A phase 1b/2 study of prolonged infusion carfilzomib in patients with relapsed and/or refractory multiple myeloma: updated efficacy and tolerability from the completed 20/56 mg/m2 expansion cohort of PX-171-007

1. A phase 1b/2 study of prolonged infusion carfilzomib in patients with relapsed and/or refractory multiple myeloma:
updated efficacy and tolerability from the completed 20/56 mg/m expansion cohort of PX-171-007
2
KP Papadopoulos, P Lee, S Singhal, JR Holahan, DH Vesole, S Rosen, L Kunkel, N Zojwalla, AL Hannah, DS Siegel
1 2 3 1 4 3 5 6 6 4
1
The START Center for Cancer Care, San Antonio, TX; 2Tower Cancer Research Foundation, Beverly Hills, CA; 3Northwestern University School of Medicine, Chicago, IL; 4John Theurer Cancer Center, Hackensack, NJ; 5Independent Consultant, San Francisco, CA; 6Onyx Pharmaceuticals, Emeryville, CA
Antitumor activity Figure 1. Pharmacokinetics of carfilzomib* Table 6. Treatment emergent adverse events of any grade (regardless
Introduction Results • A total of 28 patients were evaluable for efficacy (Table 3). of causality) in ≥25% of patients in the 20/56 mg/m2 cohort
– 20 patients were evaluable in the 20/56 mg/m2 cohort. PK Parameter 20 mg/m2 36 mg/m2 45 mg/m2 56 mg/m2 Event 20/36 20/45 20/56 20/70 Total
• Carfilzomib is a selective next-generation epoxyketone proteasome inhibitor Patients – 4 patients from this cohort withdrew, 3 due to early-onset toxicity (including
(n=26) (n=9)† ( n=9)† (n=10) mg/m2 mg/m2 mg/m2 mg/m2 (N=33)
of the chymotrypsin-like activity of both the constitutive proteasome and • A total of 33 patients were enrolled (4 at 20/36 mg/m2; 3 at 20/45 mg/m2; hypertension, neutropenia, and thrombocytopenia) that prevented escalation Cmax (ng/mL) 985 ±641 1795 ±957 1902 ±884 2513 ±1527 (n=4) (n=3) (n=24) (n=2)
immunoproteasome which binds irreversibly to the proteasome. 24 at 20/56 mg/m2; 2 at 20/70 mg/m2). to 56 mg/m2. One patient withdrew consent.
AUClast (hr ng/mL) 385 ±253 690 ±365 862 ±363 1018 ±416 Hematologic
• In patients with multiple myeloma (MM), single-agent carfilzomib is active with • Patient demographic information and baseline characteristics are detailed AUCinf (hr ng/mL) 387±255 691 ±368 864 ±366 1025 ±424 Thrombocytopenia 1 (25) 1 (33) 9 (38) 2 (100) 13 (39)
• ORR for the expanded 20/56 mg/m2 cohort was 60%, including data for 2 t½ (hr) 1.0 ±0.5 1.2 ±0.8 1.1 ±0.2 1.2 ±1.0
acceptable safety and tolerability at doses up to 27 mg/m2 when administered in Table 1. Anemia 2 (50) 1 (33) 9 (38) 0 (0) 12 (36)
patients still currently on study (Table 3). CL (L/hr) 146 ±87 123 ±54 129 ±54 124 ±43 Non hematologic
intravenously over 2–10 minutes.1
Table 1. Baseline demographics, disease characteristics, and • Median DOR for the 20/56 mg/m2 cohort was 8 months and median TTP as well 10000
Fatigue 3 (75) 3 (100) 13 (54) 1 (50) 20 (61)
• Based on preclinical safety data showing that a slower infusion was better as PFS was 7 months (Table 4). Nausea 3 (75) 2 (67) 13 (54) 1 (50) 19 (58)
tolerated and permitted higher doses than a 2–10 minute infusion, the phase treatment history Pyrexia 2 (50) 1 (33) 13 (54) 1 (50) 17 (52)
Plasma Conc. (ng/mL)
1000
1b/2 PX-171-007 (NCT00531284) study is evaluating a 30-minute infusion of Characteristic 20/36 20/45 20/56 20/70 Total Dyspnea 1 (25) 0 (0) 13 (54) 0 (0) 14 (42)
