 9,530 cases in U.S. in 2006 (M 5,720 / F 3,810) Deaths: 3,500 (M 1,830 / F 1,670) Bone sarcomas: Estimated 2,760 in U.S. in 2006 (M 1,500 / F 1,260) Deaths: 1,260 (M 730 / F 530) Jemal A, et al. CA: Cancer J for Clin. 55:1, 2005

4 Soft-Tissue Sarcoma Major Histologic Subtypes: >50 subtypes Undiff Pleomorphic (MFH) (28%) Liposarcoma (15%) Leiomyosarcoma (12%) Unclassified (11%) Synovial sarcoma (10%) Malignant peripheral nerve sheath (6%) GIST (5%) Fibrosarcoma (3%) Angiosarcoma (2%) Epithelioid (1%) Coindre JM, et al. Cancer. 91:1914, Fletcher DM, et al. WHO Classification: Tumours of Soft Tissue and Bone. IARC Press, 2002.

5 Bone Sarcoma Histologic Subtypes Osteosarcoma (36%) Chondrosarcoma (10-25%) Ewing sarcoma (6-8%) Dorfman HD. Bone Tumors. Mosby, Inc., St. Louis, Damron TA. Oncology and Basic Science. Lippincott Williams & Wilkins, Philadelphia, 2008.

6 Location Cancer: Principles & Practice of Oncology. DeVita VT, et al. 6 th ed, 2000, p

7 Past

8 Adjuvant Chemotherapy for Bone Sarcomas Osteogenic sarcoma Cisplatin/Doxorubicin +/- High-Dose Methotrexate Survival: <20% no Rx vs. >60% with Rx Ewing sarcoma family of tumors Ifosfamide/Etoposide + Vincristine/Doxorubicin/Cyclophosphamide Survival: 20% no Rx vs. >70% with Rx Chondrosarcoma Adjuvant chemotherapy NOT recommended Meyers PA, et al. J Clin Oncol. 23:2004, Grier HE, et al. N Engl J Med. 348:694, 2003.

9 Adjuvant Chemotherapy for Soft-Tissue Sarcomas Meta-analysis of 14 randomized, doxorubicin-based adjuvant chemotherapy trials 6% benefit for local recurrence-free survival (p=0.016) 10% benefit for distant recurrence-free survival (p= ) 10% benefit for overall recurrence-free survival (p=0.0001) 4% benefit for overall survival (p=0.12) Sarcoma Meta-analysis Collaboration. Lancet. 350:1647, 1997.

10 Traditional Sarcoma Chemotherapy Results of Two Consecutive Trials of Dose- Intensive Chemotherapy with Doxorubicin (A) and Ifosfamide (I) in Patients with Sarcomas AI 75/10 (Doxorubicin 75 mg/m 2 /72 hr + Ifosfamide 2 gm/m 2 /2 hr x 5 day) Overall objective RR 69% Febrile neutropenia 31% of cycles AI 90/10 (Doxorubicin 90 mg/m 2 /72 hr + Ifosfamide 2 gm/m 2 /2 hr x 5 day) Overall objective RR 59% Febrile neutropenia 56% of cycles Patel S, et al. Am J Clin Oncol. 21:317, 1998.

11 Adjuvant Chemotherapy for Soft-Tissue Sarcomas Italian adjuvant trial of 5 cycles of Epirubicin/ Ifosfamide for extremity STS (med. f/u 89.6 mos) Only 104 patients (51 control; 53 observ.) Planned 95 pts/arm (tot. 190) Interim analysis after 50% enrolled. Two-sided p < DFS Median DFS: 47 mos vs. 16 mos (p=0.09) Median OS: NR vs. 49 mos (p=0.07) 5-yr OS estimate: 66.0 % vs. 46.1% (p=0.04) Frustaci S, et al. J Clin Oncol 19:1238, Frustaci S, et al. Oncology 65 (suppl 2):30, 2003.

