third international study · 2 lch-iii report sept 2008 3 subcenter start of protocol usa/canada...

1

LCH-III Report Sept 2008 1

START: 01.04.2001

LCH-IIITHIRD INTERNATIONAL STUDY

EVALUATION: September 2008


LCH-III

STUDY REFERENCE CENTER VIENNAGADNER H.GROIS N.

MINKOV M.

PÖTSCHGER U.

THIEM E.

DATA SAFETY MONITORING BOARDFALDUM A.OTTEN J.

TUBERGEN D.

2


SUBCENTER Start of protocolUSA/CANADA April 2001 ITALY April 2001SCANDINAVIA April 2001GPOH April 2001ARGENTINA April 2001FRANCE January 2002SPAIN February 2002UK August 2002

LCH-III


RECRUITMENT OF MS-PATIENTS

3


RECRUITMENT

1131602529All

21615Brazil

381622Spain

1193980Argentina

51-51France

480327153GPOH

311219Scandinavia

893752Italy

251139112USA

512625UK

ALLSSMS


Multi-System LCHn=530

Involvement of risk organs(hematopoetic system, liver, spleen or lungs)

Risk Groupn=269(51%)

n=266

Low Risk Groupn=260(49%)

n=252

yes no

prior to Nov. 2007

4


Multi-System LCH

Involvement of risk organs(hematopoetic system, liver, spleen or lungs)

Risk Group

control arm A (PDN+VBL)

experimental arm B (PDN+VBL+MTX)

Low Risk Group

initial response at week 6

NAD/AD better Intermediate/worse

continuation treatmentfor 6 months (LR6)


Randomisation

Randomisation

yes no


MULTI-SYSTEM

518529266269252260All

15159966Brazil

2222991313Spain

798052522728Argentina

515128282323France

14315373767077GPOH

1919441515Scandinavia

525224242828Italy

11211258585454USA

2525991616UK

< 11.2007All< 11.2007All< 11.2007All

AllRiskLR

5


RISK PATIENTS

MS-LCH with involvementof „RISK“ organs

(hematopoetic system, liver, spleen orlungs)


RECRUITMENT OF RISK PATIENTS

6


INITIAL TREATMENT COURSE 1 INITIAL TREATMENT COURSE 2

NAD procede to continuation therapy arm A

A

NAD procede to

AD better AD better continuat. tx arm AAD intermediate

AD intermediate procede to salvageAD worse

RX

AD worse procede to salvage

NAD

B NAD procede to AD better continuat. tx arm B

AD better

AD intermediate

AD intermediate procede to salvageAD worse

AD worse procede to salvageday 1 8 15 22 29 36

w eek 1 2 3 4 5 6 7 8 9 10 11 12

PDN 40 mg/m2/d orally day 1-28 PDN 40 mg/m2/d orally day 1 - 3; weekly for 6 weeks

afterwards weekly reduction

MTX 500 mg/m² q 2 weeks(+Ca-folate rescue) MTX 500 mg/m² q 2 weeks (+Ca-folate rescue)

VBL 6 mg/m2 i.v. bolus; day 1,8,15,22,29,36 VBL 6 mg/m2 i.v. bolus; day 43,50,57,64,71,78

w eek

procede to continuation therapy arm B

6 WKS

EVALUATION EVALUATION

12 WKS

LCH III - RISK PATIENTS – INITIAL TREATMENT


LCH III - RISK PATIENTS

CONTINUATION TREATMENT

CONTINUATION TREATMENT

Arm A12 months

Arm B

12 months

week 7 10 13 16 52or 13 16 19 22

PDN 40 mg/m2/d orally day 1-5 of week (7, 10), 13, 16, 19, ...52 VBL 6 mg/m2/d i.v. bolus q3 weeks

