R. Angelo de Claro, MD - University of Washingtondepts.washington.edu/hemeweb/seminars-conferences/deClaro slide… · 12/9/2009 2 AML in the elderly Drug approval process Analysis

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R. Angelo de Claro, MDfDivision of Hematology

University of Washington

No conflicts of interest.

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AML in the elderly

Drug approval process

Analysis of Recent NDAs:

Mylotarg, Zarnestra, Clolar, Onrigin

Discussion

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AML Incidence per 100,000 (2002‐2006)

http://seer.cancer.gov/csr/1975_2006/browse_csr.php?section=13&page=sect_13_table.10.html

The US Population is Aging

350 < 65 years

100

150

200

250

300 > 65 years

US Bureau of the Census. 1996.

0

50

1950 1990 2030

8.1% 12.7% 20.0%

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Median Survival

80%

100%

Overall 30%

65-74 Years 44%

ReceivedChemo

3.9

1.4

2.4

Survival (months)

20%

40%

60%

Per

cen

t S

urv

ivin

g

2.2

65 74 Years 44%

75-84 Years 24%

85+ Years 6%

0%

0 3 6 9 12 15 18 21 24

Number of Months Following Diagnosis

Menzin J et al, Arch Intern Med 2002 Jul 22;162(14):1597‐603.

M.D. Anderson AML Data (provided by E. Estey)

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Cytogenetics (1=favorable/interm 2=unknown orCytogenetics (1=favorable/interm, 2=unknown or 5=unfavorable points)

De novo vs. secondary (1 or 3 points)

Age (1=60‐64,2=65‐69,3=70‐74,4=75+)

Performance status (0,1,2,3,4)

WBC (1=<10,2=10‐49,3=50‐99,4= ≥100)

Risk group 4‐6 points best7‐8 points intermediate 9+ points worst

Wheatley K et al, Br J Haematol 2009 Jun;145(5):598‐605.

Wheatley K et al, Br J Haematol 2009 Jun;145(5):598‐605.

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Adult AML

AML Genetic AML Normal Karyotype

Falini B et al, Blood 2007 Feb 1;109(3):874‐85.

Heterogeneity

Tallman MS et al, Blood, Aug 2005; 106: 1154‐1163 and update.

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Safety (FD&C Act 1938)Safety (FD&C Act 1938)

Efficacy (1962 Amendment)

Substantial evidence

Demonstrated in adequate and well‐controlled studies

Specific Indication

Defined patient population

http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm120865.pdf

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Regular Approval

Clinical benefit (longer or “better” life) OR

Established surrogate for clinical benefit

Accelerated approval (Subpart H, 1992)

Surrogate endpoint reasonably likely to predictclinical benefitclinical benefit

in AML, durable complete response*

http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm120865.pdfFleming TR, Health Aff (Millwood) 2005 Jan‐Feb;24(1):67‐78.*Appelbaum FR et al, Blood 2007 Mar 1;109(5):1810‐6.

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Serious or life‐threatening diseaseSerious or life threatening disease

Drug provides benefit over available therapy

Surrogate endpoint reasonably likely to predict clinical benefit

Subsequent confirmation of clinical benefit isSubsequent confirmation of clinical benefit is required (post‐approval commitment)

http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm120865.pdf

Induction Consolidation Post‐Consolidation

Daunomycin Mylotarg x 3 cycles

Ara-C+ Mylotarg

DaunomycinA C

Complete Remission Disease‐Free Survival

Ara-C

No Therapy

http://www.fda.gov/ohrms/DOCKETS/ac/05/briefing/2005‐4191B1_04_01‐Wyeth‐Mylotarg.pdf

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Core of 13 voting members

4‐year terms

Convened 4 times per year, 1‐2 days per session, 1 drug/biologic = ½ day session

ODAC decisions are strongly taken into consideration however are non‐binding.

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee

21 CFR 14.5(a)

Mylotarg Zarnestra Clolar Onrigin

Study Design single arm single arm single arm single arm

Proposed Indication

1st relapse First‐line First‐line First‐lineIndication

p

Population CD33+ AML AML inage 75 or65 with MDS

AML inage 60

with 1 of the ff:

• age 70• PS 2

AML inage 60

with 1 of the ff:

• age 70• PS 2

• AHD• Int/Unfavkaryotype

•Unfavkaryotype•Card/Pulm/ Liver comorbidity


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Primary Endpoint

CR, CRp CR CR, CRp CR, CRp

Complete Remission (CR)• Normal marrow morphology on light microscopy with less than 5% blasts• No peripheral blasts• Recovery of peripheral blood counts with ANC 1000 and platelets 100K

CRi (CR with incomplete recovery)• fulfill requirements for CR except for recovery of peripheral counts to• fulfill requirements for CR except for recovery of peripheral counts to required level

CRp (CR with incomplete platelet recovery)• subset of CRi where recovery of platelets < 100K

*Appelbaum FR et al, Blood 2007 Mar 1;109(5):1810‐6.

Mylotarg Study

CR(n=23)

CRp(n=19)

logrank = 0.7

Sievers EL et al, J Clin Oncol. 2001 Jul 1;19(13):3244‐54.

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CR

CR (n=1,328)

( 41)

p = 0.0001

CRp (n=41)

M.D. Anderson patients with AML1980‐2004

Walter RB et al, J Clin Oncol (submitted).


Primary Endpoint

CR, CRp CR CR, CRp CR, CRp

n = 142 136 112 140

CR 16%[11‐23]

11%[7‐18]

38%[29‐47]

27%[20‐35]

CRp 13%[8‐20]

n.d. 8% 7%[4‐13][8 20] [4 13]

Accelerated Approval * * Approved for modified indication.