12 Present

13 Angiosarcoma of the Scalp or Face Paclitaxel 175 mg/m 2 given over 1, 3, and 24 hr Memorial-Sloan Kettering Cancer Ctr 8/9 patients responded: 4 PR s, 4 clinical CR s, & 1 MR Liposomal Doxorubicin Case reports of complete response in radioresistant cutaneous angiosarcoma Fata F, et al. Cancer. 86:2034, Eiling S, et al. Brit J Derm. 147:150, 2002.

14 84 y/o W/M w/ Scalp Angiosarcoma & CR after 4 Cycles of Paclitaxel 9/13/07 1/3/08

15 Radiation-induced Angiosarcoma of the Breast 82 y/o W/F Stage 1, ER/PR/Her-2(-) multifocal breast CA in 2001; lumpectomy, adjuvant AC & XRT. 2006, developed 1. 9 cm angiosarcoma (AS) of breast; simple mastectomy. Jan, 2007, developed multifocal AS chest wall recurrence; resected w/ flap Feb, April, 2007, developed recurrence outside of vascular flap. May, 2007, 2 cycles of paclitaxel 80 mg/m2/week for 6 weeks every 8 weeks. Surgery August, 2007; path CR. Received 2 cycles of consolidation paclitaxel. Observation since Nov, 2007.

16 Ewing Sarcoma Family of Tumors AEWS0031 COG study of chemotherapy intensification by interval compression Improved EFS and OS for q2 wk doseintensive arm AEWS0031 Regimens and Age Estimated Proportion Event-Free Reg B Reg A Age Group -17 Years 18+ Years Years Womer RB, et al. CTOS Annual Meeting

17 Gemcitabine and Docetaxel MSKCC: Combination first tested in leiomyosarcoma of uterus or other organs. Gemcitabine 900 mg/m 2 /90 min (D1, D8) + Docetaxel 100 mg/m 2 /1 hr D8 + G-CSF Overall RR 53% (20% SD) U. Michigan: Tested in other sarcoma histologies. Gemcitabine 675 mg/m 2 /90 min (D1, D8) + Docetaxel 100 mg/m 2 /1 hr D8 + G-CSF Responses observed in leiomyosarcoma, osteosarcoma, angiosarcoma, MFH, malignant peripheral nerve sheath tumor, and Ewing s sarcoma. Hensley ML, et al. J Clin Oncol. 20:2824, Leu KM, et al. J Clin Oncol. 22:1706, 2004.

18 Gemcitabine and Docetaxel SARC Cooperative Group randomized phase II study of gemcitabine +/- docetaxel Gemcitabine 1200 mg/ m2/90 min (D1, D8) every 21 days. Gemcitabine 900 mg/m2/90 min (D1, D8) + Docetaxel 100 mg/m2/1 hr D8 + G-CSF every 21 days. RR 8% vs. 16% Leiomyosarcomas and MFH/HGUPS most responsive. Maki RG et al. J Clin Oncol. 25:2755, 2007.

19 Adjuvant Chemotherapy for Soft-Tissue Sarcomas EORTC randomized, phase III trial of 5 cycles of Doxorubicin (75 mg/m 2 ) & Ifosfamide (5 gm/m 2 ) q 21d vs. obs for high grade STS of any site. 351 pts accrued between LMS (15%), lipo (13%), MFH (11%), SS (11%) 66% extremity; 34% trunk/pelvis; 40% > 10 cm 73% completed the prescribed 5 cycles of Rx 63% completed without dose reduction/delay 5-yr RFS 53% obs arm vs. 51% CT arm 5-yr OS 69% obs arm vs. 64% CT arm Woll PJ, et al. Proc ASCO 25:10008a, 2007.

