What is next: Emerging JAK2 inhibitor combination studies. Alessandro M. Vannucchi. Section of Hematology, University of Florence, Italy

Transcription

1 ymposium JAK2 Inhibition in Myelofibrosis: What Can We Expect in the Clinic? 4 5 May 2012 Lisbon, Portugal What is next: Emerging JAK2 inhibitor combination studies Alessandro M. Vannucchi ection of Hematology, University of Florence, Italy Reasons for performing combination trials with JAK2 inhibitors To increase the benefits seen with JAK2 inhibitors (splenomegaly, symptoms) as well as to bring additional benefits (anemia, BM fibrosis, clone) To reduce unwanted side effects (anemia, thrombocytopenia) yet maintaining clinical benefits To facilitate stem cell transplantation 1

2 Reasons for performing combination trials with JAK2 inhibitors To increase the benefits seen with JAK2 inhibitors (splenomegaly, symptoms) as well as to bring additional benefits (anemia, BM fibrosis, clone) To reduce unwanted side effects (anemia, thrombocytopenia) yet maintaining clinical benefits To facilitate stem cell transplantation Drugs of Potential Interest for Combination tudies with JAK2 inhibitors Class Immunomodulators Molecule In vitro study Clinical trial elected References Pomalidomide Tefferi et al. JCO2009;27: Lenalidomide Mesa et al. Blood 2010;116: mtor inhibitors Everolimus Guglielmelli et al. Blood 2011;118: Hypomethylating agents Histone deacethylase inhibitors Interferons Azacitidine Mesa et al. Leukemia 2009; 23:180 2 Decitabine Danilov et al. BJH 2009; 145:131 2 Givinostat Rambaldi et al. BJH 2010; 150: Panobinostat De Angelo et al (AH annual Meeting Abstract). 2010;276 Interferon alpha Ianotto JC, BJH 2009;146: ilver RT, Blood 2011; 117: Gowin K, Haematologica 2012, online 2

3 Increased down regulation of JAK2 signaling with a combination of JAK2 inhibitor and HDACi TG Panobinostat Wang Y et al. Blood 2009;114: Combined Effects of Ruxolitinib and Panobinostat in an in vivo model of JAK2V617F mutated MPN Vehicle PAN 4 mg/kg PAN 8 mg/kg PAN 12 mg/kg 10 8 % of control 100% 27% * 20% * 11% * RUX 60 mg/kg RUX 60 mg/kg + PAN 4 mg/kg RUX 60 mg/kg + PAN 8 mg/kg RUX 60 mg/kg + PAN 12 mg/kg % of control 40% * 22% * 15% * 3% * Enhanced efficacy was observed with a combination of RUX and PAN There was no major change in tolerability, as assessed by body weight, between panobinostat alone or in combination with ruxolitinib * P < 0.05 vs. vehicle control; P < 0.05 vs. ruxolitinib; P < 0.05 vs.panobinostat at same dose Baffert et al, manuscript in preparation 3

4 A Phase 1b, open label, multi center, single arm, dose finding study to assess safety and pharmacokinetics of the oral combination of panobinostat and ruxolitinib in patients with primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (PPV MF) or postessential thrombocythemia myelofibrosis (PET MF) LBH589X2106 Combination Trial of Ruxolitininb with Panobinostat Primary Objective: to evaluate the clinical pathological response econdary Objectives: assessment of biological response including measurement of histone acetylation, JAK2V617F allele burden, bone marrow cellularity, histopathology and fibrosis. N = 48 (max) 18 years of age Int 2/High risk PMF or Post PV/ET MF or pts with MF in accelerated phase ANC 1 x 10 9 /L Platelets 75 x 10 9 /L ECOG P 3 Adequate cardiac function Participating Country: UA Principal Investigator: John Mascarenhas, MD Ruxolitinib + Panobinostat Dose Level Ruxolitinib Panobinostat 1 10 mg BID 10 mg TIW QOW 2 10 mg BID 10 mg TIW QW 3 15 mg BID 10 mg TIW QOW 4 15 mg BID 10 mg TIW QW 5 15 mg BID 15 mg TIW QOW 6 15 mg BID 15 mg TIW QW 7 20mg BID 15 mg TIW QOW 8 20 mg BID 15 mg TIW QW 3+3 DEIGN Treatment duration = 28 days A E M E N T Progressive Disease Off study Toxicity Off study or dose modification Continue until next dosage cohort is completed 4