MTX 20mg/m2/os day 7, weekly 6-MP 50 mg/m2/d orally for 12 months

7


RISK PATIENTS

UNTIL AUGUST 2007

Recruitment period: 76 months

observed expected

MS patients 489 516

Risk patients 255 275

Randomisations 222 220

87% 85%

AUGUST 2008

234 Randomisations


RISK PATIENTSRANDOMISATIONS IN SUBCENTERS

** Brazil is randomized together with GPOH

11911587%234269All

4378%79Brazil**

3478%79Spain

242798%5152Argentina

141396%2728France

292678%5576GPOH

1275%34Scandinavia

9975%1824Italy

3127100%5858USA

4489%89UK

Arm BArm A%nTotal

randomized

8


108unknown

-13 days-297 days-7 days-1.4yrs.? min-max

5 days8 daysmedian

Dx-therapy start

2428unknown

-5 days – 6.2 years-3 days-6.7yrs.min-max

57 days44 daysmedian

First Symptom-Dx

77%8973%81< 2years

10 days-17.8 years4

15d-17yrs.4

min-maxunknown

1 year 2 months1 year 2 monthsmedian

Age

75unknown

46%5247%52female

54%6053%58male

Sex

Arm B n=119

Arm A n=115


HISTOLOGICAL CONFIRMATION

96%22423495%254268All

86%6789%89Brazil

100%77100%99Spain

100%515198%5152Argentina

96%262796%2728France

95%525593%7075GPOH

100%33100%44Scandinavia

100%181896%2324Italy

91%535891%5358USA

100%88100%99UK

%n%n

hist. confpts.hist. confpts.

randomized risk patientsAll risk patients

9


RISK PATIENTSRISK ORGAN INVOLVEMENT

1. R

O o

nly

100%268100%34100%119100%115All

1%36%21%10%0missing

9%253%113%158%94 RO

21%5721%724%2819%223 RO

27%7212%424%2934%392 RO

3%96%21%15%6spleen

25%6644%1521%2523%26lung

9%233%111%138%9liver

5%136%26%73%4hema

%n%n%n%n

ALLnotrandomized

Arm BArm A


RISK PATIENTS RANDOMIZATIONSexpectation according to protocol: 35-40 randomizations/year

12

0

5

10

15

20

25

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3

2001 2002 2003 2004 2005 2006 2007

2001

n=122002

n=402003

n=422004

n=372005

n=442006

n=272007

n=29 (44)

10


RISK PATIENTSPRIMARY STUDY ENDPOINT

NON-RESPONSE IN RISK ORGANSAT WEEK 12

PDN+VB vs. PDN+VBL+MTX


RISK PATIENTSDEFINITION OF PRIMARY ENDPOINT

Non-response in risk-organs to initial therapyis defined as

• Death within 12 weeks of initial treatment

• Progression (worse) in risk organs at week 6

• Lack of response (=intermediate response orprogression) in risk organs at week 12 (compared to status of disease at week 6)

11


RISK PATIENTS POWER CONSIDERATIONS

Null hypothesis: 50% non-response in both armsAlternative hypothesis:Arm B⇒30% non-response

Two-sided α=5%, power=80% ⇒⇒⇒⇒ 228 patients

(given the group sequential design)

48 risk patients/year expectedrandomization rate = 85% ⇒ 40 randomization/year

10% LFU within 12 weeks of treatment⇒ 36 patients/year will enter the analysis

⇒⇒⇒⇒

recruitment period of 6 years


RISK PATIENTSPRIMARY ENDPOINT

Response in Risk Organs at Week 6/12

234 pts. randomised

204 (87%) with information

at wk 6/12

12




PREVIOUS INTERIM ANALYSES and

MISSING INFORMATION

April 2004 51%Sept. 2004 26%May 2005 29%Aug. 2005 26%Sept. 2006 23%Jan. 2007 19%August 2007 16%

THIS EVALUATION 13%




87%204234All

43%37Brazil

86%67Spain

94%4851Argentina

89%2427France

95%5255GPOH

100%33Scandinavia

78%1418Italy

79%4658USA

100%88UK

%n

RO-Response available

evaluable

13


RISK PATIENTSPRIMARY ENDPOINT:

Non-Response in Risk Organs at Week 6/12

Group Sequential Design according to O‘Brien Fleming

3rd interims analysis Last Evaluation Current Analyses

139 evaluable patients 177 204

Arm A: 20/70 (29%) 25/92 (27%) 31/102 (30%)

Arm B: 21/69 (30%) 25/89 (28%) 29/102 (28%)

INNER BOUNDARY CROSSED

next interim originally planned after 182 pts. Maximum Sample size 228

-6

-4

-2

0

2

4

6

0% 20% 40% 60% 80% 100%

no

min

al c

ritic

al p

oin

t

accept H0

accept alternative hypotheses



Response

14 1022 20 20 22

32 31

56 65 46 52 5058

42 45

14 12 20 16 114 7 109 6 4 4 5 6 3

312 12 13 12 10 4 9 3

1 2 1 3 4 8 5 8

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Arm A Arm B Arm A Arm B . Arm A Arm B Arm A Arm B

