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Novedades terapéuticas en Novedades terapéuticas en neoplasias neoplasias mieloproliferativasmieloproliferativasneoplasias neoplasias mieloproliferativasmieloproliferativas
Juan Carlos Hernández Boluda
Hospital Clínico Universitario de Valencia
2ª Reunión Científica GEMFIN
Madrid, Abril 2017
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Tratamiento de la TE y PV
• Final results from the phase 3 trial ARETA comparing a novel extended-release anagrelide formulation to placebo in ET pts with defined risk status(abstr 0476).
– H. Gisslinger, University of Vienna, Austria.
• Final results from PROUD-PV a randomized controlled phase 3 trial• Final results from PROUD-PV a randomized controlled phase 3 trialcomparing Ropeginterferon alfa-2b to hydroxyurea in PV patients (abstr0475).
– H. Gisslinger, University of Vienna, Austria.
• Interim analysis of the MPD-RC 112 global phase III trial of front-linepegylated interferon vs. Hydroxyurea in high risk PV and ET (abstr 0479).
– J.O. Mascarenhas, Icahn School of Medicine at Mount Sinai, NY, US.
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Development goals are to achieve:– lower peak plasma
concentration of anagrelide– reduction of the frequency
and intensity of peak-concentration related adverse events (AEs)
– easier dosing scheme (once daily vs. 2-3 times daily)
Anagrelide extended release
H Gisslinger, ASH 2016
daily vs. 2-3 times daily)– improved patient compliance
Extended release tablet containing 2mg anagrelide
Strength based on 60-70% bio-availability compared to commercial immediate release formulations
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H Gisslinger, ASH 2016
Promotor: AOP Orphan Pharmaceuticals AG
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H Gisslinger, ASH 2016
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H Gisslinger, ASH 2016
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H Gisslinger, ASH 2016
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H Gisslinger, ASH 2016
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H Gisslinger, ASH 2016
Promotor: AOP Orphan Pharmaceuticals AG
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AOP2014 (n=127) HU (n=127)
Caucasian 100% 100%
WHO2008 PV *) 100% 100%
Female 53.5% 52.8%
Age (median, range) 60 (30-85) 60 (21-81)
Disease duration (median, range) 1.9 month (0-146) 3.6 month (0-126)
AOP2014 (n=127) HU (n=127)
Caucasian 100% 100%
WHO2008 PV *) 100% 100%
Female 53.5% 52.8%
Age (median, range) 60 (30-85) 60 (21-81)
Disease duration (median, range) 1.9 month (0-146) 3.6 month (0-126)
Patient baseline demographics
Disease duration (median, range) 1.9 month (0-146) 3.6 month (0-126)
HU pretreated 47 (37%) 47 (37%)
Hematocrit (mean, SD) 49.5% (±5.4) 49.8% (±5.5)
Spleen length (median, range) 13.1 cm (7.0-25.0) 13.0 cm (7.5-24.5)
Spleen normal/slightly enlarged **) 90.6% 88.2%
Spleen length >17cm/>22cm 9.4%/2.4% 11.8%/3.9%
Mean JAK2V617F burden 42% 43%
Disease duration (median, range) 1.9 month (0-146) 3.6 month (0-126)
HU pretreated 47 (37%) 47 (37%)
Hematocrit (mean, SD) 49.5% (±5.4) 49.8% (±5.5)
Spleen length (median, range) 13.1 cm (7.0-25.0) 13.0 cm (7.5-24.5)
Spleen normal/slightly enlarged **) 90.6% 88.2%
Spleen length >17cm/>22cm 9.4%/2.4% 11.8%/3.9%
Mean JAK2V617F burden 42% 43%
*) confirmed by bone marrow biopsy**) slightly enlarged >12/13cm (f/m) – 17cm
*) confirmed by bone marrow biopsy**) slightly enlarged >12/13cm (f/m) – 17cm
H Gisslinger, ASH 2016
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H Gisslinger, ASH 2016
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H Gisslinger, ASH 2016
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H Gisslinger, ASH 2016
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H Gisslinger, ASH 2016
