-
Ph I l ti f fil ibPhase I evaluation of carfilzomib (PR-171) in
hematological ( ) g
malignanciesA K i h S O A O’C M liA. Keith Stewart, Owen A.
O’Conner, Melissa
Alsina, Suzanne Trudel, Andre Goy, and Robert Z Orlowskiand
Robert Z. Orlowski
ASCO Annual MeetingASCO Annual MeetingJune, 2007
-
Clinical Rationale for PR-171Clinical Rationale for PR-171
P t i hibiti h b lid t d• Proteasome inhibition has been
validated as a therapeutic strategy
• Bortezomib therapeutic hypothesis– Proteasome inhibition of 65
- 80% is proven to be
effective and safe– Full recovery of proteasome activity may be
required
between doses to reduce toxicitybetween doses to reduce
toxicity
• PR-171 therapeutic hypothesisI t i d t i d t i hibiti b–
Intensive and sustained proteasome inhibition can be tolerated and
will improve efficacy
2
-
Proteasome Inhibitor ComparisonBiochemical mechanism and
selectivity
PR-171 BortezomibIrreversible
(keto-epoxide tetrapeptide)Slowly reversible
(boronic acid dipeptide)Highly selective for chymotrypsin-like
Inhibits both chymotrypsin-like and caspase-g y y yp
active site within the proteasomey yp p
like activities of the proteasome
Highly selective for proteasome N-terminal threonine active
sites
Cross reactivity with serine proteases
20S proteasome particle β-subunit ring
IC50s (nM)
N terminal threonine active sites
αβ
β5*
pPR-171 Bortezomib
Chymotrypsin-like 6 7β
βα
β1β2* *
like
Caspase-like 2400 74
Trypsin-like 3600 4200
3
ββ yp
* Three distinct N-terminal threonine protease active sites
-
PR-171 Pre-Clinical Summary
Proteasome activity recovers with t1/2~24 hr( t th i )
Cellular
(new proteasome synthesis)
One-hour treatments (mimicking in vivo exposure) are more
cytotoxic with PR 171 than with bortezomibactivities more cytotoxic
with PR-171 than with bortezomib
PR-171 is cytotoxic to primary MM patient cells and b t ib i t t
ll libortezomib-resistant cells lines
Daily dosing regimens with PR-171 are well tolerated
In vivo Proteasome inhibition at MTD is greater in most tissues
with PR-171 (>80%) than with bortezomib (65-75%)properties
( ) ( )
Daily dosing schedules with PR-171 (e.g., QDx2) are most
efficacious than day 1, 4 schedule in xenograft
4models
-
PR-171 (Carfilzomib) Phase 1 Studies• Two parallel studies in
hematologic malignancies
with two dose scheduleswith two dose schedules• Multiple myeloma
(MM), non Hodgkin’s lymphoma (NHL),
Waldenstrom’s macroglobinemia (WM), Hodgkin’s disease (HD) •
Relapse or refractory >2 prior treatments• Prior bortezomib
allowed, < grade 2 neuropathy allowed
M difi d Fib i (3 3) d i• Modified Fibonacci (3+3) design
• Primary objectives: Safety, establish maximum t l bl
dtolerable dose
• Secondary objectives: Anti-tumor efficacy, y j
ypharmacokinetics, pharmacodynamics
• Subjects treated to intolerable toxicity or5
Subjects treated to intolerable toxicity or progressive
disease
-
Phase 1 Dose Schedules
0
D1 D5 PX-171-001D140
bitio
n • QDx5; 9 day rest• 2 week cycle
C ti i80
ome
inhi
b • Continuous suppression of proteasome activity
80
1 2
prot
easo
D2 D8 D9D10
D15 D16 PX-171-002QD 2 kl f 3
D28
% p 0 • QDx2 weekly for 3
weeks; 12 day rest• 4 week cycle80
Time (weeks)1 2 3 4
• Prevent full recovery of proteasome between doses
Effi i
80
6
Efficacious proteasome
inhibition threshold
-
PX-171-001 (QDx5) Dose Escalation( )September 2005-April
2007
Disease type ResponsesNHL/ MM/Cohort N NHL/ HD
MM/WD PR MR SD
1.2-8.4 mg/m2 15 11 4 3 NHL11 mg/m2 3 2 1 1 MM 1 MCL*15 mg/m2 3
1 2 1 WM20 mg/m2 5 3 2 1 MM20 mg/m2 5 3 2 1 MM
Total 27 18 9 1 2 4*Dose escalatedDose escalated
