Microsoft PowerPoint - Jagannath-ASH 2010

Long-term treatment and tolerability of the
novel proteasome inhibitor carfilzomib
in patients with relapsed and/or refractory
multiple myeloma
Sundar Jagannath,1 Ravi Vij,2 Jonathan L. Kaufman,3 Thomas Martin,4 Ruben
Niesvizky,5 Nashat Y. Gabrail,6 Melissa Alsina,7 Lori Kunkel, 8Alvin F. Wong, 9
Leanne McCulloch,9 Alison L. Hannah,9 Michael Kauffman,9 and David S. Siegel10
1Mount Sinai Medical Center, New York, NY; 2Washington University School of
Medicine, Saint Louis, MO; 3Emory University School of Medicine, Winship Cancer
Institute, Atlanta, GA; 4University of San Francisco, San Francisco, CA; 5Weill
Cornell Medical College, New York, NY; 6Gabrail Cancer Center Research, Canton,
OH; 7H. Lee Moffitt Cancer Center, Tampa, FL; 8Independent Consultant, San
Francisco, CA; 9Onyx Pharmaceuticals, Emeryville, CA; 10The John Theurer
Cancer Center Hackensack University Medical Center, Hackensack, NJ

Background (cont)

Materials and Methods
· Patients who completed the full course of carfilzomib
therapy (4 cycles in PX-171-002,12 cycles in other
studies) on a given trial had the option to enter the PX-
171-010 extension study.
· Patients who completed the full course of carfilzomib
therapy (4 cycles in PX-171-002,12 cycles in other
studies) on a given trial had the option to enter the PX-
171-010 extension study.
· Patients could continue treatment until disease
progression or unacceptable toxicity.

Materials and Methods (cont)
Efficacy and Safety Analysis
· Tumor measurements and efficacy assessments were
carried out according to International Working Group
Uniform Response Criteria.4
· Extent of disease and objective response category
were assessed within 30 days prior to enrollment to
determine eligibility, and then at least every 3 months
throughout study participation and at the end of the
study.

Results
· The study with the greatest proportion of patients
continuing beyond 12 cycles of therapy was protocol
004 (15% of patients) (Table 2).

Results (cont)

Results (cont)
· · As of 9 November 2010, 32 of 46 patients (70%)
remain on treatment (Table 6).
9 patients have completed 12 cycles of carfilzomib dosing on
protocol 010 in addition to the 12 cycles received in the original
protocol. All 9 patients remain active as of 9 November 2010.
· Longest duration of treatment is 30 cycles (28 months)
for the compassionate use patient.

Results (cont)

Results (cont)
· Of the 9 patients who entered protocol 010 with a
VGPR, six remain active. Table 7 highlights details of
these 6 patients who have maintained a long-term
VGPR with single-agent carfilzomib.
Safety
· Adverse events (AEs) were similar to those reported in
other studies of single-agent carfilzomib (Table 8).
· Peripheral neuropathy and significant renal
dysfunction were not observed within this extension
trial.
· Cumulative toxicities were not observed.

Results (cont)

Results (cont)
· There were 6 serious AEs (SAEs) reported in 3 patients
in protocol 010.
4 SAEs were considered to be possibly related to carfilzomib:
pneumonia, dyspnea, bronchitis, and asthenia (1 patient each).
2 SAEs (pneumonia and influenza) were unlikely to be related to
carfilzomib.
· Doses were maintained or interrupted and restarted for
all of the patients with SAEs considered to be related
to carfilzomib.

Conclusions
· Combining 4 separate protocols exploring doses between 1527
mg/m2 of carfilzomib (n=575), 10% of patients (n=59) received 12
cycles of single-agent carfilzomib (twice weekly for 3 of 4 weeks).
Patients in the extension study had an overall time since myeloma
diagnosis of 6 years and a median of 3 prior lines of therapy (43%
of patients had received more than 4 prior lines of therapy).
· In the maintenance setting carfilzomib sustained disease control
and provided excellent long-term tolerability, with the option for
patients to switch to twice-weekly dosing every other week.
76% received 27 mg/m2 in the extension protocol.
43% had reduced dosing frequency.
As of 9 November 2010, 32 of 46 patients (70%) remain on
treatment.

