Results of the PERSIST-1 phase III study of pacritinib
(PAC) versus best available therapy (BAT) in
primary myelofibrosis (PMF), post-polycythemia
vera myelofibrosis (PPV-MF), or post-essential
thrombocythemia-myelofibrosis (PET-MF)
Ruben A. Mesa,1 Miklos Egyed,2 Anita Szoke,3 Aleksandr Suvorov,4 Andrew Perkins,5
Jiri Mayer,6 Peter Ganly,7 Eric Jourdan,8 Harry C. Schouten,9 Patrizia Tosi,10
Charles Michael Farber,11 Pierre Zachee,12 Christof Scheid,13 James P. Dean,14
Paul Cernohous,14 Jyoti Nangalia,15 Jean-Jacques Kiladjian,16
Alessandro M. Vannucchi,17 Adam Mead,18 Claire N. Harrison19
1Mayo
Clinic, Scottsdale, AZ; 2Kaposi Mor Teaching Hospital, Kaposvar, Hungary; 3lbert Szent-Györgyi Clinical Center, Universisty of Szeged,
Szeged, Hungary; 4First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia; 5ICON Cancer Care, Brisbane, Australia; 6University Hospital Brno,
Brno, Czech Republic; 7Christchurch Hospital, Christchurch, New Zealand; 8Centre Hospitalier Universitaire de Nîmes, Nîmes, France;
9University Hosp Maastricht, Maastricht, Netherlands; 10Ospedale "Infermi", Rimini, Rimini, Italy; 11Morristown Memorial Hospital, Carol G. Simon
Cancer Center, Morristown, NJ; 12ZNA Stuivenberg, Antwerp, Belgium; 13University of Cologne, Cologne, Germany; 14CTI BioPharma Corp., Seattle,
WA; 15Cambridge Institute for Medical Research, Cambridge, United Kingdom; 16Hôpital Saint-Louis and Paris Diderot University, Paris, France;
17University of Florence, Florence, Italy; 18Oxford University Hospitals, Oxford, United Kingdom;
19Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Disclosures
• Employment – No relationships to disclose
• Leadership – No relationships to disclose
• Stock and other ownership interests – No relationships to disclose
• Honoraria – Novartis Healthcare A/S
• Consulting or advisory role – No relationships to disclose
• Speakers’ bureau – No relationships to disclose
• Research funding – CTI, Incyte, Gilead, Promedior, Genentech, Pharmessentia, Pfizer
• Patents, royalties, and other intellectual property – No relationships to disclose
• Expert testimony – No relationships to disclose
• Travel, accommodations and expenses – No relationships to disclose
• Other relationship – No relationships to disclose
Background
• Myelofibrosis is a rare hematologic malignancy, the symptoms of which
have a substantial negative impact on both patient quality of life and
overall survival1-3
• As early as 1 year from the time of diagnosis, the incidence of diseaserelated thrombocytopenia, anemia, and RBC transfusion requirements
increase dramatically4
• Thrombocytopenia is a prognostic factor for shorter overall survival and
risk of leukemic transformation5
• Current treatments have not demonstrated the ability to simultaneously
improve splenomegaly, symptoms, and cytopenias in myelofibrosis
patients
RBC, red blood cell.
1. Tefferi A, et al. Blood. 2013;122:1395-1398. 2. Mesa RA, et al. Cancer. 2007;109:68-76. 3. Geyer HL, et al. Blood. 2014;124:3529-3537. 4. Tefferi A, et al. Mayo Clin Proc.
2012;87:25-33. 5. Gangat N, et al. J Clin Oncol. 2010;29:392-397.
Pacritinib
A Selective JAK2/FLT3 Inhibitor
 Not associated with clinically significant
treatment-emergent anemia or
thrombocytopenia in clinical studies1
Kinase
JAK1
IC50 (nM)
1280
JAK2wt
6.0
JAK2V617F
9.4
JAK3
18.3
TYK2
27.0
FLT3-ITD
13.4
FLT3D835Y
4.7
CSF1R
39.5
IRAK1
13.6
CSF1R, colony stimulating factor 1 receptor; FLT, FMS-like tyrosine kinase; IC50, half-maximal inhibitory concentration; IRAK1, interleukin-1 receptor–associated kinase;
ITD, internal tandem duplication; JAK, Janus kinase; TYK, tyrosine kinase.
