AN OPEN-LABEL MULTICENTER PHASE 2 STUDY OF BEVACIZUMAB FOR THE TREATMENT OF ANGIOSARCOMA

1. M Agulnik,1 SH Okuno,2 M von Mehren,3 B Jovanovic,4 B Brockstein,1 RS Benjamin,5 A Evens1 1Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 2Division of Medical Oncology, Mayo Clinic, Rochester, MN 3Division of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA 4Northwestern University Biostatistics Core Facility, Chicago, IL 5Department of Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX AN OPEN-LABEL MULTICENTER PHASE 2 STUDY OF BEVACIZUMAB FOR THE TREATMENT OF ANGIOSARCOMA

2. Background • Patients presenting with angiosarcomas have limited therapeutic options and a poor prognosis • the 5-year survival rate: 23% Stage IV for patients and 48% for patients with Stage I-III1 • Systemic Chemotherapy: • Doxirubicin-based regimens: RR of 17% to 34% with median progression-free survival (PFS) of 4 months, and median overall survival (OS) of 8 months2 • Paclitaxel: RR the 18%–19% in metastatic or unresectable angiosarcomas, and 62% in all angiosarcomas2,3 1. Fayette et al. J Clin Oncol. 2005;23:822s. Abstract 9024. 2. Penel et al. Curr Treat Options Oncol. 2007;8:428–434. 3. Schlemmer et al. Eur J Cancer. 2008;44:2433–2436.

3. High expression of vascular endothelial growth factor (VEGF) have been reported in subtypes of angiosarcomas,4 • Overexpression of VEGF may contribute to growth of vascular tumors via an autocrine mechanism5 • Preclinical studies have shown the antitumor effects of antiangiogenic agents in tumor models of angiosarcoma6,7 • Initial experience with bevacizumab, a humanized monoclonal antibody against VEGF, also suggests activity in patients with angiosarcoma8 Background • 4. Itakura et al. J Surg Oncol. 2008;97:74–81. • 5. Amo et al. Arch Dermatol Res. 2001;293:296–301. • 6. Akhtar et al. Neoplasia. 2004;6:106–116. • 7. Taylor et al. J Interferon Cytokine Res. 2006;26:353–361. • 8. Koontz et al. Head Neck. 2008;30:262–266.

4. Methods • 2-stage open-label multicenter phase II study • Treatment consisted of single-agent bevacizumab (Bev) 15 mg/kg IV administered every 3 weeks • Treatment was continued until disease progression or unacceptable toxicity

5. STUDY OBJECTIVES • Primary • To determine the median PFS of patients with angiosarcoma or epithelioid hemangioendothelioma treated with Bev • Secondary • To evaluate the treatment effect of Bev by: - Objective RR, using modified RECIST - Duration of response - OS

6. STUDY OBJECTIVES • To explore the objective response to Bev by tumor density changes on CT scan • To evaluate the safety and tolerability of Bev in patients with angiosarcoma or epithelioid hemangioendothelioma

7. DOSE MODIFICATIONS • Dose reductions of Bev were not allowed • Bev was held for predetermined treatment-related grade 3 toxicities: - Venous thrombosis - Proteinuria - Increased LFT’s • Bev continued without dose adjustment on resolution of toxicity

8. DOSE MODIFICATIONS • Bev discontinued for predetermined toxicities: - Grade 4 hypertension or hemorrhage - Symptomatic grade 4 venous thromboembolic event - Any grade arterial thromboembolic events - Gastrointestinal perforation or wound dehiscence requiring medical intervention

9. MAJOR INCLUSION CRITERIA • Histologically confirmed, unresectable angiosarcoma or epithelioid hemangioendothelioma • Measurable disease • Prior surgery, radiation, and ≤3 prior chemotherapy treatment regimens • ECOG 0 or 1 • Adequate hematologic, liver, and renal function • Age ≥18 years • Ejection fraction >49% for patients with prior anthracycline therapy, ischemic heart disease, or history of heart failure

10. STATISTIAL CONSIDERATIONS • 2-stage optimal Simon design, maximum accrual 31 • P was defined as the probability of PFS time ≥3 months • In the first stage of the study (n=12), more than 3 patients had a PFS time >3 months; 2nd stage accrual is ongoing for a total of n=31 • If at study completion, 10 or more patients have a PFS time ≥3 months, it will suggest P > .450, and the use of Bev will be deemed successful