Conclusions
· Carfilzomib is very well-tolerated for extended therapy:
Longest duration of treatment is 30 cycles (28 months).
9 patients have completed 12 cycles of carfilzomib dosing on
protocol 010 in addition to the 12 cycles received in the original
protocol. All 9 patients remain active as of 9 November 2010.
Drug-related SAEs were rare (n=3) and patients could continue to
receive carfilzomib upon recovery.
· Recently, higher carfilzomib doses (36, 45, and 56 mg/m2) have
been successfully administered using a 30-minute infusion with
dexamethasone premedication in Cycle 1.

Materials and Methods (cont)
Study Drug
· In this extension study, carfilzomib was initially administered by
slow IV bolus (over 2 to 10 min) at the same dose-level and
frequency as given in the last cycle of the patient's previous
carfilzomib study.
In the original trials, the majority of patients initially received
carfilzomib 20 mg/m2.
In some trials, the dose was escalated following Cycle 1 to 27
mg/m2 for up to 12 cycles.
· Carfilzomib was administered on Days 1, 2, 8, 9, 15, and 16 in a
28-day cycle.
The frequency of carfilzomib administration could be reduced to
twice weekly every other week at the discretion of the
investigator.

Results (cont)

Background
· Carfilzomib is a novel, selective peptide epoxyketone proteasome
inhibitor.1
· In preclinical studies, carfilzomib demonstrated properties distinct
from those of BTZ including: a lack of off-target acitivity and no
neurotoxicity in long-term (69 mo) chronic animal toxicology
studies.3
· Single-agent carfilzomib produces durable responses in relapsed
and/or refractory (R/R) multiple myeloma (MM).
Unlike bortezomib, no dose-limiting peripheral neuropathy has
been observed with carfilzomib.
Carfilzomib can be given to patients with substantial renal
dysfunction without dose adjustment or additional safety
concerns.
· Here we report on the clinical experience with long-term treatment
(>12 cycles, >11 months) with single-agent carfilzomib in patients
with MM. Included in the present analysis were patients with MM
who initially participated in other studies (Table 1).

Results (cont)
· 59 patients with R/R MM who had completed carfilzomib
treatment in a previous study enrolled in protocol 010 (this
includes 2 patients who were entered into compassionate
use, as the protocol was not yet open).
Patients from protocol 002 had received carfilzomib as a single agent
on that study.
Patients from protocols 003, 004, and 005 had received carfilzomib
with 4 mg of dexamethasone on those studies. 4 mg of
dexamethasone was given prior to each infusion in the first cycle for
prevention of treatment-related fever, rigors, chills, and/or dyspnea.
Patients were given the option to extend the premedication with 4 mg
of dexamethasone if they continued to be symptomatic to the
injection.As of 9 November 2010, data are available for 46 patients.
· Data on baseline demographics, prior dosing, and response
(Tables 3, 4, and 5, respectively) are presented below.

Results (cont)

Acknowledgments
· We would like to thank the co-investigators, research
nurses, study coordinators, and support staff, and all
of the patients and families who contributed to this
study. This study was supported by Onyx
Pharmaceuticals, Inc, Emeryville, CA. Editorial
assistance provided by Onyx Pharmaceuticals, Inc.
and Fishawack Communications, North Wales, PA.

References
1. Demo SD, et al. Cancer Res. 2007;67:63836391.
2. Kuhn DJ, et al. Blood. 2007;110:32813290.
3. Kirk CJ, et al. Blood (ASH Annual Meeting Abstracts).
2008;112:Abstract 2765.
4. Durie BG, et al. Leukemia. 2006;20:14671473.

Results (cont)