Novedades terapéuticas en neoplasias mieloproliferativas

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

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.

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

H Gisslinger, ASH 2016

Promotor: AOP Orphan Pharmaceuticals AG

H Gisslinger, ASH 2016

H Gisslinger, ASH 2016

H Gisslinger, ASH 2016

H Gisslinger, ASH 2016

H Gisslinger, ASH 2016

Promotor: AOP Orphan Pharmaceuticals AG

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

H Gisslinger, ASH 2016

H Gisslinger, ASH 2016

H Gisslinger, ASH 2016

H Gisslinger, ASH 2016

JO Mascarenhas, ASH 2016

PEGASYS (Roche): IFN-pegilado α-2a

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

JO Mascarenhas, ASH 2016

JO Mascarenhas, ASH 2016

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

JO Mascarenhas, ASH 2016

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.

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

PERSIST-2 Phase 3 Study Design

JO Mascarenhas, ASH 2016

Patient Demographics (Cont’d)(ITT Efficacy Population)

JO Mascarenhas, ASH 2016

Patient Disposition

JO Mascarenhas, ASH 2016

Study Treatment

JO Mascarenhas, ASH 2016

Efficacy Summary

JO Mascarenhas, ASH 2016

Efficacy: Analysis by Arm

15% 22% 3%

JO Mascarenhas, ASH 2016

14%32%17%

Overall Survival (Censored at Date of Clinical Hold)

JO Mascarenhas, ASH 2016

Serious TEAEs

JO Mascarenhas, ASH 2016

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%

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

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)

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)

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

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