Overall response Response in RO . Overall response Response in RO

NAD AD: better Intermediate stable Intermediate mixed worse ? but died

Week 6 Week 12

14


6-weeks response

19 1935

48 70 75

13 1413

13 23 1812 9 14 10 13 14

0%

20%

40%

60%

80%

100%

VBL VP16 VBL VBL+VP16 VBL VBL+MTX

Responder Intermediate Non-Responder

LCH- LCH-II LCH-III

Pred 30 mg/kg

one initial pulse on 3 cons. day s,

first course only

Pred 40 mg/m² day 1-28 afterw ards w eekly reduction

Pred 40 mg/m² day 1-28 afterw ards w eekly reduction

I


RISK PATIENTSSECONDARY STUDY ENDPOINTS

• OVERALL SURVIVAL

• REACTIVATION FREE SURVIVAL

• PERMANENT CONSEQUENCIES

Complete follow up information is a prerequisite

for the evaluation of the secondary aims !!!

15


Follow up of Survivors


Randomized Risk patientsCompleteness of follow up reporting

* pts.-months observed/expected

67%67%4832202All

2%1%310.35Brazil

55%75%60455Spain

82%83%524337Argentina

70%76%493727France

73%68%473248GPOH


61%63%573613Italy

61%53%452456USA

57%44%36168UK

%

01.09.2008last followup

Survivors last

year

Months from

randomization to

16


Overall Survival in RISK

median observation time 2.7 years

0.80±0.0419119B

0.87±0.0313115A

3-yrs. pSUDeathsPatients

p=0.236


Survival

LCH-III A: n=102, 0.85±0.04

LCH-III B: n=104, 0.82±0.04

LCH-II B: n=74, 0.76±0.05

LCH-II A: n=64, 0.68±0.05

LCH-I B: n=42, 0.70±0.07

LCH-I A: n=45, 0.59±0.07

LCH-I LCH-II LCH-III Arm A Arm B

17


Arm A- Deaths

13 deaths; 10 due to progression; 7 within 12 weeks

Progression of Disease25.1.stableYYNYSpain

pneumonia grade IV, bleeding-hydrocephal. Sepsismautopsy denied8.6

worse.NNYNArgentina

infection: gram+ coco., progression2.6worseworseNNNNArgentina

disease progression30.9.worseYYNYArgentina

Progress of disease + sepsis11.3worse.YYYYArgentina

progression of disease2.1worse.worseYYYYArgentina

Progressive disease101.9betterbetterYNNYArgentina

disease progression5.1worseworseYYYYArgentina

disease related - respiratory failure1.3worseworseNNYYGPOH

Heart failure after lung transplant82.1.worseNNYNItaly

Septicemia during progressive disease (cytopenia, liver,skin,lung)11.3

worsestableYNYYItaly

Progressive disease50.1mixedmixedYYNYItaly

respiratory failure due to progressive LCH (liver failure)26.9betterworseYNYYUSA

CauseweekWeek12week 6

SP

LE

E

N

HEMALUNG

L

I

V

E

R

Center

DeathResponse in RORisk organs at Diagnoses


Arm B - Deaths

disese related25.4stablebetterNYYYBrazil

sudden death, sepsis1.6worseworseNNNNBrazil

resp. Distress, VRS+ Bronchmyolitis12.7NADstableNYNYSpain

Thrombocytopenia, pulmonary hemorraghia1.6worseworseNNNNArgentina

progr. Disease, sepsis3.0worseworseNNNNArgentina

Progressive Disease57.4..YYYYArgentina

Sepsis11.7stablebetterNYYNArgentina

Sepsis, progress of disease1.0worseworseYYNYArgentina

Disease progression, sepsis5.9worseworseNNNYArgentina

Progressive Disease131.4NAD.YYNYArgentina

sepsis, hepatic failure related to multisystem LCH81.1betterbetterNYNYGPOH

sek. HLH, cardio-pulmon. Dysf.5.4worseworseNYYYGPOH

progression of disease28.3mixedbetterYYNYGPOH

progression of disease, CMV, aspergillus,aplasia, streptococcus sepsis12.9

worseworseNNNNGPOH

Multi organ failure (progress of disease)3.7worseworseYYYYGPOH

progression of disease59.9betterstableYYNYGPOH

septicemia during retretament for progressive disease89.1.stableYYNYItaly

PROGRESSIVE DISEASE51.1NADbetterYYNYItaly

disease progression6.7worseworseYNYYUSA

Causeweekweek12week 6SPLEENHEMALUNGLIVERCenter

DeathResponse in RORisk organs at Diagnoses

18


RISK PATIENTSEARLY DEATHS WITHIN 12 WEEKS OF THERAPY

LCH-II:10% (5/50) early deaths

95% CI: 5%-23%

10% acceptable15% unacceptable

LCH-III

8% (16/191) early deaths95% CI: 4%-13%

*pts. with FU > 12 weeks only31 (14%) no information on

12-week survival !!

