1. Simplification of Bevacizumab Administration: Do we need 90, 60, or even 30 minute infusion times? LB Saltz, K-Y Chung, D Reidy, J Timoney, V Park, E. Hollywood, N Sklarin, R Muller Memorial Sloan Kettering Cancer Center, New York, NY USA

2. Background Bevacizumab (Bev) is a humanized monoclonal antibody that targets vascular endothelial growth factor-A (VEGF-A). Due to concerns of the possibility for infusion related hypersensitivity reactions (HSR’s), the phase I clinical trials of bev employed an initial 90 minute infusion of IV bevacizumab. If the 90 minute initial infusion was tolerated without a hypersensitivity reaction, the next dose was given over 60 minutes; if that dose did not produce a HSR, then all subsequent doses were given over 30 minutes.

3. Background (continued) This 90, 60, 30 minute infusion schedule has remained the standard administration schema throughout the development and registration of bevacizumab. The continued need for this practice, which was established when very little clinical experience with bev was available, has never been addressed. No significant infusion-related toxicities were reported in the pivotal phase III registration trial, which used the above schedule. (Hurwitz et al, NEJM 2004). We therefore postulated that bev could be safely administered without initially prolonged infusion times.

4. Methods We initially obtained an IRB waiver of authorization to review the records of patients at Memorial Sloan Kettering Cancer Center (MSKCC) who were treated with bev in the first 3 months of commercial availability (cut-off date 5/15/04). Subsequently, we obtained further authorization to review all patients treated with bev at our institution for the first 2 years of commercial availability (cut-off date 2/28/06).

5. Methods (continued) Computerized pharmacy records were utilized to identify all patients who had received bev during the time period in question, thereby preventing any recall bias. Our institutional adverse drug reaction reporting program was utilized to identify any infusion reactions related to bev. Additionally, patient electronic medical records were reviewed for further confirmation if any grade HSR was reported.

6. Bevacizumab Treatments at MSKCC (Feb ‘04 through Feb ’06) # pts treated with bev 892 Total # doses given8250 # pts treated at 5 mg/kg 669 Total # doses at 5 mg/kg6969 # of 5mg/kg doses with duration of dose administration recorded in electronic pharmacy record5795

7. MSKCC Institutional Adverse Drug Reaction (ADR) Reporting System Hypersensitivity reaction (HSR) kits are readily available in all chemotherapy treatment areas. Kits contain diphenhydramine, hydrocortisone, ranitidine, albuterol neb, EpiPen®, and ADR reporting form Policy & Procedure: Any time kit is used, ADR form is completed. In addition, any HSR of any grade is reported.

8. Definitions Used for Severity Reporting of HSR at MSKCC Mild: resolved with no medications given; no harm to patient Moderate: resolved, but prescription medication given. No harm to patient. Severe: any one or more of the following: –Hypoxia (0 2 sat < 89%) –Severe bronchospasm or hypotension –Use of epinephrine –Felt by MD or reviewer to be potentially life- threatening. –Contributed to permanent disability or death

9. Results Following initial commercial availability of bev in February 2004, 202 consecutive colorectal cancer (CRC) patients were treated with bev (5 mg/kg) at MSKCC starting as a 90 minute, then 60 minute, then 30 minute infusion. No hypersensitivity reactions were seen.

10. Results (continued) A decision was then made to establish an institutional practice of using 30 minute infusion times for all doses, including initial doses, of bev. Subsequently, 464 CRC patients were treated with bev 5 mg/kg, initially as a 30 minute infusion (no 90 or 60 minute infusions). No infusion hypersensitivity reactions have been observed.

11. Conclusion #1 Bevacizumab can be safely administered as a 30 minute infusion without the need for 90 minute or 60 minute initial treatments.

12. Infusion times less than 30 minutes Standard bev doses at 15 mg/kg over 30 min have an infusion rate of 0.5 mg/kg/min. As of Nov 1 st, 2005, MSKCC adopted this as the institutional standard infusion rate for all bev infusions. –15 mg/kg @ 0.5 mg/kg/min = 30 minutes –10 mg/kg @ 0.5 mg/kg/min = 20 minutes – 5 mg/kg @ 0.5 mg/kg/min = 10 minutes

13. From Nov 1, 2005 through Feb 28, 2006. 259 patients received a total of 1059 doses of bev 5mg/kg over 10 minutes –185 patients converted from ongoing 30 minute infusions to 10 minutes – no HSR’s reported. –74 patients began therapy with all doses over 10 minutes – no serious HSR’s reported (2 moderate HSR’s, each on 2 nd dose …see details that follow)

14. HSR reaction #1 71 y.o. male with CRC, received dose #1 FOLFOX bev (10 min) without incident. During cycle 2, pt felt flushed, noted to have red face and abd pain 5 min into infusion. Had small volume emesis. 0 2 sat = 95%. Patient given diphenhydramine 50 mg and ranitidine 50 mg, then completed rest of infusion over 1 hr. He received 2 further doses of bev with premeds over 90 min without incident, then changed therapy due to P.O.D.

15. HSR # 2 70 y.o. male with metastatic CRC receive 1 st dose of FOLFOX/bev (5mg/kg over 10 min) without incident. During second dose, at completion of bev (10 minutes), patient reported feeling hot. Facial flushing noted. 0 2 sat = 97%. Diphenhydramine 50 mg given and FOLFOX then completed. Patient remains on treatment with 25 mg diphenhydramine before bev, and has received 3 further doses of bev at 5 mg/kg over 10 min without incident.

16. HSR # 3 (30 min infusion, 15 mg/kg, 2 nd dose) 66 y.o. female with metastatic breast cancer, with history of allergic reaction to carboplatin, had been on long-standing paclitaxel. First dose of bev 15 mg/kg over 30 min added to paclitaxel without incident. Fifteen minutes into 2 nd bev dose, patient with shaking chill. 0 2 sat = 99%. No SOB or erythema noted. Patient had received prior diphenhydramine, ranitidine, and dexamethasone for paclitaxel. Given more diphenhydramine and dexamethasone and completed infusion without incident. Patient has continued bev, and remains on bev 10 mg/kg over 20 min 6 months later without incident.

17. Conclusions 90 and 60 minute initial infusions of bev do not appear to be necessary. Routine 30 minute initial bev infusions –appear to have a similar, excellent safety profile in terms of HSR’s to 90 min initial infusions –are more convenient for patients –require less chair time in chemotherapy units –are less expensive

18. Conclusions (continued) An infusion rate of 0.5 mg/kg/minute 5 mg/kg over 10 minutes 10 mg/kg over 20 minutes 15 mg/kg over 30 minutes –is logical, based on standard practice with high dose infusions –is our current standard practice at Memorial Sloan Kettering Cancer Center –thus far shows no serious hypersensitivity reactions