Objective responses in 3/5 MM/WM patients at ≥ 11 mg/m2
7
-
PX-171-002 (QDx2) Dose Escalation(Q )September 2005-April
2007
Disease type ResponsesNHL/Cohort N NHL/HD MM/WD PR MR SD
1.2-8.4 mg/m2 16 10 64* (1 MM,
3 NHL)g
3 NHL)11 mg/m2 4 2 2 1 MM*15 mg/m2 3 1 2 1 MM*15 mg/m 3 1 2 1
MM20 mg/m2 3 1 2 1 MM27 mg/m2 6 1 5 2 MM 1 MM 1 MM
Total 37 16 21 4 1 6*Dose escalated
8Objective responses in 5/9 MM patients at ≥ 15 mg/m2
-
Clinical MM Activity Summary• Responses characterized by rapid
decline in M-protein• Responses in heavily pre-treated patientsp y
p p
– Average of 5 prior therapies – Bortezomib,
thalidomide/lenalidomide, transplant failures
• Duration of response 55+ 288+ days• Duration of response 55+ -
288+ days– Onset of response d15 to d49
2-01-005 (15 mg/m2)
200225
200225
2-01-012 (MM; 27 mg/m2)800 6
100125150175200
100125150175200
20 mg/m2
KappaLightChain
UrinaryM-Protein(mg/24 hr) 300
400500600700
3
4
5
SerumM-protein
(g/dL)
-300 -200 -100 0 100 200 3000
255075
0255075(mg/L) (mg/24 hr)
-900 -3000
100200300
0
1
2
-200 -100 0 100
(g/dL)
9
Study Day Study Day
-
R d PX 171 001 (QD 5)Responders – PX-171-001 (QDx5)
Diagnosis(dose cohort)
ORDOT
(days)# prior ther. Vel Thal Rev SCT
1-04-005 MM (11 mg/m2 ) PR 78 5 + + - -
1-05-003 WM (15 mg/m2) MR 75 7 - - - -
1-04-008 MM (20 mg/m2) MR 45 10 ++ + + ++
• 4 SD patients (1 MM, 1 T-cell NHL, 2 MCL) with duration on
therapy 112 to 223 days py y
• Responding patients have been discontinued due to “t t t f ti
”
10“treatment fatigue”
-
Responders PX 171 002 (QDx2)Responders – PX-171-002 (QDx2)
Diagnosis(dose cohort)
ORTTP
(days)# prior ther. Vel Thal Rev SCT
2-01-005 MM (15 →20 mg/m2) PR 288+ 5 - - - +
2-01-008 MM (20 mg/m2) PR 233 6 + - - +
2-01-009 MM (27 mg/m2) PR 134+ 6 ++ + + -
2-01-011 MM (27 mg/m2) MR 134 4 - + ++ +
2-01-012 MM (27→ 20 mg/m2) PR 100+ 4 + + - +
• 6 SD patients (2 MM, 1 T cell NHL, 2 MCL) with duration on
therapy 189+ to 413 days
11
-
Pharmacokinetics and Pharmacodynamics
• Preclinical studies in rats and monkeys show that carfilzomib
is cleared from plasma within minutescarfilzomib is cleared from
plasma within minutes
• Serum concentrations approach the limits of detection within 1
hourdetection within 1 hour
• Pharmacokinetic parameters unlikely to guide selection of
doseselection of dose
• Pharmacodynamics of proteasome activity provides a more
biologically relevant characterizationa more biologically relevant
characterization– Assay measures chymotrypsin-like proteasome
activity– Whole blood and mononuclear cells examined
12
-
Pharmacodynamics: Proteasome Inhibition and Clinical Acti
itInhibition and Clinical Activity
Whole Blood PDWhole Blood PD(PX-171-001 and PX-171-002)
100110
y ol)
Assays performedone hour after first
dose of cycle 1
708090
100
e ac
tivity
e co
ntro
NHL/HD
MM/WM
30405060
teas
ome
pred
ose MM/WM
non-responders
MM/WM
1 100 300
1020
Prot
(% o
f MM/WMresponders(PR/MR)
≥80% proteasome inhibition achieved at doses above 15 mg/m2
Dose (mg/m2)
13
≥80% proteasome inhibition achieved at doses above 15 mg/m2
-
Proteasome Recovery in PBMC –PX-171-002 (QDx2)
Red blood cell
100
120
ity trol
)
PBMC
dosing
60
80
100
ome
activ
dose
con
t
2-01-0072-01-0082-02-016
20
40
Prot
easo
% o
f pre
-d Average
QDx2 schedule
0 1 2 3 4 5 6 7 8 90
Day
P(%
0 1 2 3 4 5 6 7 8 9
QDx2 schedule20 mg/m2
Day
Red blood cell proteasome activity fails to recover
between Day 2 and Day 8 due t i ibl h i
PBMC proteasome activity recovers between Day 2 and
Day 8 due to new t th i
14
to irreversible mechanism proteasome synthesis
-
Safety and Tolerability: Phase 1Safety and Tolerability: Phase 1