5 Combination Trial of Ruxolitinib and Lenalidomide (NCT ) ponsored by MDACC, PI. Verstovsek Primary Outcome: the rate of IWG defined responses after 3 cycles Projected enrolment: 49 subjects Treatment: Ruxolitinib 15 mg BID + Lenalidomide 5 mg/day d1 21. Prednisone added d in cycles 4 6 in case of no response Ongoing, 20 patients enrolled till now. Combination Trial of Ruxolitinib with peg Interferon alpha2a Efficacy reported (variably) against splenomegaly, anemia, V617F allele burden and bone marrow morphology Iannotto JC, BJH 2009; 146: Gowin K, Haematologica 2012, online ilver RT, Blood 2011; 117: A Phase 1/2 dose finding study to assess safety and pharmacokinetics of the combination of Ruxolitinib and peginterferon alpha 2a in patients with PMF, PPV MF or PET MF (PI, J.J. Kiladjian: France) 5

6 A Phase I/II trial of Everolimus in Myelofibrosis Phase I (n=9), Phase II at MTD (10 mg/die; n=30), 4 months Responses (ITT): EUMNET: overall 60%, Major 27%, Moderate 23%, Minor 10%; No response 40% IWG MRT: overall 23%, PR 3%, CI 20%, D 77% CR= 69% CR=80% Guglielmelli P et al. Blood 2011;118: A phase 1/2 study of combination therapy of Ruxolitinib and EVErolimus in patients with primary an post PV/ET MYelofibrosis (REVEMY study) Primary Objective: evaluate the safety, efficacy, and MTD of Ruxolitinib combined with Everolimus in patients with PMF and PPV/PET MF econdary Objectives: effects of the treatment on normalization of abnormal peripheral blood cell count; changes in V617F or MPL allelic burden in mutated patients N = 12 (Phase 1)* N = 20 (Phase 2) Primary myelofibrosis (WHO 2008) PPV-/PET-MF (IWG-MRT criteria) Intermediate-2/high risk or Intermediate-1 with constitutional symptoms plenomegaly l ( 5 cm from the right costal margin) Platelets >100 x 10 9 /L; ANC 1 x 10 9 /L Design Ruxolitinib + Everolimus Dose Level Ruxolitinib Everolimus 1 5 mg BID 2.5 mg QD 2 10 mg BID 5 mg QD 3 15 mg BID 7.5 mg QD 4 20 mg BID 7.5 mg QD Treatment duration = 28 days FPFV = May 2012 A E M E N T Participating Country: Italy Principal Investigator: Alessandro M Vannucchi *12 patients enrolled with 12 additional patients if necessary for DLT estimation ANC, absolute neutrophil count; MTD, maximum tolerated dose Progressive Disease Off tudy Toxicity (off study or dose modification) Continue until next dosage cohort is completed 6

7 Reasons for performing combination trials with JAK2 inhibitors To increase the benefits seen with JAK2 inhibitors (splenomegaly, symptoms) as well as to bring additional benefits (anemia, BM fibrosis, clone) To reduce unwanted side effects (anemia, thrombocytopenia) yet maintaining clinical benefits To facilitate stem cell transplantation Anemia During Ruxolitinib Treatment Ruxolitinib Comparator G3 G4 Tot G3 G4 Tot COMFORT I Hb COMFORT II Hb (% of patients) Verstovsek et al. NEJM 2012; 366: Harrison C et al. NEJM 2012; 366:

