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 disease-related 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.
Kinase IC50 (nM)
JAK1 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
Pacritinib A Selective JAK2/FLT3 Inhibitor
Not associated with clinically significant treatment-emergent anemia or thrombocytopenia in clinical studies1
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-1Study Design
• 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.
Key Eligibility Criteria
PMF, PET-MF, or PPV-MF
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
No exclusion for baseline Hgb levels
No prior treatment with JAK2 inhibitors
Best Available Therapy (BAT)a
excluding ruxolitinib
Pacritinib 400 mg qd
a Cross-over from BAT allowed after progression or after Week 24 assessment
R(2:1)
N=327
a As of data cut off: Jan 17, 2015. BAT, best available therapy; ITT, intent-to-treat; PAC, pacritinib.
Patient Dispositiona
Median Follow-up: 8.4 months (Range, 0.1-22.2)
PAC (ITT)n=220
BAT (ITT)n=107
Randomized 2:1
PAC (Safety)n=220
BAT (Safety)n=106
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%)
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%)
Ongoingn=9 (8%)
Ongoingn=124 (56%)
Crossed over to PACn=85 (79%)
Baseline Characteristics
a Derived 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.
Characteristic PAC(n=220)
BAT(n=107)
Median age, years (range) 67 (23-87) 65 (37-84)≥65 years, n (%) 135 (61) 55 (51)
Male, n (%) 125 (57) 60 (56)ECOG PS, n (%)
0-1 191 (87) 96 (90)2-3 29 (13) 11 (10)
MF diagnosis, n (%)Primary MF 144 (65) 59 (55)Post-polycythemia vera MF 48 (22) 33 (31)Post-essential thrombocythemia MF 27 (12) 15 (14)
IPSS score, n (%)a
Int-1 30 (14) 18 (17)Int-2 76 (35) 35 (33)High 106 (48) 51 (48)
Median spleen length by physical exam, cm (range)b 12 (4-33) 12 (4-30)Median spleen volume by MRI/CT, cm3 (range)c 2223 (472-7948) 2367 (436-5404)JAK2V617F positive, n (%) 154 (70) 92 (86)
Baseline CharacteristicsHematology
BAT, best available therapy; BM, bone marrow; Hgb, hemoglobin; MF, myelofibrosis; PAC, pacritinib.
Characteristic PAC(n=220)
BAT(n=107)
BM biopsy completed, n (%) 219 (100) 107 (100)Reticulin and collagen fibrosis staging
MF 0-1 32 (15) 18 (17)MF 2-3 180 (82) 83 (78)Missing 7 (3) 6 (6)
Peripheral blasts, n (%)<1% 78 (35) 44 (41)≥1% 94 (43) 38 (36)
<5% 159 (72) 74 (69)≥5% 13 (6) 8 (7)Missing 48 (22) 25 (23)
White blood cell count, n (%)≤25 ×109/L 177 (80) 80 (75)>25 ×109/L 43 (20) 26 (24)
Hemoglobin, n (%)<10 g/dL 84 (38) 47 (44)≥10 g/dL 136 (62) 59 (55)
Platelet count, n (%)<50,000/μL 35 (16) 16 (15)≥50,000 to <100,000/μL 37 (17) 18 (17)≥100,000/μL 148 (67) 73 (68)
BAT Treatment
WHO Drug Term, n (%)BAT
(n=107)WHO Drug Term, n (%)
BAT(n=107)
Watch and wait (no active Tx) 27 (25.5)
Hydroxycarbamide 59 (55.7) Anagrelide 1 (0.9)
Prednisone 7 (6.6) Azacitidine 1 (0.9)
Interferon alfa 6 (5.7) Epoetin alfa 1 (0.9)
Thalidomide 6 (5.7) Epoetin theta 1 (0.9)
Danazol 4 (3.8) Everolimus 1 (0.9)
Prednisolone 4 (3.8) Lenalidomide 1 (0.9)
Busulfan 2 (1.9) Mercaptopurine 1 (0.9)
Cytarabine 2 (1.9) Methotrexate 1 (0.9)
Peginterferon alfa-2a 2 (1.9) Vincristine 1 (0.9)
BAT, best available therapy; Tx, treatment.
Spleen Volume Reduction ≥35%At Week 24 as Assessed by MRI/CT
a 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.
• 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)C
han
ge
Fro
m B
asel
ine,
%
35% decrease
Patientsa
60
01020304050
-10-20-30-40-50-60-70-80-90
-100
PAC (n=168) BAT (n=85)
Spleen Volume Reduction ≥35%Patients With Baseline Thrombocytopenia
a 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.
ITT Evaluablea
0%
10%
20%
30%
40%
22.9%
16.7%
33.3%
23.5%
0% 0% 0% 0%
Pat
ien
ts
p=0.0451
p=0.0370
p=0.0086
p=0.0072
PAC BAT
<50,000/μL <100,000/μL <50,000/μL <100,000/μL
Correlation of SVR With OS By TreatmentLandmark Analysis at Week 24
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.