• Majority of AEs are Grade 1 or 2Majority of AEs are Grade 1 or
2
– Gastrointestinal (nausea, vomiting, diarrhea)– Systemic
(fatigue, pyrexia)Systemic (fatigue, pyrexia)– Neurologic
(headache)– Respiratory (cough dyspnea)Respiratory (cough,
dyspnea)
• Grade 2/3 reversible ↑ creatinine following 1st dose in four
patients heralding rapid decreases in M-spikep g p p– 3/5 MM
patients at 27 mg/m2, 1/6 MM patients at 20 mg/m2
– Event is self-limiting if drug is held, effect does not occur
on rechallenge, subsequent treatment well tolerated
• Reversible Grade 3/4 thrombocytopenia in patients enrolled
with Grade 2 thrombocytopenia
15
enrolled with Grade 2 thrombocytopenia• Painful peripheral
neuropathy has not been reported
-
DLT d MTD PX 1 1 001 (QD )DLT and MTD – PX-171-001 (QDx5)
Dose level Cycle/Day Event Comment
20 mg/m2 Cycle 1/ Day 4 Febrile neutropeniaResolved, continued
on
study
Cycle 1/ Not resolved20 mg/m2 Cycle 1/ Day 3 ThrombocytopeniaNot
resolved,
discontinued (PD)
• DLTs to date are hematologic• MTD not established• Study
continues to enroll at 15 mg/m2
16
-
DLT and MTD PX 171 002 (QDx2)DLT and MTD – PX-171-002 (QDx2)
Dose level Cycle/Day Event Comment
27 mg/m2 Cycle 1/ D 8 ThrombocytopeniaResolved, continued on
t d27 mg/m Day 8 Thrombocytopenia study
27 mg/m2 Cycle 1/ Day 2 HypoxiaResolved, rapid response and
continued on studyDay 2 and continued on study
20 mg/m2 Cycle 1/Day 2Acute Renal
Failure Recovering
• DLTs to date are hematologic, hypoxia and ↑Cr• 20 mg/m2
established as a “tolerable dose”• 27 mg/m2 necessitates further
management of first
17dose effect
-
Carfilzomib Phase I Summaryy• Carfilzomib is a novel
irreversible inhibitor selective for the
chymotrypsin-like active site of the proteasome y yp p•
Carfilzomib promotes >80% proteasome inhibition in blood• Dose
limiting toxicitiesDose limiting toxicities
– Myelosuppression: cyclic reversible thrombocytopenia and
neutropenia
– A “first dose effect” has occurred at doses >20 mg/m2 and
heralds rapid decline in M-protein
• Objective responses have been observed at doses of carfilzomib
ranging from 11 mg/m2 to 27 mg/m2
R id t f ( 1 th)– Rapid onset of response (1 year
-
Carfilzomib Development Planp
• Carfilzomib will be further investigated in bothCarfilzomib
will be further investigated in both hematologic malignancies and
solid tumors
– Ongoing expansion to treat NHL patients
• Phase 2 studies are beginning in refractory MMPhase 2 studies
are beginning in refractory MM and relapsed MM patients through the
Multiple Myeloma Research ConsortiumMyeloma Research Consortium
• A Phase 1b study is planned for solid tumors
19
-
Creatinine (1st week, QDx2)
3 5
4.0
4.5
Doses
20 mg/m2
2.0
2.5
3.0
3.5
2-01-0072-01-0082-02-0212-02-016
Patient # Disease Response Doses withheld
MMMM PRFL
MCLatin
ine
(mg/
dL)
1 2 3 4 5 6 7 8 9ne
0.0
0.5
1.0
1.5 2-01-0162-01-0172-06-005
MMMM #3MM
Cre
a
Bas
elin
Day
2 5
3.027 mg/m2
1.5
2.0
2.5
2-01-0092-01-0112-01-012
Patient # Disease ResponseDoses
withheld
MM PR #2, 3, 4MM MRMM PR #3, 4ni
ne (m
g/dL
)
0.0
0.5
1.02-02-0182-02-0172-06-004
MMMCLMMC
reat
in
20
1 2 3 4 5 6 7 8 9
Bas
elin
e
0.0
Day
-
Creatinine Plots (QDx2 27mg/m2)Creatinine Plots (QDx2, 27mg/m
)2-01-009 (MM, 27 mg/m2) (PR) 2-01-011 (MM, 27 mg/m2) (MR)
2
3 Dosecycle 1 cycle 2
(mg/
dL)
1.5
2.0
2.5 Dosecycle 1 cycle 2
(mg/
dL)
0
1
0
Cre
atin
ine
0 0
0.5
1.0
Cre
atin
ine
B0 0
0 10 20 30 40 50Day
B0.0
0 10 20 30 40 50day
2-01-012 (MM, 27→20 mg/m2) (PR)( , g ) ( )
2
3 1000cycle 1 (27) cycle 2 (20)
mg/
dL)
1
Cre
atin
ine
(m
21B
0 00 10 20 30 40 50
day