carfilzomib using a modified stepped-up dosing regimen.2 mg/m2 mg/m2 mg/m2 mg/m2 (N=33) Table 3. Best response to carfilzomib for all dose groups 100
Hypertension 2 (50) 1 (33) 10 (42) 1 (50) 14 (42)
(n=4) (n=3) (n=24) (n=2) Chills 1 (25) 2 (67) 9 (38) 0 (0) 12 (36)
• In myeloma, the dose-escalation phase identified a maximum tolerated dose Best Response (evaluable 20/36 20/45 20/56 20/70 Vomiting 2 (50) 1 (33) 8 (33) 1 (50) 12 (36)
Gender, n (%)
(MTD) of 56 mg/m2, with encouraging activity and an acceptable safety profile.3 Male 2 (50) 2 (67) 17 (71) 1 (50) 22 (67)
patients), n (%) mg/m2 mg/m2 mg/m2 mg/m2 10
Headache 1 (25) 1 (33) 8 (33) 0 (0) 10 (30)
(n=3) (n=3) (n=20)* (n=2)*
• Here we report the updated results from this dose-expansion phase of Age, years Diarrhea 0 (0) 1 (33) 6 (25) 1 (50) 8 (24)
sCR 0 (0) 0 (0) 1 (5) 0 (0) 0
this ongoing study, including interim efficacy and safety data for the Median (range) 63 (60–67) 73 (66–77) 63.5 (45–81) 69.5 (61–78) 65 (45–81) Insomnia 0 (0) 1 (33) 7 (29) 0 (0) 8 (24)
CR 0 (0) 0 (0) 0 (0) 0 (0)
20/56 mg/m2 cohort. Prior chemotherapeutic regimens
0.1
Dizziness 0 (0) 0 (0) 7 (29) 0 (0) 7 (21)
VGPR 0 (0) 0 (0) 4 (20) 1 (50)
(including transplants)
PR 2 (67) 1 (33) 7 (35) 0 (0)
I
I
I
I
OI
OI
OI
I
I
Median (range) 3 (1–6) 4 (4–5) 4.5 (2–9) 5 (4–6) 4(1–9)
PS
PS
EO
EO
EO
EO
tE
tE
tE
MR 0 (0) 1 (33) 1 (5) 1 (50)
Methods
ECOG Performance Status, n (%)
in
15
Conclusions
st
st
st
os
os
os
5m
po
po
po
SD 1 (33) 1 (33) 4 (20) 0 (0)
np
np
np
0 4 (100) 0 (0) 8 (33) 0 (0) 12 (36)
in
in
in
PD 0 (0) 0 (0) 3 (15) 0 (0)
mi
mi
mi
5m
0m
0m
1–2 0 (0) 3 (100) 16 (67) 2 (100) 21 (64)
15
30
60
ORR (sCR + CR + VGPR + PR) 2 (67) 1 (33) 12 (60) 1 (50)
12
24
• Patients ≥18 years of age, ECOG performance status 0–2 with relapsed and/or Antibody, n (%)
EOI, end of infusion; PSI, prior to start of infusion
• The 60% ORR attained with the 20/56 mg/m2 dose of single-agent carfilzomib
IgG Lambda 1 (25) 1 (33) 2 (8) 1 (50) 5 (15) *Data include treatment ongoing for 2 patients in the 56 mg/m2 cohort and 1 patient in the 20/70 mg/m2 cohort (at 56 mg/m2).
refractory MM after ≥2 prior treatment regimens were eligible for the study. administered as a 30-min IV infusion is noteworthy in this heavily pretreated
IgG Kappa 1 (25) 2 (67) 9 (38) 1 (50) 13 (39)
• In each 28-day cycle (C): IgA Lambda 0 (0) 0 (0) 2 (8) 0 (0) 2 (6)
*Data from patients with potential sampling errors and a single outlier patient (56 mg/m2 group) were excluded in the descriptive analysis. patient population with a median of 4.5 prior regimens.
C1D1 and C2D16 data combined.
Table 4. Time to event efficacy of carfilzomib for the 20/56 mg/m2
†
– Carfilzomib was given as a 30-min intravenous (IV) infusion on days (D) 1, 2, IgA Kappa 0 (0) 0 (0) 4 (17) 0 (0) 4 (12) • An acceptable safety profile was reported in the dose group.
8, 9, 15, and 16. Kappa 0 (0) 0 (0) 3 (13) 0 (0) 4 (12) dose group • PK and PDn results reinforce proportional increase in activity of carfilzomib with
– C1D1 & 2 doses were 20 mg/m2, followed by cohort escalation to 36, 45, 56,
Lambda 1 (25) 0 (0) 4 (17) 0 (0) 4 (12)
Median, months 20/56 mg/m2 Figure 2. Pharmacodynamics of carfilzomib higher doses, without affecting the clearance and t1/2.