20 Targeted Therapies for Soft- Tissue Sarcomas

21 Gastrointestinal Stromal Tumors (GIST) Most common gastrointestinal sarcoma Highest incidence in the year age group Recently identified as a distinct clinical and histopathologic entity GIST have an incidence of 14.5 per million annually (comparable with CML) U.S. Population 296,000,000 4,300/year Cancer Facts & Figures Fletcher et al. Hum Pathol. 2002;33:459. Miettinen et al. Pol J Pathol. 2003;54:3. Joensuu et al. Lancet Oncol. 2002;3:655. Kindblom et al. Ann Oncol. 2002;13:157. Abstract 577O. Kindblom. At:

22 GIST: Origin GIST share several characteristics with interstitial cells of Cajal (ICC) Pacemaker cells of the gut Mixture of neural and myogenous features by electron microscopy Expression of KIT (CD117) in ~95% of cases ICC hyperplasia is evident in the GI tract of patients with familial GIST GIST and ICC may arise from a common mesenchymal stem cell of the enteric neural plexus Sircar et al. Am J Surg Pathol. 1999;23:377. Wang et al. Arch Pathol Lab Med. 2000;124:1471.

23 GIST: Clinical Presentation GIST may occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum Colon 10% 15% Other (rectum, esophagus, mesentery, retroperitoneum) 50% Stomach 25% Small intestine Emory et al. Am J Surg Pathol. 1999;23:82.

GIST: Immunophenotype ~95% of reported cases of

Positive in 60%-70% Smooth-muscle actin Positive

express desmin Courtesy of Dr. C. Corless.

24 GIST: Immunophenotype ~95% of reported cases of GIST are positive for KIT (CD117) Other markers often positive in GIST CD34 (mesenchymal/hematopoietic precursor cell marker) Positive in 60%-70% Smooth-muscle actin Positive in 15%-60% S-100 Positive in 10% GIST rarely express desmin Courtesy of Dr. C. Corless. Miettinen and Lasota. Virchows Arch. 2001;438:1. Different KIT staining patterns in GIST

GIST: Identification of KIT Gain-of-Function Mutations 279:577-580, 1998 KIT staining was positive in 46 of 49 GIST (94%) 5 of 6 GIST had mutations in KIT gene Mutant forms of KIT are constitutively

25 GIST: Identification of KIT Gain-of-Function Mutations 279: , 1998 KIT staining was positive in 46 of 49 GIST (94%) 5 of 6 GIST had mutations in KIT gene Mutant forms of KIT are constitutively active Proposed that GIST may originate from ICCs Studies in knock-in mice with KIT mutations Demonstrated that constitutive KIT signaling is sufficient to induce GIST Parallel with the pathology seen with familial KIT mutations, eg, mastocytosis Sommer et al. Proc Natl Acad Sci U S A. 2003;100:6706. Hirota et al. Science. 1998;279:577.

26 GIST: Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) Mutations PDGFRA mutations are present in ~5%-7% of GIST Mutually exclusive with KIT mutations 35% of KIT wildtype GIST have PDGFRA mutations Downstream activation targets of KIT are also activated by PDGRFA mutations in GIST AKT MAP kinase STATs Heinrich M et al. Science. 2003;299:708.

27 KIT and PDGFRA Mutations in GIST KIT PDGFRA Overall mutation frequency: 87.4% Exon 9 (11%) Exon 11 (67.5%) Exon 13 (0.9%) Exon 17 (0.5%) Membrane Exon 12 (0.9%) Exon 14 (0.3%) Cytoplasm Exon 18 (6.3%) Heinrich et al. Hum Pathol. 2002;33:484. Corless et al. Proc Am Assoc Cancer Res. 2003;44. Abstract R4447.

Normal KIT Signaling The KIT kinase domain

by phosphorylation This activated substrate

cell proliferation and survival Kinase domains

Adapted from Savage and Antman. N Engl J Med.

