Abstract #2032
A dose-escalating and pharmacologic study of bortezomib in adult cancer patients with impaired renal function.
D. Mulkerin1, S. Remick2, R. Ramanathan3, A. Hamilton4, C. Takimoto5, A. Davies6, P. Ivy7, M. Karol8, J. Kolesar1, J. Wright7
for the NCI Organ Dysfunction Working Group.
University of Wisconsin Comprehensive Cancer Center, Madison, WI (1); Case Western Reserve University, Cleveland, OH (2); University of Pittsburgh Cancer Institute, Pittsburgh, PA (3); Sydney Cancer Center, Sydney, Australia (4); University of Texas Health Science Center, San Antonio, TX (5);
UC Davis Cancer Center, Sacramento, CA (6); CTEP/NCI, Rockville, MD (7); Millennium Pharmaceuticals, Inc., Cambridge, MA (8)
Updated Abstract
Methods
Clinical and Pharmacologic Results
Background: Bortezomib (VELCADE) is a highly selective and reversible inhibitor of the
proteasome with activity in multiple myeloma and other malignancies. Patients (pts.)
with renal impairment have been treated in previous trials, but there has not been a
Bortezomib clearance is independent of renal function and
systematic investigation into the effects of renal dysfunction on dosing. Study objec-
All participants had histologically confirmed malignancy including lymphoma
Patient Demographics
decreases with repeat administration.
tives were to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile
and multiple myeloma for whom effective standard therapy was not available.
of bortezomib, and to determine the maximum tolerated dose (MTD) in adults with ad-
Main eligibility included: ECOG PS 0-2, no limit on prior therapies, measurable
Bortezomib
vanced malignancy and renal insufficiency ranging in severity from mild to dialysis de-
or evaluable disease, leukocytes 1,000/µL, platelets 50,000/µL, and ad-
51 Participants as of 1/06
Disease Site (tumor type):
Clearance
pendence.
equate hepatic function. Peripheral neuropathy grade 2 precluded participa-
(L/hr)
CrCl > 60 CrCl 40-59 CrCl 20-39 CrCl < 20 Dialysis
Methods: As of January 2006, fifty-one pts have received intravenous bortezomib at 0.7
tion.
30 male; 21 female
Multiple Myeloma: 13
Day 1
mg/m2 up to the approved dose of 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. Pts.
Eleven institutions enrolled patients into one of five cohorts on the basis of
Non Hodgkin lymphoma: 1
Mean
69.5
69.0
67.5
65.2
67.9
were stratified by 24-hour creatinine clearance (CrCL) normalized to a body surface
measured CrCL normalized to bsa of 1.73 m2. Dose levels and accrual distri-
Mean age: 63 years
Carcinoma: 37
Total N
14
13
12
3
5
area of 1.73 m2 into five cohorts. Doses were escalated in cohorts of three pts in
bution per cohort are shown below. Bortezomib was administered as an i.v.
range 46-86
Std Dev.
27.0
56.2
47.8
16.5
35.9
groups B-E. Blood samples were assayed for bortezomib concentration, as well as the
push on days 1, 4, 8, and 11 every three weeks. Three patients were enrolled
SE Mean
7.2
15.6
13.8
9.5
16.1
PD endpoint of 20S inhibition.
per dose level and per renal function group with standard escalation rules ap-
Results: Escalation of bortezomib doses to 1.3 mg/m2 was well tolerated in all groups
PS 0 = 12; PS 1 = 31; PS 2 = 6
plying within each cohort excepting the normal renal function controls. At
Day 8
with CrCL 20 mL/min/1.73 m2. There has been only one instance of dose limiting tox-
(2 unknown)
MTD, cohorts were expanded up to 12 pts. to allow for expanded pharmaco-
Mean
27.6
27.0
27.5
27.5
20.0
icity (group C at 1.3 mg/m2) which did not prevent successful completion of this cohort.
logic sampling.
Total N
14
11
12
3
5
No patients discontinued therapy due to renal deterioration. Doses of 0.7 mg/m2 were
Toxicity meeting criteria for Dose Limiting Toxicity (DLT) included: Grade 4
Std Dev.
8.1
19.0
11.9
12.4
8.8
tolerable in Group D patients (CrCL< 20 mL/min/1.73 m2 ). Five dialysis pts. have been
neutropenia for 7 days or neutropenic fever; Grade 4 thrombocytopenia for
SE Mean
2.2
5.7
3.4
7.2
3.9
treated; 3 pts at 0.7 mg/m2, and 2 pts at 1.0 mg/m2. All tolerated therapy well. Based on
7 days; Grade 4 hemoglobin for 7 days; and grade 3 non hematologic toxic-
other clinical and safety data accrual to Groups D and E continues with dose levels es-
ity per NCI Common Toxicity Criteria Version 2.0. Renal toxicity was defined
Toxicities were very mild overall, despite the nature of a phase I organ
calated to 1.3 mg/m2.
as elevations of creatinine or decrease in creatinine clearance that moved a
dysfunction population. Dose limiting toxicity only occurred once, in
Conclusions: This study is the first comprehensive evaluation of bortezomib in pts.
patient into a more advanced group.
the moderate renal dysfunction cohort (Group C), a hypotensive event.
