Durable Responses with the JAK1/JAK2 p Inhibitor, INCB018424, in - - PowerPoint PPT Presentation

Durable Responses with the JAK1/JAK2 p Inhibitor, INCB018424, in Patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory or Intolerant to Hydroxyurea (HU)

Srdan Verstovsek1, Francesco Passamonti2, Alessandro Rambaldi3, Giovanni Barosi4, Peter Rosen5, Richard Levy6, Edward Bradley6, William Garrett6, Kris Vaddi6, Nancy Contel6, Victor Sandor6, Reid Huber6, Lee Schacter7, Elisa Rumi2, Elisabetta Gattoni4, Elisabetta Antonioli8, Lisa Pieri8, Mario Cazzola2, Hagop Kantarjian1, Tiziano Barbui3, Alessandro M. Vannucchi8

2010 Annual Meeting of the American Society of Hematology g y gy December 6, 2010

1Department of Leukemia, University of Texas MD Anderson Cancer Research Center, Houston,Tx, 2Division of Hematology, University of Pavia, Fondazione Istituto di Ricovero e Cura a Carattere,

Scientifico Policlinico San Matteo, Pavia, Italy, 3Division of Hematology, Ospedali Riuniti, Bergamo, 1 , , y, gy, p , g , Italy, 4Unit of Clinical Epidemiology and Center for the Study of Myelofibrosis, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia, Italy,5 Tower Cancer Research Foundation, Beverly Hills, Ca,6Incyte Corporation, Wilmington, De, 7Pfizer Corporation, New York,,8Section of

Hematology, Deparment of Critical Care, University of Florence, Italy

ET and PV

ET and PV, with MF, represent the 3 ‘classic’ BCR-ABL-negative MPNs – ET is characterized by megakaryocyte hyperplasia and persistent thrombocytosis; PV by clonal proliferation of erythroid, myeloid, and megakaryocyte cell lineages – Both are associated with increased risk of thrombosis and progression to MF or AML Normalization of platelet counts in ET and Hct % in PV are primary treatment goals – Rx also needed for symptomatic splenomegaly and debilitating symptoms that arise with disease progression Therapeutic options are limited for ET and PV patients refractory or intolerant to hydroxyurea (HU) INCB 18424 treatment in MF, Post PV-MF, and Post ET-MF has been well tolerated and associated with reductions in spleen size and

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symptom relief

Phase II Study of INCB 18424 in Patients with Advanced ET and PV

Eligibility Criteria:

• Refractory or intolerant to hydroxyurea (HU) or HU contraindicated
• PV: Hct > 45% OR phlebotomy 2 times in last 6 months, with at least

P l th i (N 34)

% p y ,

• ne phlebotomy in last 3 months
• ET: Platelets > 650 x 109/L unless on therapy

Polycythemia vera (N=34)

25 mg BID 25 mg BID (n=8) (n=8) 50 mg QD 50 mg QD (n=7) (n=7) 10 mg BID 10 mg BID (n=7) (n=7) 10 mg BID 10 mg BID (n=12) (n=12)

Essential Thrombocythemia (N=39)

( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Part 1 Part 2

Essential Thrombocythemia (N=39)

25 mg BID 25 mg BID (n=8) (n=8) 50 mg QD 50 mg QD (n=8) (n=8) 10 mg BID 10 mg BID (n=8) (n=8) 25 mg BID 25 mg BID (n=15) (n=15)

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Part 1 Part 2

ET Patient Characteristics

Characteristic (median) ET (n = 39) Age, years 51 Female 64% Months from Diagnosis 88 Refractory to HU 87% Refractory to HU 87%

• No. Prior Therapies

1 (1-3) Hct % 41.0 Platelets x109/L 849 (mean 1009) WBC x109/L 8.2 Splenomegaly 4 (10%) Splenomegaly Size, cm (range) 4 (10%) 5 (3-7) JAK2V617F positive 65%

4

JAK2V617F allele burden 16%

ET Patient Disposition

28 of 39 (72%) continue on study with a median follow- up of 21 months (range 4-27) up of 21 months (range 4 27) 11 patients (28%) have discontinued treatment

– 5 due to lack of response – 6 due to different medical reasons: fatigue, weight gain, GI disorder, renal insufficiency, foot pain (2)

< 5 mg BID 5-10 mg BID 15 mg BID 20-25 mg BID > 25 mg BID

Current Dose Distribution

< 5 mg BID 5-10 mg BID 15 mg BID 20-25 mg BID > 25 mg BID

3% 40% 17% 33% 7%

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Overall Safety in ET

Treatment-related AEs* All Grades; n (%) Grade 3; n (%) Anemia 29 (74) Weight increase 9 (23) Herpes zoster 2 (5) Herpes zoster 2 (5) Hyperuricemia 2 (5) Leukopenia 2 (5) 2 (5) Pain in extremity 2 (5) Palpitations 2 (5)