28 Normal KIT Signaling The KIT kinase domain activates a substrate protein, eg, PI3 kinase, by phosphorylation This activated substrate initiates a signaling cascade culminating in cell proliferation and survival Kinase domains ADP P P P P ATP Substrate Effector P P P Adapted from Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314. SIGNALING

29 Imatinib Mesylate: Background A selective tyrosine kinase inhibitor of KIT c-abl/arg PDGFRA/B First used in Philadelphia chromosome positive (Ph+) CML C 29 H 31 N 7 O CH 4 SO 3 MW Class: Phenylaminopyrimidines Druker et al. Nat Med. 1996;2:561.

30 Imatinib Mesylate: Mechanism of Action Imatinib mesylate occupies the ATP binding pocket of the KIT kinase domain This prevents substrate phosphorylation and signaling A lack of signaling inhibits proliferation and survival Kinase domains Imatinib mesylate P ATP Substrate Effector P P P Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314. SIGNALING

31 First Patient With GIST to Receive Imatinib Mesylate: Proof-of-Concept Exploratory study with oral imatinib mesylate at 400 mg/d Dramatic clinical response Disappearance of excess metabolic activity at 4 weeks by 18 FDG-PET 75% reduction in tumor size at 8-month follow-up Tumor biopsies showed histologic evidence of myxoid degeneration and lack of mitotic activity Symptomatic relief Joensuu et al. N Engl J Med. 2001;344:1052.

abdominal 18 FDG-accumulating uptake 4 weeks after starting

32 Imatinib Mesylate for Nonresectable and Metastatic GIST: Case Study (cont d) Multiple liver and upper A marked decrease in 18 FDG abdominal 18 FDG-accumulating uptake 4 weeks after starting metastases imatinib mesylate (400 mg/d) Joensuu et al. N Engl J Med. 2001;344:1052.

33 Effects of Imatinib Mesylate on CT Pre-Treatment Week 4 8 Months Joensuu et al. N Engl J Med. 2001;344:1052.

34 Effects of Imatinib on Histology Pre-Treatment 3 Weeks Post-Treatment H&E Ki-67 CD117 Joensuu et al. N Engl J Med. 2001;344:1052.

35 GIST: KIT Mutation Location Predicts Imatinib Mesylate Responsiveness % of total PD/NE SD PR 0 KIT Exon 11 (n=85) KIT Exon 9 (n=23) No mutation (n=9) KIT mutations are predictive of response to imatinib mesylate Exon 11 mutants respond best Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.

36 Imatinib Mesylate Therapy of GIST With Weak/Negative KIT Expression Approximately 5% of GIST are KIT-negative Weak/negative KIT staining is not predictive of a poor response to imatinib mesylate KIT-negative GIST may express imatinib mesylate sensitive mutant KIT or PDGFRA Documented clinical responses in KITnegative GIST Debiec-Rychter et al. J Pathol. 2004;202:430. Medeiros et al. Am J Surg Pathol. 2004;28:889.

37 Efficacy of Imatinib Mesylate in KIT-Negative GIST (S0033): PFS year PFS KIT-positive GIST (n=376) 48% KIT-negative GIST (n=14) 43% % of patients P= Months Blackstein et al. J Clin Oncol. 2005;23(suppl 16):818s. Abstract Blackstein et al. At: Accessed July 2005.

38 Imatinib Mesylate in GIST: Pivotal Trial Survival by Best Response Probability CR PR SD PD Weeks Even patients who achieve only SD by SWOG will experience prolonged survival on imatinib mesylate Blanke et al. ASCO Gastrointestinal Cancers Symposium, Abstract 2.

39 We Should Desist Using RECIST, at Least in GIST RECIST is insensitive in evaluating GIST response treated with imatinib. 172 met. GIST lesions eval. in 40 pts. Mean size (5.3 cm), density (72.8 HU), SUV max (5.8). 33/40 good response on FDG-PET. Decrease in size >10% or tumor density of >15% on CT had sensitivity 97% & specificity 100% by FDG-PET. Choi H et al. J Clin Oncol 25:1753, Benjamin RS, et al. J Clin Oncol 25:1760, 2007.

