Demethylating agents in MDS azacitidine update Pierre Fenaux H

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Demethylating agents in MDSazacitidine
updatePierre FenauxHôpital Avicenne, Paris 13
UniversityGFM Rouen juin 2004
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p15 gene methylation in MDS

• - p15 cycline dependant kinase inhibitor
• - frequently methylated in MDS

. almost constantly when marrow blasts gt10 .
almost never when marrow blasts lt10 p15
inactivation is an important step in the
progression of MDS (Quesnel et al,1998)
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5 Azacitidine

• Anti-leukemic agent
• Inducer of Cell Differentiation
• Hypomethylating Agent

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5 Azacytidine Induced DNAHypomethylation and
Gene Activation
5 Azacytidine inhibition of DNA
methyltransferase (DMT) results in
hypomethylation and transcription of previously
quiescent genes
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MDS Studies Phase I - II

• Entire MDS program was conducted by the CALGB
  under the sponsorship of the NCI IND

Phase Study No of patients/ Route Patient subtypes
I/II 8421 43/IV RAEB, RAEB-T
II 8921 67/SC RAEB, RAEB-T, CMML
III 9221 191/SC RA, RARS, RAEB, RAEB-T, CMML
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CALGB 8421/8921
A Phase I - II Study of 5-Azacitidine in
Mylelodysplastic Syndromes
CALGB 8421/8921
Response - CONTINUE
A S S E S S
RAEB RAEB-T CMML
No Response - OFF STUDY
M 113
M 85
M 57
M 29
M 1
M 8
M 15
M 22
5-Azacitidine 75 mg/M2/day ? 7d, continuous I.V.
/SC
RAEB Refractory Anemia with Excess Blasts
(5-20) RAEB-T Refractory Anemia with Excess
Blasts in Transformation (21-30) M Bone Marrow
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MDS Clinical Studies Phase II

• Phase I/II Study 8421
• Azacitidine administered I.V. continuous 7 days
  every 4 weeks
• Dose 75mg/m2/day, increased to 100 or 150mg/m2 if
  no response
• Mean age 65, males 63, females 37
• Open-label, single arm trial
• 43 patients evaluated
• Azacitidine with supportive care

• Phase II Study 8921
• Azacitidine administered S.C. 7 days every 4
  weeks
• Dose 75mg/m2/day, increased to 100 mg/m2 if no
  response
• Mean age 66, males 69, females 31
• Open-label, single arm trial
• 67 patients evaluated
• Azacitidine with supportive care

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MDS Clinical Studies Phase II
Efficacy Results Response
Response Category 8421 Aza(N43) 8921 Aza(N67)
Total (CR, PR, Improved) 49 52
CR 12 12
PR 25 12
Improved 12 28
Transfusion Elimination 37 (14/38) 41 (22/54)
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A Randomized Controlled Trial Of Subcutaneous
Azacitidine In Patients With The Myelodysplastic
Syndrome A Study Of The Cancer And Leukemia
Group B (CALGB 9221) L.R. Silverman, E.P.
Demakos, B. Peterson, R. Odchimar-Reissig, D.
Nelson, A.B. Kornblith, R. Stone, J.C. Holland,
B.L. Powell, C. DeCastro, J. Ellerton, R.A.
Larson, C.A. Schiffer, J.F. Holland
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MDS Clinical Studies Phase III

• Multicentre, open-label, randomized
• MDS patients stratified by FAB subtype
• 191 Patients
• Azacitidine versus supportive care
• Supportive care failure allowed to cross-over to
  Azacitidine
• Primary endpoint of response rate

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MDS Clinical Studies Phase III

• Azacitidine treatment
• Patient self-administration SC
• Start 75mg/m2 x 7 days q 4 wk
• ? dose to 100 mg/m2 if no evidence of response
  and no toxicity (other than nausea and vomiting)
  after 2 cycles
• ? dose according to protocol specified criteria

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Response Definitions
CR
PR
Improved
Bone Marrow
M1 50 of initial blasts HO Trilineage Mono
or Response Bilineage Response 0 0 0 0
50 of baseline
Peripheral Blood
Counts
Blasts
Transfusion
Silverman et. al., JCO, May 15 2002, 2429-2440
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MDS Clinical Studies Phase III
Efficacy Results Response
Response Category Aza(N99) BSC(N 92) Cross-over(N 49)
Total (CR, PR, Improved) 601 5 47
CR 72 0 10
PR 161 0 4
Improved 371 5 33
Transfusion Elimination 45 (31/68)
Note Statistical analysis does not include data
obtained after cross over 1 plt0.001 vs BSC 2
plt0.01 vs BSC
(Silverman, JCO, May 2002)
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MDS Clinical Studies Phase III
Efficacy Results Transformation and Survival
Parameter Aza BSC
Median survival 20 months1 14 months
Time to leukemic transformation or death 21 months2 12 months
Probability of transformation to AML as 1st event 153 38
1 p 0.1 vs BSC 2 p 0.007 vs BSC 3 p
0.001 vs BSC
(Silverman, JCO, May 2002)
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Time to AML Transformation
P.001
Silverman et. al., JCO, May 15 2002, 2429-2440
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Overall Survival
1.0
Azacitidine Supportive Care
0.8
Median 20 months 14 months
0.6
Probability of Remaining Event-Free
0.4
0.2
p 0.10
0.0
0
6
12
18
24
30
36
42
48
54
Months
Silverman et al., JCO 2002 20 2429
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Survival Landmark Analysis
Silverman et al., JCO 2002 20 2429
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CALGB Phase III Study 9221
Efficacy Response to Aza by FAB Category at
Baseline
Response Category RA/RARS(N 21) RAEB/RAEB-T/CMML(N 67)
CR 9 8
PR 19 14
Improved 33 39
Note Does not include data obtained after x-over
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Survival FAB Classification
Silverman et al., JCO 2002 20 2429
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Adverse Events