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JO Mascarenhas, ASH 2016
PEGASYS (Roche): IFN-pegilado α-2a
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Baseline characteristics of first 75 patients on the MPD -RC 112 trial
HU (n=39) PEG (n=36) Total (n=75) P
Value*
Age, years median (range) 66 (28-85) 56 (20-71) 61 (20-85) <0.001
Gender, Female 19 (49%) 16 (44%) 35 (47%) 0.71
MPN subtype, ET/PV 16 (41%) /23 (59%) 15 (42%)/21 (58%) 31 (41%) /44 (59%) 0.95
JAK2V617F 36 (92%) 32 (89%) 68 (91%) 0.51
ECOG PS, 0 34 (87%) 29 (81%) 63 (84%) 0.44
Age >60 years 27 (69%) 15 (42%) 42 (56%) 0.02
History of venous thrombosis 6 (15%) 5 (14%) 11 (15%) 0.86
HU (n=39) PEG (n=36) Total (n=75) P
Value*
Age, years median (range) 66 (28-85) 56 (20-71) 61 (20-85) <0.001
Gender, Female 19 (49%) 16 (44%) 35 (47%) 0.71
MPN subtype, ET/PV 16 (41%) /23 (59%) 15 (42%)/21 (58%) 31 (41%) /44 (59%) 0.95
JAK2V617F 36 (92%) 32 (89%) 68 (91%) 0.51
ECOG PS, 0 34 (87%) 29 (81%) 63 (84%) 0.44
Age >60 years 27 (69%) 15 (42%) 42 (56%) 0.02
History of venous thrombosis 6 (15%) 5 (14%) 11 (15%) 0.86
* Based on t-test for continuous variables and z-test for binary variables.- -
History of venous thrombosis 6 (15%) 5 (14%) 11 (15%) 0.86
History of arterial thrombosis 4 (10%) 9 (25%) 13 (17%) 0.09
Cardiovascular risk factors 25 (64%) 16 (44%) 41 (55%) 0.09
Palpable spleen 10 (26%) 7 (19%) 17 (23%) 0.52
Spleen length by palpation (cm
below left costal margin)
1.5 (0-10) 1.0 (0-10) 1.3 (0-10) 0.52
Spleen length by ultrasound (cm) 12.4 (0-18) 13.0 (0-20.2) 12.6 (0-20.2) 0.90
Leukocytes (x 109/L) 10.3 (4.8-20.0) 8.1 (4.0-23.4) 9.3 (4.0-23.4) 0.43
Hemoglobin (g/dL) 14.1 (12.1-22.4) 14.4 (11.3-16.6) 14.4 (11.3-16.6) 0.17
Hematocrit (%) 45.7 (36.2-70.2) 43.9 (33.5-60.7) 45.0 (33.5 -70.2) 0.33
Platelets (x 109/L) 615 (142-1444) 538 (112-1382) 592 (112-1444) 0.24
History of venous thrombosis 6 (15%) 5 (14%) 11 (15%) 0.86
History of arterial thrombosis 4 (10%) 9 (25%) 13 (17%) 0.09
Cardiovascular risk factors 25 (64%) 16 (44%) 41 (55%) 0.09
Palpable spleen 10 (26%) 7 (19%) 17 (23%) 0.52
Spleen length by palpation (cm
below left costal margin)
1.5 (0-10) 1.0 (0-10) 1.3 (0-10) 0.52
Spleen length by ultrasound (cm) 12.4 (0-18) 13.0 (0-20.2) 12.6 (0-20.2) 0.90
Leukocytes (x 109/L) 10.3 (4.8-20.0) 8.1 (4.0-23.4) 9.3 (4.0-23.4) 0.43
Hemoglobin (g/dL) 14.1 (12.1-22.4) 14.4 (11.3-16.6) 14.4 (11.3-16.6) 0.17
Hematocrit (%) 45.7 (36.2-70.2) 43.9 (33.5-60.7) 45.0 (33.5 -70.2) 0.33
Platelets (x 109/L) 615 (142-1444) 538 (112-1382) 592 (112-1444) 0.24
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JO Mascarenhas, ASH 2016
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JO Mascarenhas, ASH 2016
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Complete Histopathologic Bone Marrow Response at 12 mo by Blinded Central
Review
HU PEG
ET+PV 8/22 2/24
Histopathology Criteria� Normalized BM
cellularity � < grade 2 reticulin
fibrosis
ET 5/10 2/10
PV 3/12 0/14
� ET: Disappearance of
megakaryocyte
hyperplasia, and
abnormal
megakaryocyte
histotopography
� PV: Disappearance of
trilineage hyperplasia
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JO Mascarenhas, ASH 2016
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Tratamiento de la MF
• Results of the PERSIST-2 phase 3 study of pacritinib vs. Best availabletherapy, including ruxolitinib, in pts with MF and platelet counts<100,000/µl (LBA-5).
– J.O. Mascarenhas, Icahn School of Medicine at Mount Sinai, NY, US.
• Momelotinib therapy in myelofibrosis: 6-years follow-up data on safety,efficacy and the impact of mutations on overall and relapse-free survivalefficacy and the impact of mutations on overall and relapse-free survival(abstr 1123).
– A. Tefferi, Mayo Clinic, Rochester, US.
• Ensayos fase 3 de momelotinib en mielofibrosis (Simplify 1 & 2)– Avance de resultados por Gilead.