0

5

10

15

20

25

30

35

0 40 80 120 160 200 240

number of patients with 12 week evaluationn

um

ber

of

death

s

wit

hin

12 w

eeks o

f th

era

py

unacceptable high

early death rate

acceptable

early death rate

ALL: 16/191 (8%)B: 9/95 (9%)

A: 6/96 (7%)

boundaries from Wald‘s

sequential probatility ratio test

a=13%, power=78%


Risk patients

26827Total

11912Arm B

11515Arm A

340not randomized

2-CDA+ARA C pts.

19


Time to NAD

Arm A: n=112 1-year CI=0.51±0.05 82 NAD, 12 Deaths w/o NAD

Arm B: n=114 1-year CI=0.50±0.05 77 NAD, 15 Deaths w/o NAD


RISK-Reactivations

reactivations/pts. 1-year cumulative incidenceArm A: 19/75 0.21±0.05 8 in risk-organsArm B: 13/61 0.19±0.06 6 in risk-organs

20


Reactivations

LR

Risk

0.34±0.081346120.57±0.09245660.35±0.071969B0.29±0.061975A3-yrs. pReactEventsPatients


Reactivations

0.42±0.100.55±0.080.44±0.070.38±0.073-yrs. pReact

0.30±0.100.44±0.060.27±0.070.32±0.072-yrs. pReact

0.16±0.100.24±0.080.12±0.060.16±0.071-yrs. pReact

LR

Risk

126BA

21


Reactivations Arm A

NNNNNNN.YNNNN2.07820081507080

NNNNYNN.N.YNN0.17220081507107

...N.N.N.....1.86720071505606

...NYN..Y....0.92320071503066

NNNYNNNYYNNYN0.35620071502207

NNNNNNN.YY.NN0.83220061507068

NNNNNNNNYNNNN0.57820061506605


NNNNYNNNYNNNN0.62120051507024


NNNNYNNNYNNNY0.90120051505476

...........Y.0.17520051503058

...N.N..Y..Y.1.97920051502075

NNNNYNN.NNNNN0.22220041507033

NNNNYNN.YNNNN1.04620041507031

....Y...Y....0.24920041503027

NNNYYNYYYNYNN0.98620041502046

NN.NYN.NNNYNN0.37220031506009

...NYN...NN..0.19220031502084


OTHSTTMucous

HYPO

SKINNERVES

LYMPH

DIBONE

HEMA

SPLEEN

LUNG

LIVER

afterNAD

yearHSUPN


Reactivations Arm B


NNNNNNYNYNNNN2.18520071506632

NNNNYNNNNNNNN2.0720071506621

NNYNYNN.NNNNN0.40820071505678

...NYN...N.NY0.45720071503094

NNNNYNNYYNNNN2.28120071502155




.........Y.YN0.8320051503048

NNNNYNN.NNYYY0.58620051502098

NNNNYNN.YNNNN0.21620041507040

NNNYNNNYYNNNN1.5520041506003

....Y...Y...N0.98320041503013

.....N.YY....1.07320041503009

NNNNYNN.NNNNY0.13420031508001


NNNNNNN.YNNYN0.61920031505068

..Y...Y...Y.Y0.41920021503001

OTHSTTMucous

HYPO

SKINNERVES

LYMPH

DIBONE

HEMA

SPLEEN

LUNG

LIVER

afterNAD

yearHSUPN

22


Reactivations at 2 yrs

LCH-I A: n=62, 0.30±0.06

LCH-I B: n=61, 0.22±0.05

LCH-II B: n=48, 0.41±0.07

LCH-II A: n=36, 0.38±0.09

LCH-III A: n=23, 0.45±0.10

LCH-III B: n=27, 0.45±0.10

LCH-I LCH-II LCH-III Arm A Arm A


Toxicities within 6 weeksFUN1

FUN n % n % n % n % n % n % n % n % n % n %

Leukopenia 75 74% 14 14% 10 10% 1 1% 2 2% 70 67% 13 13% 13 13% 6 6% 2 2% 0.168Thrombocytopenia 94 92% 5 5% 0 0% 3 3% 0 0% 82 79% 5 5% 6 6% 8 8% 3 3% 0.002