• Leukopenia 43 (43 Pts)
• Neutropenia 58
• Thrombocytopenia 52 (51 Pts)
• NV 4 (6 Pts)
• Treatment Related Mortality lt1
• No Diarrhea, Elevated Transaminases, or Erythema
  at Injection Site

Silverman LR, et. al. J Clin Oncol
2002202429-40. 9221 Silverman L. Cancer
Medicine. 2000a Edition 51931-46.
9221 Silverman L. ASH Meeting. 2000b. 9221
abstract. Silverman L, et. al.
Cancer Inves. 199917(Suppl)4-5.
9221.abstract 5. Silverman LR, et. al. Proc
Am Soc Clin Onco. 199817. 9221 abstract 53.
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Azacitidine in MDS Quality of Life

• Significant Improvement in Quality of Life
  compared to Best Supportive Care
• Decreased fatigue (p.001)
• Decreased dyspnea (p .0014)
• Improved physical functioning (p.0002)
• Improved psychological state
• Positive affect (p.0077)
• Decreased psychological distress (p.015)
• Improvement in Quality of Life paralleled the
  clinical response
• Kornblith et al, JCO May 15, 2002, 2441-2452

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Quality of Life Impact EORTC Fatigue, Dyspnea
Physical Functioning of Crossover Patients on
Supportive Care for 4 months Prior to Crossover
(N30)
Supportive Care Crossover AZA Time (days)
Higher Scores Better Functioning
Lower Scores Symptom Improvement
Kornblith et al., JCO 2002 20 2441-52
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Clinical Protocol Azacitidine

•  A Multicenter, Randomized, Open-Label,
  Parallel-Group, Phase 3 Trial of Subcutaneous
  Azacitidine Plus Best Supportive Care Versus
  Conventional Care Regimens Plus Best Supportive
  Care for the Treatment of Myelodysplastic
  Syndromes (MDS)

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Azacitidine Confirmatory Trial Study Objectives

• Primary Objective
• To determine the effect of azacitidine plus Best
  Supportive Care versus Conventional Care Regimens
  plus Best Supportive Care, on SURVIVAL in MDS
  patients.

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Azacitidine Confirmatory Trial Study Objectives

• Secondary Objectives
• Hematologic status (peripheral counts, need for
  platelet and red blood cell transfusions)
• Hematologic response and hematologic improvement
  (status according to IWG criteria)
• Episodes of infections requiring intravenous
  antibiotics (anti-bacterial or anti-fungal)
• Time to relapse after CR or PR, or disease
  progression (according to IWG criteria)

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Azacitidine Confirmatory Trial Study Objectives

• Secondary Objectives (cont)
• Time to transformation to AML
• Time to transformation or death from any cause
• Determine the safety and toxicity
• Pharmacoeconomics

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Azacitidine Confirmatory Trial Study Design

• Open label, randomized, parallel-group
• Patient Population
• MDS with RAEB or RAEB-T
• IPSS score INT-2 or High

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Azacitidine Confirmatory Trial

Protocol Study Design
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Azacitidine Confirmatory Trial Protocol Synopsis

• Treatments
• Azacitidine 75 mg/m2/day SQ X 7d q28d plus best
  supportive care versus One of Three options for
  Standard of Care
• Standard of Care consists of
• Best Supportive Care (consisting of blood
  products, antibiotics as needed)
• Low Dose Ara-C (20 mg/m2/day,2 weeks on,2 weeks
  off)
• Ara-C plus anthracycline
• All options will have a standard,
  protocol-defined regimen for dose and duration of
  dosing

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Azacitidine Confirmatory Trial    Study Endpoints

• Primary Endpoint
• Survival from any cause
• Secondary Endpoints
• Time to transformation to AML
• Time to transformation to AML or death

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Azacitidine Confirmatory Trial Study Endpoints

• Secondary Endpoints (cont)
• Transfusion need
• Number of Infections Requiring IV Antibiotics
• Time to relapse after CR or PR or disease
  progression
• Duration of response or improvement
• Hematologic response
• Hematologic improvement

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Azacitidine Confirmatory Trial

• 65 centers in 10 countries
• Australia
• France
• Germany
• Greece
• Italy

• Spain
• Sweden
• Netherlands
• UK
• US