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Background
• MF is a life-threatening hematologic malignancy characterized by splenomegaly and debilitating constitutional symptoms1-3
– ~1/4 of MF pts present with thrombocytopenia;4 platelets <50,000/µL associated with reduced QoL,1 more severe symptom burden, and shorter overall survival5
• Approved JAK1/2 inhibitor RUX reduces splenomegaly and symptoms, but is associated with dose-limiting cytopenias and not indicated for pts with platelets <50,000/µL6,7with platelets <50,000/µL6,7
• PAC: oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, & CSF1R8
• PERSIST-1 trial : sustained spleen volume reduction (SVR) and symptom control with PAC vs BAT (excluding JAK2 inhibitors) in pts with MF regardless of baseline platelet count 9
• PAC placed on full clinical hold by the US FDA (2/8/2016) due to concerns over interim survival results, bleeding, and cardiovascular events
JO Mascarenhas, ASH 2016
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PERSIST-2 Phase 3 Study Design
JO Mascarenhas, ASH 2016
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Patient Demographics (Cont’d)(ITT Efficacy Population)
JO Mascarenhas, ASH 2016
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Patient Disposition
JO Mascarenhas, ASH 2016
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Study Treatment
JO Mascarenhas, ASH 2016
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Efficacy Summary
JO Mascarenhas, ASH 2016
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Efficacy: Analysis by Arm
15% 22% 3%
JO Mascarenhas, ASH 2016
14%32%17%
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Overall Survival (Censored at Date of Clinical Hold)
JO Mascarenhas, ASH 2016
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Serious TEAEs
JO Mascarenhas, ASH 2016
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Momelotinib in MF: 6 -years follow -upPhase 1-2 trial (n=100)
• DIPSS+: High/Int-2 99%
• Median follow-up: 3.2 yrs
• Discontinuation: 88 pts
• Peripheral neurotoxicity G1/2: 47%
A Tefferi, ASH 2016
• Peripheral neurotoxicity G1/2: 47%
• Anemia response: 44%
• Spleen response: 43%
• SRV at 5 yr: 32%
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Ensayos fase 3 de momelotinib en mielofibrosis
JAK inhibitor naïve
• Randomized, Double Blind
• Primary endpoint: Spleen Response by MRI at week 24
Ruxolitinib + placebo
N = 420 1:1
randomization
Momelotinib + placebo
Previous JAK inhibitor exposure
• Randomized, Open Label
• Required ruxolitinib dose adjustment to < 20mg BID and concurrent hematologic toxicity
• Primary endpoint: Spleen Response by MRI at week 24
N = 150 2:1
randomization
MomelotinibN = 100
Best Available Therapy (ruxolitinib and no treatment allowed)
N = 50
Day 1 Week 24 Year 5
Year 5Day 1 Week 24
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Ensayos Simplify: datos no publicados
SIMPLIFY-1
• Objetivo 1º: resp. esplénica sem 24:– 26.5% Momelotinib– 29% Ruxolitinib� No inferioridad (p=0.011)
SIMPLIFY-2
• Objetivo 1º: resp. esplénica sem 24:– 6.7% Momelotinib– 5.8% BAT (88% ruxolitinib)� Superioridad (p=0.90)� No inferioridad (p=0.011)
• Objetivo 2º: resp. control síntomas:– Ruxolitinib mejor
� Superioridad (p=0.90)
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Inhibidores de cinasas JAK en MF
Ruxolitinib (Jakavi ®) Novartis JAK1, JAK2 Aprobado
Momelotinib (CYT387) Gilead JAK1, JAK2 III (retirado)
Pacritinib (SB1518) CTI-Bio/Baxalta JAK2, FLT3 III
NS-018 NS Pharma JAK2 I/II
Agente Compañía Diana Fase
NS-018 NS Pharma JAK2 I/II
Itacitinib (INCB039110) Incyte JAK1 II
Fedratinib (SAR302503) Sanofi JAK2, FLT3 III (retirado)
Gandotinib (LY2784544) Lilly JAK2 I (retirado)
Lestaurtinib (CEP701) Cephalon JAK2, FLT3 II (retirado)
AZD1480 AstraZeneca JAK2, JAK1 I (retirado)
XL019 Exelixis JAK2 I (retirado)
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Fármacos frente a otras dianas
PEG-IFN α-2a (Pegasys ) Roche Inmunomodulador II
Nivolumab BMS PD1 II
Panobinostat (Faridak ) Novartis Histona deacetilasa II
Azacitidina (Vidaza®) Pharmion Metiltransferasa II
Sonidegib (LDE225) Novartis Smoothened Ib/II
Agente Compañía Diana Fase
Saridegib (IPI926) Infinity Hedgeh og I
Imetelstat Geron/Janssen Telomerasa II
Buparlisib (BKM120) Novartis PI3K I
Everolimus (Afinitor®) Novartis mTOR I/I
Luminespib (AUY922) Novartis HSP90 II
Simtuzumab (GS6624) Gilead LOXL2 II
PRM151 Promedior Agonista PTX2 II
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Estudios de combinación de ruxolitinib con otros fármacos en mielofibrosis
Ruxo + danazol (fase II)
Ruxo + pomalidomida (fase I-II)
Ruxo + lenalidomida (fase II)
Ruxo + panobinostat (fase I-II)
Ruxo + azacitidina (fase II)
Ruxo + buparlisib (fase I)
Ruxo + sonidegib (fase Ib-II)
Ruxo + interferón α2 (fase II)
Ruxo + nilotinib + prednisona (fase Ib-II)
www.ClinicalTrials.gov