Nausea/Vomiting 92 90% 4 4% 5 5% 1 1% . . 88 85% 7 7% 5 5% 4 4% . . 0.213Oral tox. 98 96% 1 1% 2 2% 1 1% 0 0% 86 83% 7 7% 2 2% 7 7% 2 2% 0.004

Diarrhoea 92 90% 5 5% 3 3% 2 2% . . 87 84% 6 6% 6 6% 5 5% . . 0.118Creatinine 102 100% 0 0% . . . . . . 102 98% 2 2% . . . . . . 0.160Clearance 101 99% 1 1% 0 0% . . 0 0% 101 97% 1 1% 1 1% . . 1 1% 0.205Bilirubin 94 92% 4 4% 2 2% 1 1% 1 1% 91 88% 2 2% 7 7% 4 4% 0 0% 0.195GOT/GPT 91 89% 4 4% 2 2% 4 4% 1 1% 74 71% 6 6% 6 6% 12 12% 6 6% 0.001

Skin 88 86% 10 10% 4 4% . . 0 0% 82 79% 10 10% 11 11% . . 1 1% 0.054Neurotox 101 99% 0 0% 1 1% . . . . 102 98% 1 1% 1 1% . . . . 0.750Cardiotox 102 100% . . . . . . . . 104 100% . . . . . . . .

Echocardiography 101 99% 1 1% . . . . . . 104 100% 0 0% . . . . . . 0.313Ototoxicity 101 99% 1 1% . . 0 0% . . 102 98% 1 1% . . 1 1% . . 0.372Hering loss 101 99% . . . . . . 1 1% 104 100% . . . . . . 0 0% 0.313Pulmonary 97 95% 1 1% 1 1% 1 1% 2 2% 94 90% 6 6% 2 2% 0 0% 2 2% 0.693Alopecia 96 94% 4 4% 0 0% 2 2% . . 87 84% 13 13% 2 2% 2 2% . . 0.090Infection 72 71% 9 9% 12 12% 6 6% 3 3% 74 71% 3 3% 11 11% 15 14% 1 1% 0.554

1 2

p-value

(MH-

test)

3 4

Arm A Arm B

0 1 2 3 4 0

23


Toxicities week 6 – week 12FUN2

FUN n % n % n % n % n % n % n % n % n % n %

Leukopenia 64 74% 11 13% 8 9% 3 3% 1 1% 63 69% 14 15% 10 11% 0 0% 4 4% 0.527Thrombocytopenia 84 97% 1 1% 2 2% 0 0% 0 0% 83 91% 2 2% 3 3% 2 2% 1 1% 0.090Nausea/Vomiting 76 87% 4 5% 7 8% 0 0% . . 77 85% 3 3% 7 8% 4 4% . . 0.286Oral tox. 83 95% 2 2% 2 2% 0 0% 0 0% 85 93% 2 2% 1 1% 2 2% 1 1% 0.276

Diarrhoea 79 91% 5 6% 1 1% 2 2% . . 83 91% 4 4% 3 3% 1 1% . . 0.933Creatinine 87 100% 0 0% . . . . . . 90 99% 1 1% . . . . . . 0.328Clearance 87 100% . . . . 0 0% 0 0% 89 98% . . . . 1 1% 1 1% 0.170Bilirubin 85 98% 1 1% 0 0% 0 0% 1 1% 85 93% 1 1% 2 2% 2 2% 1 1% 0.210GOT/GPT 78 90% 2 2% 5 6% 2 2% 0 0% 72 79% 6 7% 3 3% 8 9% 2 2% 0.038

Skin 80 92% 6 7% 1 1% . . . . 84 92% 6 7% 1 1% . . . . 0.934Neurotox 87 100% 0 0% 0 0% . . . . 89 98% 1 1% 1 1% . . . . 0.189Cardiotox 87 100% . . . . 0 0% . . 90 99% . . . . 1 1% . . 0.328Echocardiography 87 100% . . . . . . . . 91 100% . . . . . . . .

