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FDA’s Oncologic Drugs Advisory Committee Meeting. DASATINIB (BMS-354825). 2 June 2006. Donna Morgan Murray, PhD Bristol-Myers Squibb Global Regulatory Sciences. Introduction. BMS Presentation. Introduction . ……………….. Donna Morgan Murray, PhD BMS, Global Regulatory Sciences

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donna morgan murray phd bristol myers squibb global regulatory sciences
Donna Morgan Murray, PhD

Bristol-Myers SquibbGlobal Regulatory Sciences

Introduction

bms presentation
BMS Presentation
  • Introduction .………………..Donna Morgan Murray, PhDBMS,Global Regulatory Sciences
  • Scientific Rationale ……….Neil Shah, MD, PhDUCSF School of Medicine
  • Clinical Program ……………Claude Nicaise, MDBMS,Global Development
  • Clinical Perspective ……...Hagop Kantarjian, MDMD Anderson Cancer Center
  • Conclusion ………………….Donna Morgan Murray, PhD
consultants available to the committee
Consultants Available to the Committee
  • Neil Shah, MD, PhDAssistant Professor Division of Hematology/OncologyDepartment of MedicineUCSF School of MedicineSan Francisco, CA
  • Hagop Kantarjian, MDChairman & ProfessorLeukemia DepartmentThe University of TexasMD Anderson Cancer CenterHouston, TX
medical need for therapeutic options in cml
Medical Need for Therapeutic Options in CML

Chronic

Accelerated

Blast

  • Chronic Myeloid Leukemia (CML) is usually treated with imatinib, although resistance and intolerance develops
  • After imatinib failure, therapeutic options are limited (e.g., escalated doses of imatinib, hydroxyurea, interferon, investigational agents, stem cell transplants)
  • Dasatinib offers a therapeutic option to patientsin all phases of CML after failure with imatinib
proposed indications for dasatinib
Proposed Indications for Dasatinib
  • Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib
  • Treatment of adults with Philadelphia chromosome‑positive (Ph+) acute lymphoblastic leukemia (ALL) and lymphoid blast chronic myeloid leukemia with resistance or intolerance to prior therapy
the philadelphia ph chromosome leads to cml

CML

The Philadelphia (Ph) Chromosome Leads to CML

BCR

ABL

Ph chromosome

BCR-ABL (activated tyrosine kinase)

loss of response to imatinib in cml
Chronic Phase – Frontline 16% (42 months)

Chronic Phase – IFN failure 26%

Accelerated Phase 73% (48 months)

Blast Crisis 95%

Loss of Response to Imatinib in CML

Rate of Relapse/Progression

For most imatinib-resistant or -intolerant patients, effective therapeutic options are severely limited

Silver et al, 2004; Guilhot et al, 2004; Bhatia et al, 2002; Graham et al, 2002

clinical resistance to imatinib is associated with restoration of bcr abl kinase activity
Clinical Resistance to Imatinib is Associatedwith Restoration of BCR-ABL Kinase Activity
  • Mechanisms
    • Outgrowth of one or more clones harboring an imatinib-resistant BCR-ABL kinase domain mutation (most common)
    • Overproduction of BCR-ABL via genomic amplification
    • BCR-ABL-independent mechanisms
map of bcr abl kinase domain mutations associated with clinical resistance to imatinib
Map of BCR-ABL Kinase Domain Mutations Associated with Clinical Resistance to Imatinib

L248V

G383D

L298V

F311L/I

L387F/M

G250E/A/F

A397P

E453G/K

E292V

T315I/N

M388L

Q252H/R

E459K/Q

E450G/Q

H396R/P

Y253H/F

F317L

S417Y

F486S

L364I

E255K/V

x

A

C

P

V379I

D276G

M351T

M244V

E355G/D

T277A

V289A

E279K

F359C/V/D/I

E281A

Gorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; Roche-L’Estienne et al, 2002; Shah et al, 2002; Hochhaus et al, 2002; Al-Ali et al, 2004

Courtesy Tim Hughes

dasatinib inhibits growth of 14 15 imatinib resistant bcr abl expressing ba f3 cell lines in vitro

Ba/F3

Bcr-Abl

E255K

T315I

M351T

M244V

G250E

Q252H

Q252R

Y253F

Y253H

E255V

F317L

E355G

F359V

H396R

F486S

Dasatinib Inhibits Growth of 14/15 Imatinib-Resistant BCR-ABL-Expressing Ba/F3 Cell Lines in vitro

1.2

Parental Ba/F3 cells

1

T315I

0.8

Normalized cell number 48 hours of drug exposure

0.6

0.4

0.2

0

0

0.5

2.5

5

25

50

Concentration of dasatinib (nM)*

*Dasatinib is 300-400x more potent than imatinib in vitro

Shah et al, Science, 2004

slide13

Dasatinib Selectively Inhibits BCR-ABL-dependent Hematopoiesis in vitro

CML

imatinib-sensitive

(no mutation)

CML

imatinib-resistant

(BCR-ABL/M351T)