11. FOLLOWUP • Patients wer re-evaluated for response : - Every 6 weeks (2 cycles) for the first 12 weeks - Then every 9 weeks (3 cycles) thereafter • The long-term follow-up period begins after the last administration of Bev, every 3-4 months for 2 years

12. PATIENT CHARACTERISTICS Characteristic Patients (N=28) Median age 62 range 18–94 Gender, no. (%) Male 11 (39) Female 17 (61) Race, no. (%) White 26 (93) Black 2 (7) Site of primary disease no. (%) Breast 4 (14) Cutaneous (including scalp, head and neck, face) 9 (32) Soft tissue (including extremities) 4 (14) Visceral 9 (32) Bone 2 (7) Metastatic disease, no. (%) 11 (39)

13. RESULTS as of 10/29/09 • The median duration on study for the 25 patients that have completed treatment was 11.6 weeks (range, 1.4–115.9 weeks) • PD: n=19, • toxicity: n=4 • refusal: n=2 • One patient was lost to follow-up approximately three months after completing study treatment

14. Results • Three patients continue on protocol treatment • have been on study for 25.0, 66.7, and 115.9 weeks • Among all 28 patients, median number of bev cycles is 3.5 (range, 1–37 cycles) • Three patients are still on study: 8, 22 and 37 cycles to date

15. TOXICITY • The majority of adverse events observed with bev were grade 1 or 2 • Most common grade 1 AE: fatigue (n=4), and elevations in AST/ALT levels (n=4) • Grade 2 adverse events are shown in Table 2 • During 193 cycles of therapy, only 1 grade 4 adverse event occured: thrombocytopenia • Approximately 2 months after Bev therapy, a patient had a hepatic resection and splenectomy complicated by pleural effusion and colitis

16. WORST TOXICITY BY GRADE No. of patients with event (%) (N=28)__________ Adverse event Grade 2 Grade 3 Grade 4 Thrombocytopenia 1 (3.5) Shortness of breath 2 (7) Hypertension 2 (7) 1 (3.5) Pain 2 (7) 1 (3.5) Nausea 1 (3.5) 1 (3.5) Infection 1 (3.5) 1 (3.5) Headache 1 (3.5) Anemia 1 (3.5) Decline in FEV1 1 (3.5) Transient ischemic attack 1 (3.5) Neuromotor function 1 (3.5) Cardiac (congestive heart failure) 1 (3.5) Pleural effusion 1 (3.5) 1FEV1 forced expiratory volume in 1 second

17. WORST TOXICITY BY GRADE No. of patients with event (%) (N=28)__________ Adverse event Grade 2 Grade 3 Grade 4 Hyperglycemia 1 (3.5) Liver—clinical 1 (3.5) Anorexia 1 (3.5) Fatigue 1 (3.5) Alopecia 1 (3.5) Dizziness 1 (3.5) Edema 1 (3.5) Hemorrhage (epistaxis) 1 (3.5) Dementia 1 (3.5)____________________

18. RESPONSE BY DISEASE STATUS Best response, n (%) PR SD PD__ Metastatic (n=11) 2 (18) 4 (36) 5 (45) Nonmetastatic (n=16) 2 (13) 9 (56) 5 (31) All patients (n=27)4 (15) 13 (48) 10 (37) PD, progressive disease; PR, partial response; SD, stable disease

19. EFFICACY • The median follow-up: 49.2 weeks (range, 2.9–158.0 weeks) • Progressive disease has been noted in 2 patients with PR: 7.1 and 14.6 weeks after achieving PR • In the remaining patients with PR, response continued for duration of 84.9 and 99.00 weeks

20. PFS • The median PFS to date is 12 weeks (95% CI, 6–21 weeks)  • Eighteen of 28 patients were alive as of the data cutoff: PD n=9 Unknown cause n=1

21. PFS

22. Conclusions • No unexpected adverse events were seen with the administration of Bev in patients with angiosarcomas compared to other tumor types9-11 • Bev monotherapy for angiosarcomas resulted in an overall response rate of 15% • Tumor stabilization was achieved in 63% of patients • Further studies with Bev in combination with chemotherapy are warranted in angiosarcomas 9. Hurwitz et al. N Engl J Med. 2004;350:2335–2342. 10. Miller et al. N Engl J Med. 2007;357:2666–2676. 11. Sandler et al.N Engl J Med. 2006;355:2542–2550.

23. THANKS FOR YOUR ATTENTION ! Margaret.vonMehren@fccc.edu