8 Development of Anemia Does not Affect Response to Ruxolitinib Treatment Verstovsek et al. NEJM 2012; 366: Endogenous Epo Levels During Ruxolitinib Treatment Erythropoietin Verstovsek et al. N Engl J Med. 2010; 363:

9 Is there a Rationale for Adding Epo to Ruxolitinib? trictly speaking, mutuating the experience from MD where endogenous EPO levels >500 U/L negatively correlated with response, NO or LITTLE But, anedoctal experience of 9 (+1) patients in COMFORT II suggested efficacy without unwanted increase in spleen size An open label, multicenter study of Ruxolitinib and Erythropoietic timulating Agents for patients with PMF or PPV MF or PET MF and anemia (PI, H. Katrin Al Ali: Germany) Pomalidomide for MF associated Anemia 5 phase I/II studies with >240 patients Best anemia responses at doses of 0.5 mg/day (±prednisone) Median duration of anemia response: 16 months Modest activity against splenomegaly, up to 58% platelet responses A placebo controlled, phase 3 study (NCT ) Months 3 6 ses Respons 100% Tefferi A et al. J Clin Oncol 2009; 27:4563 9; Mesa R et al. Am J Hematol 2010; 85:129 30; Begna K et al. Leukemia 2011; 25:301 4; Begna K et al. Am J Hematol 2011;on line A Phase Ib/II tudy of Ruxolitinib and Pomalidomide Combination Therapy in Patients with Primary and econdary Myelofibrosis: The POMINC tudy. (PI, K. Dohner: Germany) 50% 9

10 Reasons for performing combination trials with JAK2 inhibitors To increase the benefits seen with JAK2 inhibitors (splenomegaly, symptoms) as well as to bring additional benefits (anemia, BM fibrosis, clone) To reduce unwanted side effects (anemia, thrombocytopenia) yet maintaining clinical benefits To facilitate stem cell transplantation Does plenomegaly Negatively Affect Hematopoietic Recovery after CT? Extensive splenomegaly raises concerns about excessive sequestration of transplanted Cs as well as increased transfusionalsional support after CT There is a negative correlation between time to neutrophil engraftment and extent of splenomegaly in some 1 but not all 2 series In a study of 11 splenectomized vs 15 non splenectomized MF patients there was evidence of faster granulocyte recovery although with no impact on outcome 3 1 Ciurea et al. BJH 2008; 141:80 3; 2 cott BL, Blood 2012; 119: ; 3 Li z et al., Blood 2001; 97:

11 plenomegaly is a Negative Risk Factor for urvival after CT Risk variables pleen >22 cm Transfusions >20 Donor other than HLA id sibling Low risk= 0 1 variables High risk= >2 variables 1 Bacigalupo A, BMT 2010; 45: JAK2 Inhibitors as Part of the TC Procedure plenectomy was protective against disease relapse (13% vs 56% in splenectomized vs non splenectomized pts) in an Italian study 1 In a study of 31 splenectomized vs 180non non splenectomized pts, pre HCT splenectomy was the only variable associated with reduced mortality (HR 0.51, p=0.05) 2. However, the risks associated with surgery do not justify the routine use of splenectomy unless in very selected cases Feasibility of administering Ruxolitinib with reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (RIC HCT) in MF patients (PI, V. Gupta: UA, Canada, Italy, Germany, UK, Israel) 1 Bacigalupo A, BMT 2010; 45:458 63; 2 cott BL, Blood 2012; 119:

12 Combinations..at a glance Ruxolitinib plus azacitidine Low dose azacitidine to be added to ruxolitinib after 3 months. (. Verstovsek, personal communication) Ruxolitinib followed by decitabine in MPN related AML Ruxolitinib and mo inhibitors (R.Hoffman, personal communication) (in preparation) 12