Normal

Normal

vehicle

vehicle

BMS-354825

5 nM dasatinib

nM

5

Shah et al, Science 2004

summary of scientific rationale dasatinib for imatinib resistant and intolerant cml
Summary of Scientific Rationale: Dasatinib for Imatinib-resistant and -intolerant CML
  • Imatinib resistance
    • Potently inhibits nearly all imatinib-resistant BCR-ABL kinase domain mutations
    • 300-400x more potent than imatinib at inhibiting the activity of BCR-ABL
  • Imatinib intolerance
    • Structurally unrelated to imatinib, therefore, cross-intolerance not likely
  • Selectively inhibits the growth of BCR-ABL-positive hematopoietic progenitors
claude nicaise md bristol myers squibb global development
Claude Nicaise, MD

Bristol-Myers SquibbGlobal Development

Clinical Program

clinical program six studies at 68 centers
Clinical Program – Six Studies at 68 Centers
  • One Phase I Study (002)
    • Dose escalation study
      • 15 mg to 180 mg QD and 25 mg to 70 mg BID in chronic phase
      • 35 mg to 120 mg BID in advanced disease
    • Intrapatient dose escalation / decrease to safe and effective dose
  • Four Phase II Studies (013, 005, 006 and 015)
    • Open label
    • Patients resistant or intolerant to imatinib
  • One Randomized Phase II Study (017)
    • Open label
    • Control group: imatinib 800 mg/day
    • Cross-over for lack of response or intolerance
rationale for 70 mg bid dose selection
Rationale for 70 mg BID Dose Selection
  • Optimal drug exposure
    • Pharmacokinetic parameters
      • Cmax: 45 ng/mL (90 nM)
    • Pharmacodynamics and inhibition of pCRKL
      • ≈ 100% at doses  100 mg/day
      • BID > QD
  • Effective dose in Phase I study (002) 70 mg BID
  • Acceptable safety in Phase I study (002)
imatinib resistance
Imatinib Resistance
  • Resistance at the maximum tolerated dose of imatinib
    • Primary resistance
      • No complete hematologic response at 3 months
      • No cytogenetic response at 6 months
      • No major cytogenetic response at 1 year
    • Secondary resistance
      • Loss of complete hematologic response
      • Loss of major cytogenetic response
      • Progression to accelerated / blast
imatinib intolerance
Imatinib Intolerance
  • Imatinib toxicities leading to intolerance
    • Grade 3-4 non-hematologic toxicity
    • Grade 4 hematologic toxicity lasting more than 7 days
  • Patients who responded to imatinib
    • Developed intolerance while in response
    • Unable to resume therapy
  • Patients who never responded to imatinib
    • Unable to tolerate imatinib at a dose of at least 400 mg
response criteria
Response Criteria
  • Cytogenetic Response
  • Complete (CCyR) Partial (PCyR) Major (MCyR)
  • 0% Ph+ 1% – 35% Ph+ CCyR + PCyR
patients in clinical program
Patients in Clinical Program

Randomized Trial: Study 017

36 patients (22 dasatinib and 14 imatinib)

major cytogenetic response rate in imatinib resistant patients

Chronic Phase CML

Major Cytogenetic Response Rate inImatinib-resistant Patients

Percent Responders

N =

32

29

25

28

127

98

92

60

n/N =

12/32

10/29

9/25

10/27

40/127

30/98

32/92

25/60

progression free survival

Chronic Phase CML

Progression-free Survival

013 Int

002 Int

013 Res

002 Res

Proportion Not Progressed

+ + ++

Censored

Months

progression free survival32

Accelerated Phase CML

Progression-free Survival

005

002

Proportion Not Progressed

+ +

Censored

Months

progression free survival35

Myeloid Blast Phase CML

Progression-free Survival

Proportion Not Progressed

006

002

+ +

Censored

Months

progression free survival38

Lymphoid Blast Phase CML / Ph+ ALL

Progression-free Survival

Proportion Not Progressed

015 ALL

015 LB

+ + +

Censored

002 LB/ALL

Months

hematologic responses by mutation status
Hematologic Responses by Mutation Status

C

A

P

  • M244V
  • G250E
  • Y253H/F
  • E255K/V
  • T315I
  • M351T
  • E355G
  • F359C/I/V
  • H396R/P
  • MaHR
  • 13/17
  • 19/31
  • 15/20
  • 8/19
  • 0/19
  • 12/15
  • 6/10
  • 8/16
  • 14/21
  • MCyR
  • 9/17
  • 9/31
  • 10/20
  • 2/19
  • 0/19
  • 7/15
  • 2/10
  • 6/16
  • 7/21

