5/15/2012

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What is next:

SymposiumJAK2 Inhibition in Myelofibrosis:What Can We Expect in the Clinic?

4‐5 May 2012Lisbon, Portugal

What is next: 

Emerging JAK2 inhibitor combination 

studies

Alessandro M. Vannucchi

Section of Hematology,

University of Florence, Italy

www.progettoagimm.it

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

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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 Studies with JAK2 inhibitors

Class MoleculeIn vitro study

Clinical trial

Selected Referencesy

ImmunomodulatorsPomalidomide Tefferi et al. JCO2009;27:4563‐9. 

Lenalidomide Mesa et al. Blood 2010;116:4436‐8

mTOR inhibitors Everolimus Guglielmelli et al . Blood 2011;118:2069‐76

Hypomethylating agents

Azacitidine Mesa et al. Leukemia 2009; 23:180‐2

Decitabine Danilov et al. BJH 2009; 145:131‐2

Givinostat Rambaldi et al BJH 2010; 150:446 55Histone deacethylase inhibitors

Givinostat Rambaldi et al. BJH 2010; 150:446‐55

Panobinostat De Angelo et al (ASH annual Meeting Abstract). 2010;276

InterferonsInterferon alpha

Ianotto JC, BJH 2009;146:317‐21Silver RT, Blood 2011; 117:6669‐72Gowin K, Haematologica 2012, online

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Increased down‐regulation of JAK2 signaling with a 

combination of JAK2 inhibitor and HDACi

• TG101209• Panobinostat

Wang Y et al. Blood 2009;114:5024‐5033

Combined Effects of Ruxolitinib and Panobinostat in an 

in vivo model of JAK2V617F mutated MPNVehicle PAN 4 mg/kg PAN 8 mg/kg PAN 12 mg/kg

10

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

8

6

4

2

% ofcontrol 11% *20% *27% *100% 

% ofcontrol 3% *† ‡15% *†22% *40% *

* P < 0.05 vs. vehicle control; † P < 0.05 vs. ruxolitinib; ‡ P < 0.05 vs .panobinostat at same dose 

• 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

Baffert et al, manuscript in preparation 

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A Phase 1b, open‐label, multi‐center, single arm, dose 

finding study to assess safety and pharmacokinetics of 

h l b f b d l bthe oral combination of panobinostat and ruxolitinib 

in patients with primary myelofibrosis (PMF), post‐

polycythemia vera‐myelofibrosis (PPV‐MF) or post‐

essential thrombocythemia‐myelofibrosis (PET‐MF)

LBH589X2106

Combination Trial of Ruxolitininb with Panobinostat

• Primary Objective: to evaluate the clinical‐pathological response 

• Secondary Objectives: assessment of biological response including 

measurement of histone acetylation, JAK2V617F allele burden, bone 

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 BID 10 TIW QW

y

marrow cellularity, histopathology and fibrosis. 

Ruxolitinib + PanobinostatN = 48 (max)

• ≥18 years of age• Int‐2/High risk  PMF or Post PV/ET MF or pts  with MF in accelerated phase

A

S

S

E

S

S

Progressive DiseaseOffstudy

Toxicity Off study or dose 

difi ti4 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

accelerated phase• ANC ≥1 x 109/L• Platelets ≥75 x 109/L• ECOG PS ≤3• Adequate cardiac function

3+3 DESIGNTreatment duration = 28 days

M

E

N

T

modification

Continue until next dosage cohort is completed

Participating Country: USAPrincipal Investigator: John Mascarenhas, MD

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Combination Trial of Ruxolitinib and Lenalidomide

(NCT01375140)

• Sponsored by MDACC, PI S. 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 P d i dd d i l 4 6 i f21. Prednisone added 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)

Silver RT, Blood 2011; 117:6669‐72

Efficacy reported (variably) 

against splenomegaly, anemia,

V617F allele burden and bone 

marrow morphology 

Iannotto JC, BJH 2009; 146:317‐21Gowin K, Haematologica 2012, online

A Phase 1/2 dose finding study to assess safety and 

pharmacokinetics of the combination of Ruxolitinib and peg‐

interferon alpha‐2a in patients with PMF, PPV‐MF or PET‐MF

(PI, J.J. Kiladjian: France)