40 We Should Desist Using RECIST, at Least in GIST

41 Adjuvant Imatinib for GIST ACOSOG Z9001 [A Phase III Randomized Double-blind Study of Adjuvant Imatinib vs. Placebo in Patients Following Resection of Primary GIST] Pts with GIST > 3 cm, not ruptured, nor multifocal eligible for randomization to imatinib 400 mg/day for 1 yr vs. placebo. Interim results reported 97% RFS for imatinib vs. 83% for 1 yr. On-going adjuvant trials in Europe EORTC: 2 years imatinib vs. observation Scandinavian Sarcoma Group: 1 yr vs. 3 yr of imatinib

42 The Next Intergroup GIST Study SWOG S0502: A Phase III Randomized Study of Imatinib, with or without Bevacizumab, in Patients with Metastatic or Unresectable GIST.

43 Other Potential Imatinib-Sensitive Sarcomas Dermatofibrosarcoma Protuberans Uncommon, low-gr, fibrohistiocytic tumor of interm. malignant potential of dermis and subcutis Caused by autocrine/paracrine activation of plateletderived growth factor receptor-b (PDGFR-B) via translocation (COL1A1-PDGFB fusion) Rubin BP, et al. J Clin Oncol. 20:3586, SARC004: Phase II Study of IM in DFSP Extraabdominal Desmoid Tumors (Fibromatosis) Rare, monoclonal tumor of deep musculoaponeurotic structures Mace J, et al. Cancer. 95:2373, SWOG S0525: Phase II Study of IM in Desmoid Tumors

44 Other Potential Imatinib-Sensitive Sarcomas Chordomas Very, rare tumor that originate from remnant of notochord. Casali PG, et al. Cancer. 101:2086, Ewing s Sarcoma/PNET? Phase 2 trial of IM for tx of pediatric solid tumors: A Children s Oncology Group Study Bond M, et al. Pediatr Blood Cancer. E-pub, /24 pts with PR. Phase 2 SARC trial (Chugh D. Proc ASCO 22: 90001a, 2004). 0/13 pts with PR Imatinib mesylate therapy for recurrent Ewing s family of tumors (EFT) [Chow WA, et al. Proc ASCO. 22:9054a, 2004] 1/7 pts with PR (Kit & PDGFR-a expression)

45 Imatinib Resistance in GIST

46 GIST: Mechanisms of Potential Resistance to Imatinib Mesylate Resistance can be primary or secondary (following initial response) Mechanisms Imatinib mesylate resistant mutations in KIT or PDGFR-A kinase domain KIT or PDGFR-A gene amplification Activation of alternative kinase Resistance may be evidenced as progression of some lesions but not others Fletcher et al. Proc Am Soc Clin Oncol. 2003;22:815. Abstract 3275.

47 Imatinib Mesylate in GIST: Focal Resistance Following Response Pretreatment 6 months 10 months Courtesy of Dr. R. DeMatteo.

48 GIST: Sunitinib Treatment An inhibitor of the receptor tyrosine kinases PDGFR, VEGFR, KIT, RET, and FLT3 Has antiangiogenic effects on HUVECs in vitro Achieved tumor control in conjunction with irradiation in murine tumor models Clinical activity observed in patients intolerant of or who progressed on imatinib mesylate DLT: fatigue, nausea, vomiting HUVECs = human umbilical vein endothelial cells. Demetri et al. Proc Am Soc Clin Oncol. 2003;22:814. Abstract Mendel et al. Clin Cancer Res. 2003;9:327. Hallahan et al. Proc Am Soc Clin Oncol. 2003;22:873. Abstract 3508.

49 GIST Resistant to Imatinib Mesylate: Phase II Trial of Sunitinib % of patients N= PR SD PD 65% of patients in a phase I/II trial experienced clinical benefit Demetri et al. Proc Am Soc Clin Oncol. 2004;23:195. Abstract Demetri et al. At: Accessed July 2004.

