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AN OPEN-LABEL MULTICENTER PHASE 2 STUDY OF BEVACIZUMAB

FOR THE TREATMENT OF ANGIOSARCOMA

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, IL2Division of Medical Oncology, Mayo Clinic, Rochester, MN

3Division of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA

4Northwestern University Biostatistics Core Facility, Chicago, IL5Department of Sarcoma Medical Oncology, University of Texas, MD

Anderson Cancer Center, Houston, TX

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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.

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BACKGROUND 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

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.

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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

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STUDY OBJECTIVESPrimary 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

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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

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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

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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

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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

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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

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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

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PATIENT CHARACTERISTICS

Characteristic Patients (N=28)

Median age 62range 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)

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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

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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

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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

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WORST TOXICITY BY GRADE

No. of patients with event (%) (N=28)__________

Adverse event Grade 2 Grade 3 Grade 4Thrombocytopenia 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

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WORST TOXICITY BY GRADE

No. of patients with event (%) (N=28)__________

Adverse event Grade 2 Grade 3 Grade 4Hyperglycemia 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)____________________

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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

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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

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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

 

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PFS

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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.

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Margaret.vonMehren@fccc.edu

THANKS FOR YOUR ATTENTION !