Pacritinib, a Dual JAK2/FLT3 Inhibitor: Integrated

Pacritinib, a Dual JAK2/FLT3 Inhibitor:
Integrated Efficacy and Safety Analysis of
Phase II Trial in Patients with Primary and
Secondary Myelofibrosis with Platelet
Counts ≤100,000/µl
Rami S Komrokji, MD1, Ruben A. Mesa, MD2,
James P. Dean, MD, PhD3, Lixia Wang, PhD3,
Han Myint, MD3, John F. Seymour, MBBS, FRACP, PhD4*,
and Srdan Verstovsek, MD, PhD5
1Malignant
Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ
3Cell Therapeutics, Inc., Seattle, WA
4Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, Australia
2Division
5Department
of Leukemia, Division of Cancer Medicine, The University of Texas, MD
Anderson Cancer Center, Houston, TX
Background
•  Platelet counts ≤100,000/µL in myelofibrosis (MF)1
–  Independent prognostic marker for leukemic
transformation
–  Associated with inferior survival
–  ~1/3 of all patients with MF
•  Most clinical studies excluded patients with platelet
counts of <100,000/µL or <50,000/µL
–  Treatment emergent thrombocytopenia is a limitation of
most JAK1/JAK2 inhibitors
1Huang
et al, Cancer 2008, 112(12)2726
Pacritinib: A Selective JAK2/FLT3 Inhibitor
Kinase
IC50 (nM)
JAK1
1280
JAK2wt
23
JAK2V617F
19
JAK3
520
TYK2
50
FLT3
22
FLT3-D835Y
6
•  Pacritinib (SB1518): oral,
selective, dual JAK2/FLT3
inhibitor
•  Potent inhibition of JAK2-STAT3
-STAT5 pathway without
myelosuppression in preclinical
studies
•  Did not appear to be associated
with clinically significant
treatment emergent anemia or
thrombocytopenia in early clinical
studies
William et al, J Med Chem 2011, 54:4638
Hart et al, Leukemia 2011, 25:1751
Analysis Of 2 Phase II Trials Of Pacritinib In Patients
With Baseline Platelet Counts Of ≤100,000/µl
•  International Phase II studies (001, 003) conducted between
2010-2012 (n=65)
–  Pacritinib dosed 400 mg oral once daily
–  Spleen size assessed by physical exam (PE) and MRI
–  Patient-reported outcomes assessed using the
Myelofibrosis Symptom Assessment Form (MF-SAF)1
–  Standard adverse event (AE) reporting and central
laboratory testing
•  Databases were integrated to evaluate safety and efficacy in
patients with baseline platelet counts of ≤100,000/µL or
>100,000/µL
1
Mesa et al, Leuk Res 2009, 33(9)1199
Overview of the Phase 2 Studies in This
Pooled Analysis
•  Inclusion/Exclusion Criteria
–  Myelofibrosis patients requiring therapy who were relapsed,
refractory, or without other treatment options
–  Splenomegaly
–  Typical I/E criteria for ECOG PS, Liver, Renal, Cardiac function and
recent/ongoing medical history, no concurrent CYP3A4 meds
–  Essentially identical between the studies, except exclusion for prior
JAK2 on SB1518-003 only
Subgroup Distribution by Phase 2 Study
≤100k
>100k
SB1518-001
13
18
SB1518-003
15
19
Demographics
Baseline Platelets
≤100,000/µL
(n=28)
Baseline Platelets
>100,000/µL
(n=37)
All
(n=65)
69 (46-85)
68 (44-85)
68 (44-85)
19 (68%)
28 (76%)
47 (72%)
Primary MF
21 (75%)
19 (51%)
40 (62%)
Post-PV MF
5 (18%)
11 (30%)
16 (25%)
Post-ET MF
2 (7%)
7 (19%)
9 (14%)
Intermediate-1
3 (11%)
11 (30%)
14 (22%)
Intermediate-2
11 (39%)
9 (24%)
20 (31%)
High
4 (14%)
10 (27%)
14 (22%)
DIPSS indeterminate *
10 (36%)
7 (19%)
17 (26%)
JAK2V617F positive, N (%)
23 (82%)
29 (78%)
52 (80%)
Age, Median (range)
Male, N (%)
MF Diagnosis, N (%)
DIPSS Risk Category, N (%)
* DIPSS was calculated post-hoc and could not be calculated for these patients
Baseline Hematologic Parameters
Baseline Platelets Baseline Platelets
≤100,000/µL
>100,000/µL
(n=28)
(n=37)
All
(n=65)
Platelet Count (x103/ml)
Mean (SD)
Median (IQR)
Range
Platelet transfusions
within 180 days prior to
study screening, N (%)
Hemoglobin (g/dl),
Median (range)
RBC transfusions within
180 days prior to study
screening, N (%)
56 (± 23)
261 (± 147)
173 (± 151)
59
(34-70)
227
(163-315)
121
(60-238)
15-97
104-859
15-859
3 (11%)
0 (0%)
3 (5%)
8.8 (3.7-14)
10.7 (7.4-14.4)
9.7 (3.7-14.4)
13 (46%)
13 (35%)
26 (40%)
Pacritinib Exposure - Duration And Intensity
Baseline
Platelets
≤100,000/µL
(n=28)*
Baseline
Platelets
>100,000/µL
(n=37)*
All
(n=65)
90 (± 13)
87 (± 19)
88 (± 17)
46.6 (± 28.3)
43.0 (± 30.4)
44.6 (± 29.3)
46.9 (5.7-86.4)
40.9 (1.3-87.4)
44.1 (1.3-87.4)
≥6 Months
18 (64%)
22 (60%)
40 (62%)
≥12 Months
13 (46%)
15 (41%)
28 (43%)
≥18 Months**
4 (31%)
7 (39%)
11 (36%)
Pacritinib
400 mg QD
Relative Dose Intensity (%)
Mean (± SD)
Duration on Treatment (weeks)
Mean Weeks (± SD)
Median Weeks (range)
* No significant differences were observed between the two groups
**Only study 001 was included because study 003 was closed before all
patients reached 18 months of observation.