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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%

ll• IWG‐MRT: overall 23%, PR 3%, CI 20%, SD 77%

CR= 69%

Guglielmelli P et al. Blood 2011;118:2069‐2076

CR=80%

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

• Secondary Objectives: effects of the treatment on normalization of abnormal peripheral blood cell count; changes in V617F or MPL allelic burden in mutated patients

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

Ruxolitinib + Everolimus

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 symptomsS l l (≥5 f

A

S

S

E

S

S

M

Progressive Disease Off Study

Toxicity (off study or dose modification)

3 + 3 Design

3 15 mg BID 7.5 mg QD

4 20 mg BID 7.5 mg QD

• Splenomegaly (≥5 cm from the right costal margin)

• Platelets >100 x 109/L; ANC ≥1 x 109/L

Treatment duration = 28 days

E

N

T

Participating Country: ItalyPrincipal Investigator: Alessandro M Vannucchi

FPFV = May 2012

Continue until next dosage cohort is completed

*12 patients enrolled with 12 additional patients if necessary for DLT estimationANC, absolute neutrophil count; MTD, maximum tolerated dose

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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 34.2 11.0 44.2 15.9 3.3 19.2

COMFORT‐IICOMFORT II

Hb 34 8 42 21 10 31

(% of patients)

Verstovsek S et al. NEJM 2012; 366:799‐807. Harrison C et al. NEJM 2012; 366:787‐98

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Development of Anemia Does not Affect Responseto Ruxolitinib Treatment

Verstovsek S et al. NEJM 2012; 366:799‐807.

Endogenous Epo Levels During Ruxolitinib Treatment

Verstovsek et al. N Engl J Med. 2010; 363:1117‐27.

Erythropoietin

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Is there a Rationale for Adding Epo to Ruxolitinib?

• Strictly speaking, mutuating the experience from MDS where

endogenous EPO levels >500 U/L negatively correlated with g g y

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 Stimulating 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)

100%

ses

(±prednisone)

• Median duration of anemia response: 16 months

• Modest activity against splenomegaly, up to 58% 

platelet responses

•A placebo‐controlled, phase‐3 study (NCT01178281)  63

50%

Respons

Months

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

A Phase‐Ib/II Study of Ruxolitinib and Pomalidomide

Combination Therapy in Patients with Primary and Secondary

Myelofibrosis: The POMINC Study.

(PI, K. Dohner: Germany)

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

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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

• Extensive splenomegaly raises concerns about excessive sequestration of

transplanted SCs as ell as increased transf sional s pport after SCT

Does Splenomegaly Negatively Affect

Hematopoietic Recovery after SCT?

transplanted SCs as well as increased transfusional support after SCT

• There is a negative correlation between time to neutrophil engraftment and

extent of splenomegaly in some1 but not all2 series

• In a study of 11 splenectomized vs 

15 non‐splenectomized MF 

patients there was evidence of

1 Ciurea S et al. BJH 2008; 141:80‐3; 2 Scott BL, Blood 2012; 119:2657‐64 ; 3 Li z et al., Blood 2001; 97: 2180‐1 

patients there was evidence of 

faster granulocyte recovery

although with no impact on 

outcome3

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Splenomegaly is a Negative Risk Factor for Survival

after SCT

Risk variables

• Spleen >22 cm• Transfusions >20• Donor other thanHLA id ibliHLA‐id sibling

Low risk= 0‐1 variables

High risk= >2 variables1 Bacigalupo A, BMT 2010; 45:458‐63  

• Splenectomy was protective against disease relapse (13% vs 56%

in splenectomized vs non  splenectomized pts) in an Italian study1

• In a study of 31 splenectomized vs 180 non splenectomized pts pre

JAK2 Inhibitors as Part of the STC Procedure 

• In a study of 31 splenectomized vs 180 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 

1 Bacigalupo A, BMT 2010; 45:458‐63; 2 Scott BL, Blood 2012; 119:2657‐64  

Feasibility of administering Ruxolitinib with reduced intensity 

conditioning (RIC) allogeneic hematopoietic cell transplantation 

(RIC‐HSCT) in MF patients 

(PI, V. Gupta: USA, Canada, Italy, Germany, UK, Israel)

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Combinations……..at a glance

• Ruxolitinib plus azacitidine

Low‐dose azacitidine to be added to ruxolitinib after 3 months. 

(S. Verstovsek, personal communication)

• Ruxolitinib followed by decitabine in MPN‐related AML

(R.Hoffman, personal communication)(R.Hoffman, personal communication)

• Ruxolitinib and Smo inhibitors   

(in preparation)