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90

100

All Patients

50

40

30

20

60

70

80 Censored

All Patients

Median 164 days

Pat

ien

ts (

%)

0

10

0 100 200 300 400 600 700500 1000800 900

Number of patients136 68 31 19 13 10 4 3 1 0 0

Days

http://www.fda.gov/ohrms/dockets/ac/05/slides/2005‐4138‐Index.htm

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Median survival: 40.7 wks (95CI, 28.3‐53.0 wks)


• “In general, approval of new drugs for initial

treatment of AML is based on results of

randomized controlled trials.

• It will be difficult to interpret the results of this

trial without a control; we recommend that you

conduct a randomized controlled study.”

pre‐sNDA meeting for Clofarabine, 12/4/07


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Cytotoxic Therapy with Curative Intent

p = 0.054

Mengis C et al, J Clin Oncol. 2003 November 1; 21(21):3933‐9.

Patient populationAge 70AML, de novo or secondaryNo previous chemo

Overall Survival

No previous chemoECOG PS 0‐2

n = 457

CR rate = 8%

Harousseau JL et al, Blood 2009 Aug 6;114(6):1166‐73.

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Study Population:Relapsed AML, age 18‐60

Placebo/Ara‐C (n=86)


Laromustine/Ara‐C (n=177)

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Study Design single arm single arm single arm single arm

Proposed Indication

1st relapse First‐line First‐line First‐lineIndication

p


AML inage 60

with 1 of the ff:

• age 70• PS 2

AML inage 60

with 1 of the ff:

• age 70• PS 2

• AHD• Int/Unfavkaryotype

•Unfav karyotype•Card/Pulm/ Liver comorbidity


too sick to receiveother therapy?



AML inage 60

with 1 of the ff:

AML inage 60

with 1 of the ff:

MDS• age 70• PS 2• AHD• Int/Unfavkaryotype

• age 70• PS 2•Unfavkaryotype•Card/Pulm/ Liver comorbidity

7+3 salvage % received[% eligible]

7% 21%[25‐41%]

?[30%]

HSCT salvage 11%


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Randomized clinical trial

Inclusion Criteria

previously untreated AML or RAEB with IPI1.5

age 60 years

WHO PS 0‐2

Löwenberg B et al, N Engl J Med 2009 Sep 24;361(13):1235‐48.

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Treatment

Cycle 1: Daunorubicin 45 vs 90 mg/m2 D1‐3 + cytarabine 200 mg/m2 CIV D1‐7

Cycle 2: Cytarabine 1 gm/m2 IV D1‐6

If in CR after cycle 2If in CR after cycle 2,

(optional) allo‐SCT if with HLA‐matched donor

Randomization to (1) mylotarg 6 mg/m2 x 3 cycles OR (2) observation


C ti l E l t dConventional(n=411)

Escalated(n=402)

Age 70 26% 27%

PS 2 10% 10%

Secondary AML 18% 23%

CytogeneticsCytogeneticsUnfavorable + Very Unfavorable*

11 + 13% 9 + 12%

*Very unfavorable risk: a monosomal karyotype, defined by the presence of twoautosomal monosomies or one autosomal monosomy in combination with at least onestructural abnormality other than core binding factor

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Complete Remission Rate % Conventional Escalated

Overall 54 2 64 2

Age 70 52 5 60 5

PS 1 or 2 51 3 58 3

Unfavorable cytogenetics 48 8 66 8

Very Unfavorable cytogenetics 28 6 42 7


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Mortality and morbidity in patients receiving encainide, flecainide, or placebo.receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial

(CAST)

DS Echt, PR Liebson, LB Mitchell, RW Peters, D Obias‐Manno, AH B k D A b A B k L F i d HL G d t lBarker, D Arensberg, A Baker, L Friedman, HL Greene, and et al

Echt DS et al, N Engl J Med 1991 Mar 21;324(12):781‐8.

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Clinical equipoise means that there is

i t i t h th tgenuine uncertainty over whether or not

the treatment will be beneficial.

uncertainty among expert medical community rather

than in the investigator

thi l j tifi ti f d i ti i li i l t i lethical justification for randomization in clinical trials

Freedman B, N Engl J Med 1987 Jul 16;317(3):141‐5.

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FDA approval = Marketing approval

Insurance coverageAdvertising

Return of Investment

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1999: IND filed by MDACC,

eventually licensed to Bioenvision

2001: Co‐development agreement

ILEXBioenvision

G

2004: Genzyme

acquires ILEX for

US$1B

2007: Genzyme

acquires Bioenvision

for US$350MGenzyme for US$350M

Other Interesting Facts:2007 Genzyme Revenue US$4.6B2007 FDA Budget US$2.0B

Resource burden

need more patientsneed more patients

longer accrual time

more expensive

Physician discomfort with randomization

ff t ti t’ tiaffects patient’s perceptions

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Adaptive randomization

Baseline adaptive (biased coin urn design) versusBaseline adaptive (biased coin, urn design) versus

response adaptive (play‐the‐winner, two‐armed‐bandit)

less statistical power with unbalanced arms

Zelen Design

randomization before informed consent [? IRB approval]

Seamless Phase II/III Design

? Acceptance by FDA

Randomized control trials in elderly AML are feasible, however are more resource‐intensive.

If clinical equipoise is present, then randomization is ethically acceptable.

Recent FDA actions strongly favor use of randomized control trials in non‐relapsed/ refractory settingsrefractory settings.

Reduces bias (selection, volunteer, etc.)

Balances patient heterogeneity

Allows for adequate interpretation of efficacy and safety data

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Eli Estey

Tom Fleming

R. Angelo de Claro, MD - University of Washingtondepts.washington.edu/hemeweb/seminars-conferences/deClaro slide… · 12/9/2009 2 AML in the elderly Drug approval process Analysis

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