1. William AD, et al. J Med Chem. 2011;54:4638-465. 2. Hart S, et al. Leukemia. 2011;25:1751-1759.
PERSIST-1
Study Design
Key Eligibility Criteria
PMF, PET-MF, or PPV-MF
Pacritinib 400 mg qd
Intermediate- or high-risk disease
Palpable spleen ≥5 cm
No exclusion for baseline platelet levels;
stratified for platelet counts <100,000/µL and
<50,000/µL
R
(2:1)
N=327
Best Available
Therapy (BAT)a
No exclusion for baseline Hgb levels
No prior treatment with JAK2 inhibitors
excluding ruxolitinib
a Cross-over
from BAT allowed after progression or
after Week 24 assessment
• Stratification at randomization: platelet count, risk category, and region
• Study endpoints
• Primary: proportion of patients achieving a ≥35% reduction in spleen volume
•
(by MRI/CT) from baseline to Week 24
Secondary: proportion of patients with ≥50% reduction in TSS from baseline to
Week 24 on the Myeloproliferative Neoplasm Symptom Assessment Form
CT, computed tomography; Hgb, hemoglobin JAK, Janus kinase; MRI, magnetic resonance imaging; PET-MF, post-essential thrombocythemia myelofibrosis;
PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; R, randomized; TSS, total symptom score.
Patient Dispositiona
Median Follow-up: 8.4 months (Range, 0.1-22.2)
Randomized 2:1
PAC (ITT)
n=220
BAT (ITT)
n=107
PAC (Safety)
n=220
BAT (Safety)
n=106
Discontinued: n=96 (44%)
Adverse event: n=32 (15%)
Patient withdrawal: n=28 (13%)
Investigator decision: n=16 (7%)
Progressive disease: n=10 (5%)
Death: n=3 (1%)
Other: n=7 (3%)
Ongoing
n=124 (56%)
a
As of data cut off: Jan 17, 2015.
BAT, best available therapy; ITT,
intent-to-treat; PAC, pacritinib.
Discontinued: n=98 (92%)
Adverse event: n=3 (3%)
Patient withdrawal: n=3 (3%)
Investigator decision: n=78 (73%)
Progressive disease: n=12 (11%)
Death: n=1 (1%)
Non-compliance: n=1 (1%)
Crossed over to PAC
n=85 (79%)
Ongoing
n=9 (8%)
Baseline Characteristics
Characteristic
Median age, years (range)
≥65 years, n (%)
Male, n (%)
ECOG PS, n (%)
0-1
2-3
MF diagnosis, n (%)
Primary MF
Post-polycythemia vera MF
Post-essential thrombocythemia MF
IPSS score, n (%)a
Int-1
Int-2
High
Median spleen length by physical exam, cm (range)b
Median spleen volume by MRI/CT, cm3 (range)c
JAK2V617F positive, n (%)
a Derived
PAC
(n=220)
67
(23-87)
135
(61)
125
(57)
BAT
(n=107)
65
(37-84)
55
(51)
60
(56)
191
29
(87)
(13)
96
11
(90)
(10)
144
48
27
(65)
(22)
(12)
59
33
15
(55)
(31)
(14)
30
76
106
12
2223
154
(14)
(35)
(48)
(4-33)
(472-7948)
(70)
18
35
51
12
2367
92
(17)
(33)
(48)
(4-30)
(436-5404)
(86)
from central laboratory data; b n=219 for PAC, n=106 for BAT; c n=218 for PAC, n=107 for BAT.