50 Imatinib Mesylate in GIST: Pivotal Trial Survival by Best Response Probability CR PR SD PD Weeks Even patients who achieve only SD by SWOG will experience prolonged survival on imatinib mesylate Blanke et al. ASCO Gastrointestinal Cancers Symposium, Abstract 2.

51 GIST Resistant to Imatinib Mesylate: Phase III Trial of Sunitinib Median TTP 27.3 wks vs. 6.4 wks for placebo 7% PR (58% SD) vs. 0% for placebo 10% of pts exhibited PR & 7% SD after crossover Pts with Exon 9 mutation responded better than pts with Exon 11 (opposite of imatinib). Demetri G, et al. Lancet 368: 1329, 2006.

52 Future

53 AP23573, an mtor Inhibitor AP23573, an analog of rapamycin (Sirolimus) Inhibits the mammalian target of rapamycin (mtor) protein kinase. mtor is a central controller of cell proliferation Treatment of cells with rapamycin inhibits: Cell growth Cell division

54 mtor Signaling Abraham RT, et al. Clin Cancer Res. 13:3109, 2007.

55 Phase 2 Study of AP23573 in Patients with Advanced Sarcomas 12.5 mg IV daily X 5 days ever 2 weeks 25 previously treated pts (14M/11F): Bone (5) Leiomyosarcoma (5) Liposarcoma (1) Others (11) 39% demonstrated > 25% decrease in [ 18 F] FDG PET uptake. Symptomatic improvement in 13 pts. Sankhala KK, et al. Proc ASCO 23:9028a, 2005.

56 Phase III Trial of AP23573 Maintenance Rx in STS/Bone Sarcomas Randomized, placebo-controlled, double-blinded trial to compare efficacy of PO AP mg QDx5/week vs. placebo. Met. sarcoma patients who have CR/PR following 4-12 cycles of cytotoxic chemotherapy. Ariad. Protocol AP , 2007.

57 Sorafenib Raf kinase, PDGFR-β, and VEGF-R inhibitor that inhibits tumor proliferation and angiogenesis. Multi-center, phase II trial for non-gist sarcomas reported at ASCO, /37 RECIST PR s in leiomyosarcoma (6% RR) 3/23 PR s in angiiosarcoma (13% RR) U. Chicago consortium trial in imatinib and sunitinib-resistant GIST. D Adamo DR, et al. Proc ASCO 25:10001a, Kindler HL, et al. Proc ASCO 26, 2008.

58 Dasatinib (BMS ) c-src is a proto-oncogene, non-receptor tyrosine kinase; induces VEGF expression thru STAT3. Dasatinib is a broad spectrum ATP-competitive inhibitor of SRC family kinases, BCR-ABL, c- KIT, EPhA2 receptor, and PDGFR-β. Dasatinib is 2-3 logs more potent than imatinib mesylate in inhibiting BCR-ABL. Dasatinib is capable of binding to both the open (active) and closed (inactive) conformations of c-abl; imatinib mesylate can only bind to the inactive state. SARC. Protocol 009, 2007.

59 Eli Lilly: LY Novel cytotoxic agent w/ activity across broad range of human cancer cell lines. Unique MOA unlike other cytotoxics. Promotes apoptosis via increase ROS. Phase II, open-label study as 2 nd or 3 rd line therapy for unresectable or met STS (1 must be doxorubicin-based). Eli Lilly and Co. Protocol H8K-MC-JZAD, 2007.

60 Amgen: Phase Ib/2 Study of AMG Doxorubicin for 1 st line Rx of STS Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) is natural ligand for TRAIL receptor 2 (DR5). Activation of TR2/DR5 initiates caspase cascade and apoptosis. AMG 655 mimics endogenous TRAIL. Sarcomas express high levels of TR-1 and TR-2. AMG 655 AE s: fever, fatigue, anemia, nausea, increased lipase, hypomagnesmia, lymphopenia. Amgen. Protocol , 2007.