Other (Urine total protein) 1 (25) 0 (0) 0 (0) 0 (0) 1 (3)
or 70 mg/m2 (stepped-up dosing). Duration of response, (n=12) • These results support the preclinical data that longer infusion times enable
PBMC higher doses and achieve greater levels of proteasome inhibition suggesting
– Prior to infusion of carfilzomib, dexamethasone (4 mg for ≤45 mg/m2, 8 mg Dosing information Median, (95% CI) 8.0 (6.2–8.7)
(Normalized to Pre-Dose of Same Day)
100 that higher dosing may lead to higher efficacy with an acceptable safety profile.
for >45 mg/m2) was given as premedication to mitigate potential • In the phase 1b portion of this study, patients received stepped-up carfilzomib Time to progression, (n=20) 20 mg/m2 (N=16)
infusion-related reactions. These findings are being explored in the clinical investigation of higher doses of
doses ranging from 36 mg/m2 to 70 mg/m2. Median, (95% CI) 7.0 (1.9–8.4)
80 56 mg/m2 (N=10–12)
– The MTD was defined as the highest dose at which ≤33% of patients carfilzomib administered via 30-min IV infusion.
• No DLTs were seen in the initial 20/36 mg/m2, 20/45 mg/m2, or 20/56 mg/m2 Progression free survival, (n=20)
experienced treatment-related dose-limiting toxicity (DLT) during the first dose cohorts. Median, (95% CI) 7.0 (1.9–8.4)
cycle or, when appropriate, the maximum planned dose. 60
• Reversible DLTs were recorded in 2 patients in the 20/70 mg/m2 cohort;
% Activity
• Study endpoints both patients were successfully rechallenged and continued on treatment at
– Overall response rate [ORR; stringent complete response (sCR) + complete reduced doses. Pharmacokinetic and pharmacodynamic analysis 40
response (CR) + very good partial response (VGPR) + partial response (PR)] • MTD was determined as 56 mg/m2 and this cohort was expanded to a total of • PK analysis demonstrates a proportional increase in Cmax and AUC with
throughout the study period 24 patients. increasing dose, without affecting t1/2 or clearance of carfilzomib (Figure 1). 20 References
– Duration of response (DOR) • At 20/56 mg/m2, 38% of patients have started at least 7 cycles of treatment and • PDn analysis demonstrated an increased inhibition of proteasome 1. Siegel DS, et al. J Clin Oncol. 2011;29:Abstract 8027. 2. Yang J, et al. Drug Metab Dispos.
79% did not require dose reductions due to an AE (Table 2). chymotrypsin-like activity and all 3 subunits of immunoproteasome with a 0 2011;39(10):1873-82. 3. Papadopoulos KP, et al. Haematology. 2011;96(Suppl 2):Abstract 0898.
– Median duration of progression-free survival (PFS) and time to progression
(TTP) higher dose of carfilzomib (Figure 2). 4. Durie BGM, et al. Leukemia. 2006;20:1467-73. 5. Bladé J, et al. Br J Haematol. 1998;102:1115-23.
Table 2. Patient exposure to carfilzomib • At 56 mg/m2, >75% of total immunoproteasome activity is inhibited. 6. Rajkumar SV, et al. Blood. 2011;117(18)4691-5.
– Pharmacokinetic (PK) and pharmacodynamic (PDn) parameters of
20/36 20/45 20/56 20/70 Total
carfilzomib mg/m2 mg/m2 mg/m2 mg/m2 (N=33) CT-L, chymotrypsin-like activity of constitutive proteasome; LMP7, CT-L activity of immunoproteasome; MECL1, trypsin-like activity of
– Safety analysis (n=4) (n=3) (n=24) (n=2) Safety analysis
immunoproteasome; LMP2, caspase-like activity of immunoproteasome Acknowledgments
• Responses were determined according to the International Myeloma Working Cycles started, n • The most common ≥G3 AEs in the 20/56 mg/m2 cohort were thrombocytopenia We would like to thank the co-investigators, research nurses, study coordinators, and support staff,
Group Uniform Response Criteria with minimal response (MR) per European and all of the patients and families who contributed to this study. Thanks also are due to Susan Lee,
Mean (SD) 7.8 (6.5) 4.0 (2.0) 4.8 (3.3) 9.5 (9.2) 5.3 (4.1) (38%), anemia (21%), and hypertension (13%) (Table 5).