SVR Hazard Ratio (95% CI)a p-value
Pacritinib
≥10% to <20% (n=37) 0.15 (0.02, 1.18) 0.071
≥20% (n=98) 0.26 (0.09, 0.76) 0.014
BAT
≥10% to <20% (n=5) 2.31 (0.50, 10.81) 0.287
≥20% (n=11) NA NA
a 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.
Patients Achieving ≥50% Reduction in TSSa
At Week 24 (ITT Populationb)
Series10%
5%
10%
15%
20%
25%
30%
0.245
0.2
0.25 0.243
0.065 0.0630.088
0.055
Pat
ien
ts
All Patients
Platelet Subgroup
<50,000/μL <100,000/μL ≥100,000/μL
p<0.0001
p=0.4086
p=0.0677 p=0.0004PAC BAT
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 TSSa
At Week 24 (Evaluable Populationb)
Series10%5%
10%15%20%25%30%35%40%45%50%
0.409
0.318
0.419 0.404
0.099 0.1110.167
0.075
Pat
ien
ts
All Patients
p<0.0001
p=0.3791
p=0.0790 p<0.0001PAC BAT
Platelet Subgroup
<50,000/μL <100,000/μL ≥100,000/μL
Patients Achieving ≥50% Reduction in TSSReduction Over Time (Evaluable Populationa)
a Patients had both baseline and the corresponding post-baseline TSS value.BAT, best available therapy; ITT, intent to treat; TSS, total symptom score.
Weeks
50
45
40
35
30
25
20
15
10
5
0
Pat
ien
ts w
ith
≥50
% R
edu
ctio
n i
n
Tota
l S
ymp
tom
Sco
re,
%
PACBAT
1 4 8 12 16 20 24
Mean % Change in Body Weight Over Time
BAT, best available therapy; PAC, pacritinib.
4 8 12 16 20 24 36
-0.5
0
0.5
1
1.5
2
2.5
PAC BAT
Mea
n C
ha
ng
e F
rom
Bas
eli
ne
, %
Baseline Weeks
Series1-20
0
20
40
60
80
100
Weeks
Me
an
% C
ha
ng
e i
n H
gb
(±
SE
M)
Hemoglobin Over TimeBy Central Laboratory
BAT, best available therapy; BL, baseline; Hgb, hemoglobin; SEM, standard error of the mean.
Mean % Change in Hgb (± SEM) Mean Hgb (g/dL) (± SEM)
Safety Population Patients With Baseline Hgb <10 g/dL
Mea
n H
gb
(g
/dL
) (±
SE
M)
Weeks
10
9.5
9
8
8.5
PACBAT
PACBAT
BL 3 4 8 12 16 20 24 BL 3 4 8 12 16 20 24
Platelets Over TimeBy Central Laboratory
a Based on linear regression using mixed model.BAT, best available therapy; BL, baseline; PAC, pacritinib; SEM, standard error of the mean.
Mean Platelets×109/L (± SEM)Mean % Change Platelets (± SEM)
Safety Population Patients With Baseline Platelets <50,000/μL
Mea
n %
Ch
ang
e P
late
lets
(±
SE
M)
Weeks
100
80
60
-20
40
20
0
PACBAT
Mea
n P
late
lets
×10
9 /L
(±
SE
M)
Weeks
60
50
40
0
30
20
10
PACBAT
p=0.0034a
p=0.1927a
BL 3 4 8 12 16 20 24 BL 3 4 8 12 16 20 24
RBC Transfusion Independence
a ≥ 6units/90 days.BAT, best available therapy; PAC, pacritinib; RBC, red blood cell.
• At baseline, 15.9% PAC and 14.0% BAT patients were RBC transfusion dependent, per Gale criteriaa
Series10%
5%
10%
15%
20%
25%
30%25.7%
0%
PACBAT
p=0.043P
atie
nts
Patients Achieving Transfusion Independence
Most Common Adverse EventsWithin 24 Weeks (by Investigator)
AE, adverse event; BAT, best available therapy; PAC, pacritinib.
All Grades Grade 3 Grade 4
Adverse Event, n (%) PAC(n=220)
BAT(n=106)
PAC(n=220)
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
Hematologic (>2%)
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)
Neutropenia 8 (3.6) 2 (1.9) 1 (0.5) 1 (0.9) 4 (1.8) 1 (0.9)
• 10% of patients in the PAC arm had dose reductions due to AE (3% diarrhea; 2% anemia)
Side Effects of InterestGastrointestinal
• 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
MPN, myeloproliferative neoplasm; RBC, red blood cell; TSS, total symptom score.
• 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
PERSIST-2Study Design
CT, computed tomography; JAK, Janus kinase; MRI, magnetic resonance imaging; TSS, total symptom score.
Status: reached agreement with FDA on SPA October 2013
Sites: North America, Europe, Russia, and Oceania
Anticipated patient accrual: ~ 300
Principal investigator: Srdan Verstovseka Crossover from BAT allowed after progression or assessment of the primary endpoint.
b BAT may include ruxolitinib at the approved dose for platelet count
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
Best available therapy (BAT)b
Pacritinib400 mg qd
Pacritinib200 mg bid
Eligibility Criteria
Patients with platelet counts ≤ 100,000/µL,
prior/current JAK2 therapy allowed
1:1:1
Randomizationa
N=300
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
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