*Occurring in at least 2 subjects; at least ‘possibly’ related

No treatment-related Grade 4 AEs have occurred on study Hematologic AEs are generally reversible and managed with dose reduction or temporary interruption

g j p y

6

reduction or temporary interruption

Serious Adverse Events in ET

Five patients have reported 5 treatment emergent SAEs: Five patients have reported 5 treatment-emergent SAEs:

– Gastric bleeding (unrelated): continued therapy g ( ) py – Bronchitis (unrelated): continued therapy – Cholecystitis (unlikely related): continued therapy – Headache (unlikely related): continued therapy – Renal failure (possibly related): discontinued therapy

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Platelet Count Reduction in ET

1500 1750

All Patients (n=39) Baseline >1000 x 109/L

9/L)

750 1000 1250

Baseline >1000 x 10 /L (n=14)

• unt (x10

n + SEM)

250 500 750

Platelet Co (mean

3 6 9 12 15 18 21

Months of Treatment P

49% achieved normal platelet counts and 79% achieved <600,000

• r a ≥50% reduction as of last follow-up visit

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13 of 14 subjects with baseline platelet counts >1,000,000 have achieved a greater than 50% reduction

ET Results: WBC, Splenomegaly, Symptoms

WBC counts for all 11 patients with baseline >10 x 109/L normalized within first month and were maintained for a median of 14 months Of 4 patients with splenomegaly at baseline all have achieved and maintained non-palpable spleen (3) or a > 50% reduction (1) through last follow-up visit % of ET Patients with a > 50% Reduction in Symptom Scores

80 90 50 60 70 80

P a tie n ts

83% 68% 65% 64%

10 20 30 40

%

• f P

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Night Sweats Bone Pain Pruritus Peripheral Numbness n=12 n=22 n=18 n=28

ET Response

Response Criteria - European LeukemiaNet1

– CR: Platelet count < 400 x109/L, WBC < 10 x109/L, normal spleen, no disease-related symptoms

(pruritus headache microvascular disturbances) (pruritus, headache, microvascular disturbances)

– PR: Platelet count < 600 x109/L OR decrease > 50% from baseline

90% overall response

– 26% CR 26% CR – 64% PR

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1Barosi et al., Blood 113:4829-4833, 2009

PV Patient Characteristics

Characteristic (median) PV (n = 34) Age, years 58 Female 50% Months from Diagnosis 115 Refractory to HU 74% Refractory to HU 74%

• No. Prior Therapies

1 (1-3) Hct % 46.7 Phlebotomy in last 6 months 76% Platelets x109/L 527 WBC x109/L 13.2 Splenomegaly Size, cm (range) 25 (74%) 9 (1-21) JAK2V617F positive 100%

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JAK2 positive 100% JAK2V617F allele burden 72%

PV Patient Disposition

28 of 34 (82%) continue on study with a median follow-up

• f 21 months (range 8-28)

6 patients (18%) have discontinued treatment:

– 1 due to lack of response – 4 due to different medical reasons: shortness of breath desire to 4 due to different medical reasons: shortness of breath, desire to conceive, abdominal pain/leucopenia, renal tumor – 1 for disease progression

< 5 mg BID 5-10 mg BID 15 mg BID 20-25 mg BID > 25 mg BID

Current Dose Distribution

g g g g g

0% 66% 14% 14% 7%

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Overall Safety in PV

Treatment-related AEs* All Grades; n (%) Grade 3; n (%) Anemia 25 (74) Thrombocytopenia 10 (29) 2 (6) Leukopenia 5 (15) p ( ) Weight increase 5 (15) Diarrhea 3 (9) Hyperuricemia 3 (9) Hyperuricemia 3 (9) Insomnia 3 (9) Palpitations 3 (9)

*O i i t l t 3 bj t t l t ‘ ibl ’ l t d

No treatment-related Grade 4 AEs have occurred on study Hematologic AEs are generally reversible and managed with dose reduction or t i t ti

*Occurring in at least 3 subjects; at least ‘possibly’ related

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temporary interruption

Serious Adverse Events in PV

Five subjects have reported 8 treatment-emergent Five subjects have reported 8 treatment emergent serious adverse events (SAEs):

– Pneumonia and, one year later, congestive heart failure (both unrelated): continued therapy Pneumonia (unrelated): continued therapy – Pneumonia (unrelated): continued therapy – Gastric bleeding (unlikely related): continued therapy – Renal tumor (possibly related): discontinued therapy ( y ) y – Thrombocytopenia and anemia (unrelated) and atrial flutter (possibly related): discontinued therapy

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PV Results: Hematocrit Control (Hct ≤ 45%) without Phlebotomy

97% of patients have achieved hematocrit ≤ 45% without the use of phlebotomy without the use of phlebotomy