Spleen response
Baseline Platelets
≤100,000/µL
(n=28)*
Baseline Platelets
>100,000/µL
(n=37)*
All
(n=65)
Up to 24
weeks
12 / 28 (43%)
14 / 34 (41%)
26 / 62 (42%)
Up to last
visit on
treatment
13 / 28 (46%)
14 / 35 (40%)
27 / 63 (43%)
Up to 24
weeks
7 / 23 (30%)
6 / 26 (23%)
13 / 49 (27%)
Up to last
visit on
treatment
10 / 23 (44%)
8 / 26 (31%)
18 / 49 (37%)
Time Period
Endpoint
≥ 50%
Reduction in
spleen size by
PE
≥ 35%
Reduction in
spleen volume
by MRI
* No significant differences were observed between the two groups
≥50% Reduction In Patient-reported
Symptom Score*
Baseline Platelets
≤100,000/µL
(n=28)**
Baseline Platelets
>100,000/µL
(n=37)**
All
(n=65)
Up to 24
weeks
11 / 28 (39%)
16 / 34 (47%)
27 / 62 (44%)
Up to last
visit on
treatment
13 / 28 (46%)
17 / 34 (50%)
30 / 62 (48%)
* The symptom score is the sum of the individual scores for worst fatigue, early satiety,
abdominal pain or discomfort, night sweats, itching and bone pain reported on the MFSAF (Mesa et al, Leuk Res 2009, 33(9)1199).
** No significant differences were observed between the two groups
Mean Percent Change in
Platelet Count (± SEM)
Mean Percent Change in
Platelet Count (± SEM)
Mean Percent Change in
Platelet Count (± SEM)
Platelet Count Change Over Time
Baseline platelets ≤100,000/µL
Baseline platelets >100,000/µL
Baseline platelets >350,000/µL
Hemoglobin Change Over Time
Baseline platelets >100,000/µL
Mean Percent Change in
Hemoglobin (± SEM)
Mean Percent Change in
Hemoglobin (± SEM)
Baseline platelets ≤100,000/µL
Most Common Non-hematologic AEs
(occurring in 15% or more of patients overall*)
Preferred Term
Baseline Platelets
≤100,000/µL (n=28)
Baseline Platelets
>100,000/µL (n=37)
All Grade
Grade 3-4
All Grade
Grade 3-4
Diarrhea
25 (89%)
5 (18%)
30 (81%)
3 (8%)
Nausea
14 (50%)
0 (0%)
17 (46%)
1 (3%)
Fatigue
14 (50%)
5 (18%)
16 (43%)
4 (11%)
Vomiting
11 (39%)
0 (0%)
11 (30%)
1 (3%)
Abdominal Pain
8 (29%)
1 (4%)
10 (27%)
4 (11%)
Pruritis
5 (18%)
0 (0%)
12 (32%)
2 (5%)
Peripheral Edema
7 (25%)
1 (4%)
8 (22%)
0 (0%)
Insomnia
5 (18%)
0 (0%)
9 (24%)
0 (0%)
Bone Pain
4 (14%)
2 (7%)
7 (19%)
2 (5%)
Dyspnea
3 (11%)
1 (4%)
7 (19%)
0 (0%)
* Of note, there were no thrombocytopenia-associated AEs occurring at
this frequency in either group
Pacritinib: Conclusions
•  Demonstrated encouraging spleen size and patientreported symptom score reduction regardless of
baseline platelet counts
•  Duration of exposure and daily dose were unaffected by
starting platelet counts
•  There was no apparent association with clinically
significant treatment emergent anemia or
thrombocytopenia
•  A Phase III trial, PERSIST-2, will evaluate pacritinib in MF
patients with platelet counts ≤ 100,000/µL vs. BAT,
including ruxolitinib
•  The PERSIST-1 Phase III trial, which compares pacritinib
to BAT, not including a JAK2 inhibitor, is currently
enrolling, has no upper or lower limit for platelet counts
Acknowledgements
•  Patients and Families
•  All the SB1518-001 and -003 Investigators
–  Srdan Verstovsek, University of Texas MD Anderson Cancer Center
–  Ruben Mesa, Mayo Clinic Scottsdale
–  Rami Komrokji, H. Lee Moffitt Cancer Center & Research Institute
–  John Seymour, Peter MacCallum Cancer Centre
–  H. Joachim Deeg, Fred Hutchinson Cancer Research Center
–  Toyosi Odenike, University of Chicago Comprehensive Cancer Center
–  Andrew Roberts, Royal Melbourne Hospital, The Walter and Eliza Hall
Institute of Medical Research
–  Bik To, Royal Adelaide Hospital Cancer Centre
–  Martha Wadleigh, Dana Farber Cancer Institute
•  CTI support for this presentation (Mary Campbell, MD, Paul Cernohous,
MS, Susan Caldwell, PhD)