34 unique mutations

9 amino acid substitutions account for 68% of all BCR-ABL mutations

summary of efficacy
Summary of Efficacy
  • Chronic Phase CML
    • High rate of major cytogenetic response in imatinib-resistant and imatinib-intolerant patients
    • Durable responses extending beyond 1 year
    • Progression-free survival at 6 months predictive oflong-term benefit
  • Advanced Disease (Accelerated, Blast, Ph+ ALL)
    • High rate of major hematologic responses
    • Durable, complete responses in Ph+ ALL
    • Long-term survivors identified at all stages including patients in blast transformation
safety overview
Safety Overview
  • Safety Database
    • 511 leukemic patients treated with dasatinib BID
    • Minimum 8 months of follow-up
  • Major Findings
    • Myelosuppression, mostly thrombocytopenia
    • Fluid retention, including pleural effusion
effect on cardiac repolarization
Effect on Cardiac Repolarization
  • Nonclinical evaluation
    • hERG IC50: 14,300 nM
    • No ECG change in telemetered monkeys
  • Clinical findings
    • Mean ∆ QTcF: 3–6 msec
  • QTc outlier analysis (serial ECGs in Phase II)
    • QTcF: 3/446 >500 msec on Day 8
    • ∆ QTcF: 13/441 >60 msec on Day 8
  • Adverse events
    • 9 AEs of QT prolongation
    • No arrhythmia associated with QT prolongation
dasatinib in imatinib intolerant patients
Dasatinib in Imatinib-intolerant Patients
  • 94 intolerant patients
  • Similar safety profile to the entire population
    • Myelosuppression
    • Fluid retention
  • Minimal cross-intolerance with imatinib
    • No recurrent hepatotoxicity or skin toxicity
    • Three patients developed the same grade 3 toxicity on dasatinib (nausea, diarrhea, fatigue)
safety summary
Safety Summary
  • Myelosuppression
    • Predictable, frequently severe
    • Rarely complicated by severe bleeding or infection
    • Manageable by dose interruption, dose reduction and occasionally by transfusion
  • Fluid retention including pleural effusion
    • Common, likely related to PDGFR inhibition
    • Managed with diuretics, corticosteroids, dose interruptions and, occasionally, invasive procedures
  • Minimal hepatotoxicity
  • Other adverse events were usually mild to moderate
hagop m kantarjian md chairman professor leukemia department md anderson
Hagop M. Kantarjian, MD

Chairman & Professor, Leukemia DepartmentMD Anderson

Clinical Perspective

chronic phase cml imatinib resistant
Chronic Phase CML – Imatinib-resistant
  • Poor prognosis after imatinib failure
    • Few cytogenetic responses
    • Poor survival: <2 years; <1 year with P-loop mutations
  • Limited treatment options: stem cell transplant, escalate imatinib, hydroxyurea, IFN-, investigational agents
  • Major benefit with dasatinib:
    • CHR 87% and MCyR >30%
    • Duration of response > 1 year
chronic phase cml imatinib intolerant
Chronic Phase CML – Imatinib-intolerant
  • Highest unmet medical need
    • No benefit from targeted therapy
  • Imatinib intolerance uncommon, but often associated with resistance
  • 67 patients with intolerance, mostlynon-hematologic, treated
    • Hematologic and cytogenetic responses similar to those achieved with imatinib post-interferon
    • Responses durable; all patients progression-free (follow-up 6 to 20 months)
  • Minimal cross-intolerance
accelerated phase cml post imatinib failure
Accelerated Phase CML Post-imatinib Failure
  • Initial diagnosis of accelerated phase uncommon; most patients progress from chronic phase and are imatinib-resistant
  • Poor prognosis: median survival <1 yr
    • Limited options: hydroxyurea,intensive chemotherapy +/- stem cell transplant, investigational agents
    • No durable responses
  • Dasatinib highly effective
    • High rates of durable hematologic and cytogenetic response
blast phase cml post imatinib failure
Blast Phase CML Post-imatinib Failure
  • Almost all patients progressed to blast phase and were imatinib resistant
  • Very poor survival; rarely exceeds few months
    • Most had prior chemotherapy
    • Limited options: intensive chemotherapy, investigational therapy
  • Dasatinib induces durable responses unexpected with other therapeutic options
ph all post imatinib failure
Ph+ ALL Post-imatinib Failure
  • Worst prognosis
    • No treatment options due to failure of prior therapies including chemotherapy and stem cell transplant
    • Expected survival less than 3 months
  • Dasatinib highly effective
    • Durable complete hematologic and cytogenetic responses
    • Duration of response > 4 months
overall safety
Overall Safety
  • Most important safety issues myelosuppression and fluid retention
  • Potentially severe, but manageable with early interventions
    • Dose interruption
    • Dose reduction
    • Non-invasive interventions
      • Growth factors for myelosuppression
      • Diuretics and steroids for fluid retention
dasatinib benefit risk potential
Dasatinib Benefit:Risk Potential
  • Benefits patients with CML and Ph+ ALL who have no other treatment options
  • Highly effective in all CML phases post-imatinib failure
  • Minimal cross-intolerance with imatinib
  • Myelosuppression predictable and manageable
  • Other toxicities (including pleural effusion) manageable with early intervention
donna morgan murray phd bristol myers squibb global regulatory sciences64
Donna Morgan Murray, PhD

Bristol-Myers SquibbGlobal Regulatory Sciences

Conclusion

proposed indications for dasatinib65
Proposed Indications for Dasatinib
  • Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib
  • Treatment of adults with Philadelphia chromosome‑positive (Ph+) acute lymphoblastic leukemia (ALL) and lymphoid blast chronic myeloid leukemia with resistance or intolerance to prior therapy