BAT, best available therapy; CT, computed tomography; ECOG PS, Eastern Cooperative Oncology Group performance status; Int, intermediate; IPSS, International Prognostic
Scoring System; JAK, Janus kinase; MF, myelofibrosis; MRI, magnetic resonance imaging; PAC, pacritinib.
Baseline Characteristics
Hematology
Characteristic
BM biopsy completed, n (%)
Reticulin and collagen fibrosis staging
MF 0-1
MF 2-3
Missing
Peripheral blasts, n (%)
<1%
≥1%
<5%
≥5%
Missing
White blood cell count, n (%)
≤25 ×109/L
>25 ×109/L
Hemoglobin, n (%)
<10 g/dL
≥10 g/dL
Platelet count, n (%)
<50,000/μL
≥50,000 to <100,000/μL
≥100,000/μL
BAT, best available therapy; BM, bone marrow; Hgb, hemoglobin; MF, myelofibrosis; PAC, pacritinib.
PAC
(n=220)
219
(100)
BAT
(n=107)
107
(100)
32
180
7
(15)
(82)
(3)
18
83
6
(17)
(78)
(6)
78
94
(35)
(43)
44
38
(41)
(36)
159
13
48
(72)
(6)
(22)
74
8
25
(69)
(7)
(23)
177
43
(80)
(20)
80
26
(75)
(24)
84
136
(38)
(62)
47
59
(44)
(55)
35
37
148
(16)
(17)
(67)
16
18
73
(15)
(17)
(68)
BAT Treatment
WHO Drug Term, n (%)
BAT
(n=107)
Watch and wait (no active Tx)
27 (25.5)
Hydroxycarbamide
Prednisone
Interferon alfa
Thalidomide
Danazol
Prednisolone
Busulfan
Cytarabine
Peginterferon alfa-2a
59 (55.7)
7 (6.6)
6 (5.7)
6 (5.7)
4 (3.8)
4 (3.8)
2 (1.9)
2 (1.9)
2 (1.9)
BAT, best available therapy; Tx, treatment.
WHO Drug Term, n (%)
Anagrelide
Azacitidine
Epoetin alfa
Epoetin theta
Everolimus
Lenalidomide
Mercaptopurine
Methotrexate
Vincristine
BAT
(n=107)
1
1
1
1
1
1
1
1
1
(0.9)
(0.9)
(0.9)
(0.9)
(0.9)
(0.9)
(0.9)
(0.9)
(0.9)
Spleen Volume Reduction ≥35%
At Week 24 as Assessed by MRI/CT
Change From Baseline, %
• ITT population: 19.1% vs 4.7%, PAC vs BAT (p=0.0003)
• Evaluablea population: 25.0% vs 5.9%, PAC vs BAT (p=0.0001)
a
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
PAC (n=168)
BAT (n=85)
35% decrease
Patientsa
Evaluable Population: patients had both baseline and Week 24 spleen assessment by MRI or CT; n=168 for PAC and n=85 for BAT.
BAT, best available therapy; CT, computed tomography; ITT, intent to treat; MRI, magnetic resonance imaging; PAC, pacritinib.
Spleen Volume Reduction ≥35%
Patients With Baseline Thrombocytopenia
ITT
PAC
Evaluablea
BAT
p=0.0370
40%
33.3%
Patients
p=0.0451
30%
p=0.0072
p=0.0086
22.9%
20%
23.5%
16.7%
10%
0%
0%
<50,000/μL
a
0%
0%
<100,000/μL
<50,000/μL
Patients had both baseline and Week 24 spleen assessment by MRI or CT; n=168 for PAC and n=85 for BAT.
BAT, best available therapy; CT, computed tomography; ITT, intent to treat; MRI, magnetic resonance imaging; PAC, pacritinib.
0%
<100,000/μL
Correlation of SVR With OS By Treatment
Landmark Analysis at Week 24
Hazard Ratio (95% CI)a
p-value
≥10% to <20% (n=37)
0.15 (0.02, 1.18)
0.071
≥20% (n=98)
0.26 (0.09, 0.76)
0.014
2.31 (0.50, 10.81)
0.287
NA
NA
SVR
Pacritinib
BAT
≥10% to <20% (n=5)
≥20% (n=11)
a
Reference to < 10% SVR as assessed by MRI/CT.