Zhengping Wang, Jessica Taylor, Darrin Bomba, and Lois Kellerman of Onyx Pharmaceuticals.This
Blood and Marrow Transplantation Group criteria included, on C1D15 and Median (min, max) 6.0 (2, 17) 4.0 (2, 6) 3.5 (1, 11) 9.5 (3, 16) 4.0 (1, 17)
• The majority of the AEs in this cohort were G1–2 in severity (Table 6). Table 5. Treatment emergent adverse events ≥ Grade 3 (regardless
Cycles, n (%) study was supported by Onyx Pharmaceuticals, Inc, South San Francisco, CA. Editorial assistance
D1 of each subsequent cycle.4,5
1–3 1 (25) 1 (33) 12 (50) 1 (50) 15 (46) • There was 1 report of peripheral neuropathy (G1) in the 20/56 mg/m2 cohort. of causality) in ≥5% of patients in the 20/56 mg/m cohort
2
provided by Onyx Pharmaceuticals, Inc. and Fishawack Communications, North Wales, PA.
• Pharmacokinetic (PK) analyses were performed on samples obtained at 4–6 2 (50) 2 (67) 3 (13) 0 (0) 7 (21) Event 20/36 20/45 20/56 20/70 Total
C1D1 and C2D16. 7–9 0 (0) 0 (0) 6 (25) 0 (0) 6 (18) mg/m2 mg/m2 mg/m2 mg/m2 (N=33)
• Peripheral blood samples for pharmacodynamic (PDn) analysis were collected 10–12 0 (0) 0 (0) 3 (13) 0 (0) 3 (9) (n=4) (n=3) (n=24) (n=2) Disclosures
Kyriakos P. Papadopoulos: Consultancy for Proteolix; Research Funding for Proteolix and Onyx Pharmaceuticals. Peter Lee: No relevant
on C1D1 and C1D8 or C2D1. >12 1 (25) 0 (0) 0 (0) 1 (50)* 2 (6) Hematologic financial relationship(s) to disclose. Seema Singhal: Speakers Bureau for Celgene and Millennium; Research Funding for Onyx
Pharmaceuticals. Joseph R. Holahan: Consultancy and Research Funding for Onyx Pharmaceuticals. David H. Vesole: Board of Directors
Dose reductions due to AE, n (%) Anemia 0 (0) 1 (33) 5 (21) 0 (0) 6 (18)
• Safety assessments were graded by CTCAE v3.0. 0 3 (75) 0 (0) 19 (79) 0 (0) 22 (67)
or advisory committee membership for Celgene; Speakers Bureau for Celgene and Millennium. Steven T. Rosen: No relevant financial
relationship(s) to disclose. Lori Kunkel: Consultancy for VLST Biotech, Threshold, and Onyx Pharmaceuticals. Alison L. Hannah:
Neutropenia 0 (0) 0 (0) 2 (8) 0 (0) 2 (6)
• Treatment-related adverse events (AEs) occurring during C1 were defined as 1 1 (25) 2 (67) 4 (17) 2 (100) 9 (27) Thrombocytopenia 0 (0) 1 (33) 9 (38) 2 (100) 12 (36)
Consultancy for Onyx Pharmaceuticals. David Siegel: Consultancy, Honoraria, and Board of Directors or advisory committee membership
for Millennium and Celgene.
DLT as follows: ≥Grade (G) 2 neuropathy with pain, ≥G3 non-hematologic ≥2 0 (0) 1 (33) 1 (4) 0 (0) 2 (6) Non hematologic
toxicity, G4 neutropenia >7 days, febrile neutropenia, G4 thrombocytopenia Discontinued study drug early, n (%) 3 (75) 3 (100) 22 (92) 1 (50) 29 (88) Dyspnea 0 (0) 0 (0) 2 (8) 0 (0) 2 (6)
lasting >7 days despite withholding carfilzomib, G3/4 thrombocytopenia with Primary reason for discontinuation, n (%) Fatigue 0 (0) 0 (0) 2 (8) 0 (0) 2 (6)
Progressive disease 3 (75) 3 (100) 11 (46) 1 (50) 18 (55)
bleeding, or ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal Hypertension 0 (0) 0 (0) 3 (13) 0 (0) 3 (9)
Adverse event 0 (0) 0 (0) 7 (29) 0 (0) 7 (21) Hypoxia 0 (0) 0 (0) 2 (8) 0 (0) 2 (6)
antiemetic/antidiarrheal therapy. Withdrew consent 0 (0) 0 (0) 3 (13) 0 (0) 3 (9) Pneumonia 0 (0) 0 (0) 3 (13) 0 (0) 3 (9)
Other 0 (0) 0 (0) 1 (4)† 0 (0) 1 (3)
*Patient ongoing at 56 mg/m2.
†
Patient qualified for autologous stem cell transplantation
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