100

it

80 100

Hematocr ebotomy

40 60

Achieving Without Phl

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Patients A Control W

n=34 n=34 n=34 n=33 n=31 n=29 n=28 n=19

15

1 3 6 9 12 15 18 21

Months of Treatment % C

PV Results: Splenomegaly

12 Baseline Spleen > 0 cm

h

Rapid and Durable Reductions in Palpable Spleen Length

9 12 Baseline Spleen > 0 cm (n=25) Baseline Spleen > 5 cm (n=17)

en Length )

SEM) 3 6

able Splee (cm)

(mean + S 3 6 9 12 15 18 21 3

Palpa

• 80% of patients with palpable splenomegaly (n=25) achieved

Months of Treatment

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≥ 50% reduction as of the last follow-up (68% achieved complete resolution of palpable splenomegaly)

PV Results: WBC Counts

Rapid and Durable Reductions in WBC Count

21 24 27 All PV Patients (n=34) WBC > 15K at baseline (n=15) x 109/L) M) 9 12 15 18

C Count (x

mean + SEM 3 6 9

WBC

(m

• Leukocytosis (>15x109/L) was present in 15 patients at baseline:

3 6 9 12 15 18 21

Months of Treatment

17

Leukocytosis ( 15x10 /L) was present in 15 patients at baseline: 73% normalized WBC as of the last follow-up visit

PV Results: Platelet Counts

Rapid and Durable Reductions in Platelet Counts

1000

All PV Patients (n=34)

PLT > 600K at Baseline /L)

• Thrombocytosis (>600 x109/L)

was present in 13 patients at b li l t l t li d i

600 800 PLT > 600K at Baseline (n=13)

• unt (x 109/

+ SEM)

baseline: platelets normalized in 69% as of the last follow-up visit

200 400

Platelet Co

(mean 3 6 9 12 15 18 21

Months of Treatment P

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PV Results: Symptoms

Pruritus

R id i t i

Mean Symptom Severity Scores

5

• Rapid improvements in

patient reported symptom scores observed

1 2 3 4

Symptoms Severity Scale

(mean + STD)

4 5

verity

M)

Bone Pain

• Responses have been

durable in the majority of

Baseline 3 6 9 12 15 18 21 Baseline 3 6 9 12 15 18 21 1 2 3

Symptoms Sev Scale

(mean + SEM

durable in the majority of responding patients through the last follow-up visit

2 3 4 5 6

toms Severity Scale

mean + STD)

Night Sweats

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Baseline 1 2 3 6 9 12 15 18 21 1 2

Months of Treatment Symp

(m

PV Response

Response Criteria - European LeukemiaNet1

– CR: Hct < 45% without phlebotomy, platelet count < 400,000, WBC < 10,000, normal spleen, no disease- related symptoms (pruritus headache microvascular related symptoms (pruritus, headache, microvascular

disturbances)

– PR: Hct < 45% OR response in > 3 of the other criteria

97% overall response

– 50% CR 50% CR – 47% PR (spleen measured by palpation)

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1Barosi et al., Blood 113:4829-4833, 2009

PV Results: JAK2 V617F Allele Burden

• JAK2V617F mutation occurs in > 95% of PV and ~ 50% of ET patients
• Downward trend has been observed in V617F allele burden in PV

ti t (4 ti t h i d > 50% d ) patients (4 patients have experienced a > 50% decrease)

• Clinical response does not correlate with JAK2V617F allele burden

JAK2V617F % Change from Baseline in Advanced PV Patients

100 80 90 100

* ** * ** ** **

n=34 n=31 n=33 n=31 n=28

K2V617F f Baseline)

60 70 80

* P<0.05 ** P<0.01

n=27 n=20 n=9

JAK (% of

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3 6 9 12 15 18 21 60

Months of Treatment

INCB 18424 in ET and PV: Conclusions

After a median follow-up of 21 months, INCB 18424 continues to be well tolerated in ET and PV patients refractory or intolerant to HU Durable clinical benefits have been demonstrated in Durable clinical benefits have been demonstrated in advanced ET and PV patients:

– Resolution of splenomegaly in high percentage of patients p g y g p g p – Phlebotomy independence in nearly all PV patients – Normalization or improvement in hematological parameters in most patients parameters in most patients – Marked symptomatic benefits in both ET and PV

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Results support further development in ET and PV

Phase 3 Trial in PV: The RESPONSE Study

INCB18424

e

• I. HU resistance or

intolerance (LEN criteria)

n

N=150 R

dpoint Failure

• II. q3month phlebotomy

requirement III P l bl l

se Progression

HCT 40-45% N 150 crossover Best Available Therapy

1o End

• III. Palpable spleen

(≥5cm)

• IV. WBC >15K and/or

l t l t 600K

Diseas

inclusive Week Week N=150

Special protocol assessment agreement reached with FDA 1o it d i t H t it t l i th b f

platelet >600K Week 32 Week 80

1o composite endpoint: Hematocrit control in the absence of phlebotomy and ≥ 35% reduction in spleen volume at Week 32 2o endpoints: Complete hematologic remission at Week 32; % of

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subjects who maintain 1o endpoint response for ≥ 48 weeks NCT01243944; www.responsetrial.com