BAT, best available therapy; CT, computed tomography; MRI, magnetic resonance imaging; NA, not applicable; OS, overall survival; SVR, spleen volume reduction.
Patients Achieving ≥50% Reduction in TSSa
At Week 24 (ITT Populationb)
PAC
30%
Patients
25%
BAT
p<0.0001
24.5%
p=0.4086
p=0.0677
p=0.0004
25.0%
24.3%
20.0%
20%
15%
10%
8.8%
6.5%
6.3%
5.5%
5%
0%
All Patients
a
<50,000/μL
TSS and TSS 2.0 combined; b n=220 for PAC and n=107 for BAT.
BAT, best available therapy; ITT, intent to treat; PAC, pacritinib; TSS, total symptom score.
<100,000/μL
≥100,000/μL
Platelet Subgroup
Patients Achieving ≥50% Reduction in TSSa
At Week 24 (Evaluable Populationb)
PAC
50%
BAT
p=0.0790
p<0.0001
41.9%
40.4%
p<0.0001
40.9%
p=0.3791
Patients
40%
31.8%
30%
16.7%
20%
10%
9.9%
11.1%
7.5%
0%
All Patients
<50,000/μL
<100,000/μL
≥100,000/μL
Platelet Subgroup
a
TSS and TSS 2.0 combined; b Patients had both baseline and Week 24 TSS value; n=132 for PAC and n=71 for BAT.
BAT, best available therapy; PAC, pacritinib; TSS, total symptom score.
Patients Achieving ≥50% Reduction in TSS
Reduction Over Time (Evaluable Populationa)
PAC
BAT
Patients with ≥50% Reduction in
Total Symptom Score, %
50
45
40
35
30
25
20
15
10
5
0
1
a
4
8
Patients had both baseline and the corresponding post-baseline TSS value.
BAT, best available therapy; ITT, intent to treat; TSS, total symptom score.
12
Weeks
16
20
24
Mean Change From Baseline, %
Mean % Change in Body Weight Over Time
2.5
PAC
2
BAT
1.5
1
0.5
0
-0.5
Baseline
BAT, best available therapy; PAC, pacritinib.
4
8
12
16
Weeks
20
24
36
Hemoglobin Over Time
By Central Laboratory
Mean % Change in Hgb (± SEM)
Mean Hgb (g/dL) (± SEM)
10
PAC
BAT
80
Mean Hgb (g/dL) (± SEM)
Mean % Change in Hgb (± SEM)
100
60
40
20
0
PAC
BAT
9.5
9
8.5
8
-20
BL
3 4
8
12
Weeks
16
20
24
BL
Safety Population
BAT, best available therapy; BL, baseline; Hgb, hemoglobin; SEM, standard error of the mean.
3 4
8
12
16
Weeks
Patients With Baseline
Hgb <10 g/dL
20
24
Platelets Over Time
By Central Laboratory
Mean Platelets×109/L (± SEM)
Mean % Change Platelets (± SEM)
60
PAC
BAT
Mean Platelets×109/L (± SEM)
Mean % Change Platelets (± SEM)
100
80
60
40
20
0
-20
50
p=0.0034a
40
30
20
p=0.1927a
10
0
BL
3 4
8
12
16
20
24
Weeks
Safety Population
a
PAC
BAT
Based on linear regression using mixed model.
BAT, best available therapy; BL, baseline; PAC, pacritinib; SEM, standard error of the mean.
BL
3 4
8
12
16
Weeks
Patients With Baseline
Platelets <50,000/μL
20
24
RBC Transfusion Independence
• At baseline, 15.9% PAC and 14.0% BAT patients were RBC transfusion
dependent, per Gale criteriaa
Patients Achieving Transfusion Independence
p=0.043
30%
25.7%
Patients
25%
PAC
BAT
20%
15%
10%
5%
0%
≥ 6units/90 days.