61 Insulin-like Growth Factor-1 Signaling Sachdev, et al. Mol Cancer Ther 6: 1-12, 2007.

62 Sarcoma Alliance for Research thru Collaboration (SARC) #011 Phase II Trial of R1507 (MoAb Insulin-Like Growth Factor-1 Receptor): Ewing s sarcoma Osteosarcoma Synovial sarcoma Rhabdomyosarcoma Other sarcomas High levels of IGF1R expressed in no. of pediatric solid tumors. R1507 inhibits downstream targets of IGF- 1R (PI-3K, MAPK) SARC. Protocol 011, 2007.

liposarcoma apoptosis Induces G 1 cell cycle block Phase I/II trial of Nelfinavir for recurrent liposarcomas 100 80 60 40 20 0 SW872 Cells Control 2.

63 COH: Nelfinavir and Liposarcoma Nelfinavir is an HIV protease inhibitor. HAART results in HIV lipodystrophy syndrome. In vitro, nelfinavir: inhibits liposarcoma clonogenicity via upregulation of SREBP-1 Induces expression of Fas, Bax and p21 WAF1/CIP1 Induces liposarcoma apoptosis Induces G 1 cell cycle block Phase I/II trial of Nelfinavir for recurrent liposarcomas SW872 Cells Control 2.5uM 10uM 20uM SW872 Annexin V 3.2% Nelfinavir [0 μm] Annexin V 6.7% Annexin V 3.5% [2.5 μm] Annexin V 25.0% Control 2.5 um 10 um 20 um SREBP Kda SREBP-1 68 Kda Nelfinavir [10 μm] [20 μm]

64 Patient #2; 2 nd Cohort (1750 mg BID) 1/17/07 4/25/07 7/23/07 1/15/08

65 Patient #2; 2 nd Cohort (1750 mg BID) 1/17/07 4/25/07 7/23/07 1/15/08

66 Patient #2; 2 nd Cohort (1750 mg BID) 1/17/07 4/25/07 7/23/07 1/15/08

67 Conclusions Benefit of adjuvant chemotherapy with Ifosfamide and an anthracycline is probably limited. Other chemotherapies indicated for specific histologic types of sarcomas. Imatinib mesylate for GISTs has produced active research in tyrosine kinase inhibition for GIST and other sarcomas. New targets are currently being identified in sarcomas, which may result in development of novel therapeutics.

68 Acknowledgements Chow Laboratory Min Guan, Ph.D. Chunling Jiang, Ph.D. Song Guo (U. Wisconsin)

69 Imatinib Mesylate: Spectrum of Activity Kinases Inhibited Kit Bcr-Abl PDGFR-A/B Kinases Not Inhibited EGFR (HER1) VEGFR-2 (KDR) IGFR C-Src PKC-α FGFR-1 GFR = growth factor receptor; EGFR = epidermal GFR; VEGFR = vascular endothelial GFR; IGFR = insulin-like GFR; PKC = protein kinase C; FGFR = fibroblast GFR. Manley et al. Eur J Cancer. 2002;38(suppl 5):S19.

70 GIST: Preclinical Efficacy of Imatinib Mesylate on GIST Cell Cultures In Vitro Imatinib mesylate inhibits proliferation and induces apoptosis in GIST cell culture No. of cells 10, μm imatinib mesylate (GIST-882) PBS (GIST-882) PBS (ST88-014) 10 μm imatinib mesylate (ST88-014) Days 10 μm imatinib mesylate *GIST-882 and ST are GIST- and peripheral nerve sheath derived cell lines, respectively. Tuveson et al. Oncogene. 2001;20:5054. % Annexin (+), PI (-) PBS 4 days 7 days

Clinical Trials. Phase II Studies. Connective Tissue Oncology Society. Jon Trent, MD, PhD

Clinical Trials. Phase II Studies. Connective Tissue Oncology Society. Jon Trent, MD, PhD Clinical Trials Phase II Studies Jon Trent, MD, PhD Associate Professor Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cancer Center Connective Tissue Oncology Society GIST Overview