Other Grade 3 toxicities at least possibly related to therapy are tabu-
Conclusions
with various degrees of renal insufficiency including dialysis dependence. Bortezemib
Pts. underwent blood sampling for 20S proteasome activity pre-treatment and
at the approved dose of 1.3 mg/m2 on this schedule is well tolerated by pts with CrCL
at 1, 6, and 24 hours post treatment on days 1 and 8. The 20S proteasome in-
lated below. There were no Grade 4 toxicities fitting this attribution.
20 mL/min/1.73 m2. Preliminary analysis suggests that both bortezomib clearance and
hibition was assessed by a fluorogenic substrate assay conducted at Millen-
* = 1st Occurence
Bortezomib administered at 1.3 mg/m2 was well tolerated in all groups
proteasome inhibition are independent of renal function. Results of this trial will allow
nium Pharmaceuticals that followed the validated ex vivo proteasome assay
CYCLE 1* CYCLE 2+* OVERALL
Red = DLT
Number of Number of Number of
with CrCL 20 mL/min/1.73 m2
. Accrual continues at 1.3 mg/m2 in pts
for dosing recommendations for bortezomib use in pts. with renal insufficiency.
based on the chymotryptic:tryptic ratio method.
episodes
episodes
episodes
with CrCL < 20 mL/min/1.73 m2 and dialysis dependence but commer-
Additional blood was drawn and plasma extracted for assaying bortezomib
Toxicity
Grade 3
Grade 3
Grade 3
cial availability of bortezomib and clinical safety and efficacy data may
concentration on day 1 and day 8 pre-infusion and at the following time points
Hypotension
1
1
2
be barriers to accruing the remaining cohorts. Prospective assignment
post treatment: 5, 15, 30, and 60 minutes, and 2, 4, 6, 8, 12, and 24 hours. Bort-
Introduction
Diarrhea
1
1
2
to renal function cohorts normalized to body surface area and accrual
ezomib concentration was determined using a LC/MS/MS-based method. A
Motor Neuropathy
-
1
1
of multiple dialysis patients are additional strengths of our study.
liquid-liquid extraction method was used for sample preparation and analysis.
Neutropenia
-
2
2
Leukopenia
-
2
2
Pharmacokinetic and pharmacodynamic assays have been completed
One hundred fifty microliters of plasma were diluted with 10 µL of a stable
Bortezomib was recently approved by the U.S. FDA as therapy for multiple myeloma
Lymphopenia
1
5
6
for the high majority of patients accrued thus far. Bortezomib clear-
isotope-labeled internal standard (13C MP341) followed by 10 µL of 1% formic
Thrombocytopenia
2
7
9
9
pts. who have received at least one prior therapy. Evidence of activity in this setting
ance appears independent of renal function. The decline of bortezomib
acid in acetonitrile:water (50:50). The samples were then extracted with cold
Anemia
1
1
2
has been clear with a 27% response rate reported in a large phase II trial (1). More
clearance from day 1 to day 8 is consistent with prior observations.
0.1% formic acid in acetonitrile, evaporated, reconstituted and injected onto a
Dizzy/Lightheaded
-
1
1
recent data from a randomized phase III trial demonstrate superiority of bortezomib
The pharmacodynamic endpoint of 20S proteasome inhibition corre-
liquid chromatography/tandem mass spectrometry (LC/MS/MS) system for
Fatigue
1
2
3
in comparison to high dose dexamethasone in patients with previously treated mul-
lates with bortezomib concentration in each renal dysfunction group.
analysis. A reverse-phase gradient method provided sample stacking and
tiple myeloma(2). As a single agent, bortezomib is well tolerated; major side effects
Clinical: The median number of cycles delivered was 2, range =
separation. Bortezomib and the internal standard were ionized under a nega-
include dose dependent peripheral neuropathy, and myelosuppression followed by
1-26. Six patients had prolonged therapy (>6 cycles). There was 1
tive ion spray mode and detected through multiple-reaction monitoring (MRM).
orthostatic hypotension.
partial response (multiple myeloma); 30 pts had progression as best
Bortezomib clearance was calculated and tabulated by day of therapy and
In early phase trials, the pharmacodynamic effect of proteasome inhibition has been
response, and 20 had stable disease as best response.
References
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