Transcript 2006_files/Saltz ASCO 2006 poster

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
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.
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.
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).
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.
Bevacizumab Treatments at
MSKCC (Feb ‘04 through Feb ’06)
•
•
•
•
•
# pts treated with bev
892
Total # doses given
8250
# pts treated at 5 mg/kg
669
Total # doses at 5 mg/kg
6969
# of 5mg/kg doses with duration of
dose administration recorded in
electronic pharmacy record
5795
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.
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 (02 sat < 89%)
Severe bronchospasm or hypotension
Use of epinephrine
Felt by MD or reviewer to be potentially lifethreatening.
– Contributed to permanent disability or death
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.
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.
Conclusion #1
• Bevacizumab can be safely
administered as a 30 minute
infusion without the need for 90
minute or 60 minute initial
treatments.
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 1st, 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
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 2nd dose …see
details that follow)
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. 02 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.
HSR # 2
• 70 y.o. male with metastatic CRC receive 1st
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. 02 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.
HSR # 3
(30 min infusion, 15 mg/kg, 2nd 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 2nd bev
dose, patient with shaking chill. 02 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.
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
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