BAT, best available therapy; PAC, pacritinib; RBC, red blood cell.
a
0%
Most Common Adverse Events
Within 24 Weeks (by Investigator)
All Grades
Adverse Event, n (%)
PAC
(n=220)
BAT
(n=106)
Grade 3
PAC
(n=220)
Grade 4
BAT
(n=106)
PAC
(n=220)
BAT
(n=106)
Non-hematologic (>10%)
Diarrhea
117 (53.2)
13 (12.3)
11 (5.0)
0
0
0
Nausea
59 (26.8)
7 (6.6)
2 (0.9)
0
0
0
Vomiting
35 (15.9)
6 (5.7)
2 (0.9)
0
0
0
Peripheral edema
16 (7.3)
12 (11.3)
1 (0.5)
1 (0.9)
0
0
Pyrexia
11 (5.0)
11 (10.4)
4 (1.8)
1 (0.9)
0
0
Anemia
49 (22.3)
21 (19.8)
32 (14.5)
13 (12.3)
5 (2.3)
3 (2.8)
Thrombocytopenia
37 (16.8)
14 (13.2)
12 (5.5)
7 (6.6)
14 (6.4)
3 (2.8)
8 (3.6)
2 (1.9)
1 (0.5)
1 (0.9)
4 (1.8)
1 (0.9)
Hematologic (>2%)
Neutropenia
• 10% of patients in the PAC arm had dose reductions due to AE (3% diarrhea; 2% anemia)
AE, adverse event; BAT, best available therapy; PAC, pacritinib.
Side Effects of Interest
Gastrointestinal
• Majority of cases occur within the first 2 weeks
• Benefit (SVR, TSS) preserved irrespective of any gastrointestinal side
effects
• More frequent in patients aged >65 years and patients with platelets
<100,000/μL
• Diarrhea resolves in a little over 1 week irrespective of grade with
antimotility agents
• Diarrhea resulted in discontinuation or dose interruption (average 1 week)
in only 3 and 13 patients, respectively
SVR, spleen volume reduction; TSS, total symptom score.
Conclusions
• Significantly greater proportion of patients with ≥35% reduction of spleen
volume, regardless of baseline platelet count (p=0.0003)
• Significant treatment effect (p<0.05) in highest-risk subset (baseline platelets
<50,000/μL)
• Significant reduction in TSS (p<0.0001)
• Significantly higher proportion of patients became RBC transfusion
independent (p<0.05)
• Patients with baseline platelets <50,000/μL had mean increase in platelet
counts of 35% by Week 24
• Based on preliminary data, pacritinib may be disease modifying and warrants
combination studies with other potentially disease-modifying agents in MPNs
MPN, myeloproliferative neoplasm; RBC, red blood cell; TSS, total symptom score.
PERSIST-2
Study Design
Pacritinib
400 mg qd
Eligibility Criteria
Patients with platelet
counts ≤ 100,000/µL,
prior/current JAK2
therapy allowed
1:1:1
Randomizationa
N=300
Pacritinib
200 mg bid
Best available
therapy (BAT)b
Status: reached agreement with FDA on SPA October 2013
Sites: North America, Europe, Russia, and Oceania
Anticipated patient accrual: ~ 300
Principal investigator: Srdan Verstovsek
a Crossover
b BAT
from BAT allowed after progression or assessment of the primary endpoint.
may include ruxolitinib at the approved dose for platelet count
CT, computed tomography; JAK, Janus kinase; MRI, magnetic resonance imaging; TSS, total symptom score.
Co-Primary
Endpoints
% of patients achieving
≥35% reduction in
spleen volume from baseline
to Week 24 (MRI/CT)
Patients achieving ≥50%
reduction in TSS from
baseline to Week 24
Acknowledgments
• We would like to thank all the patients, investigators,
and personnel who contributed to this study
• Medical editorial assistance funded by CTI Biopharma
Corporation was provided by Nexus Global Group
Science, LLC