Ototoxicity 86 99% . . 1 1% 0 0% . . 88 97% . . 1 1% 2 2% . . 0.253Hering loss 86 99% . . 0 0% . . 1 1% 90 99% . . 1 1% . . 0 0% 0.632Pulmonary 83 95% 1 1% 2 2% . . 1 1% 89 98% 1 1% 0 0% . . 1 1% 0.501Alopecia 79 91% 4 5% 3 3% 1 1% . . 79 87% 7 8% 2 2% 3 3% . . 0.424Infection 62 71% 1 1% 16 18% 8 9% 0 0% 60 66% 7 8% 13 14% 8 9% 3 3% 0.544

3 44 0 1 2

Arm A Arm B p-value

(MH-

test)

0 1 2 3


LOW RISK PATIENTS

MS-LCH without involvement of „RISK“ organs(hematopoetic system, liver, spleen or lungs)

24


RECRUITMENT OF LOW RISK PATIENTS


Low Risk Group

initial response at week 6

NAD/AD better Intermediate/worse



Randomisation

25


LCH III - LOW RISK PATIENTS

TREATMENT PLAN

INITIAL TREATMENT COURSE 1 CONTINUATION TREATMENT

Arm LR 6 6 months

BETTER

Arm LR 12

7 10 13 25 52w eek

day 1 8 15 22 29 36 INTERMEDIATE, WORSE INITIAL TREATMENT COURSE 2 (RISK PATIENTS ARM A)

w eek 1 2 3 4 5 6

PDN 40 mg/m2/d orally day 1-28 PDN 40 mg/m2/d orally

afterwards weekly reduction

VBL 6 mg/m2 i.v. bolus day 1,8,15,22,29,36 VBL 6 mg/m2/d i.v. bolus day 1 q 3 wks for 6 or 12 months

day 1-5 q 3 wks for 6 or 12 months

RX

6 WKSEVALUATION


Low Risk Groupn=234

NAD/AD better

n=195

Intermediate

/worse

n=38/4

154randomized

wk6 response?

n=23

10randomized

21/0randomized

Eligibility?Eligible NOT Eligible

186 randomizations

26


LOW RISK PATIENTS RANDOMIZATIONSexpectation according to protocol: 29 randomizations/year

1 1 3 5 4 5 4 8 4 6 8 8 5 7 6 6 10 7 5 1 6 10 8 7 3 11 1

2

2

13

11

3

3

1

0

0 01

00

00

3

3

00

0

1

2

2

0

0

0

00

0

01

1

0

0

2

4

6

8

10

12

14

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3

eligible Response? not eligible

2001

n=82002

n=192003

n=362004

n=302005

n=352006

n=282007

n=17


0 6 12

LR6

LR12

therapy start 6 months 12 months

Low Risk PatientsTime to randomisation

Randomisation of Respondersafter 6 weeks

Randomised< 12 weeks144 pts. (62%)

(10 not eligible?

9 response?)

too late

3 pts. after week 26typing error?

too late?

25 (11%) between week 12-24

(4 not eligible3 response?)

DMC – Study committee (Sept. 2005):

Decision that randomisation must be done within 12 weeks

234 pts.

27


LOW RISK PATIENTS

observed expectedPatients 234 239Randomised 172 172Randomised and not ineligible 158Randomisation-rate** 68% 72%

Results August 2007


LOW RISK PATIENTS

71%18575%16473%102341%214281%154195260All

50%360%3-000%0160%356Brazil

69%964%70%01100%2267%71013Spain

82%2381%2250%23-1168%202428Argent.

96%2294%1593%55100%77100%101123France

45%3556%35-050%01571%355777GPOH

60%964%950%1250%0178%81215Scand

82%2379%19-0175%4483%192328Italy

91%4998%4275%3464%71197%393954USA

81%1381%130%02-0093%131416UK

%n%n%n%n%n

randomize

dpts

randomize

dpts

randomize

dpts

Total randomize

d

Randomized

and not

ineligble

eligible?not eligibleeligibleeva-

lua

blepts.

28


HISTOLOGICAL CONFIRMATION

91%16918690%233260All

100%33100%66Brazil

78%7969%913Spain

91%212393%2628Argentina

100%2222100%2323France

91%323586%6677GPOH


91%212393%2628Italy

84%414985%4654USA

100%1313100%1616UK

%nn%nn

hist confirmedhist confirmed

Randomized patientsAll patients

LCH-III Report Sept 2008 5677unknown

-9 days- 2.3yrs.?-18 days-1.4 yrs?min-max


Dx-therapy start

2326unknown

0 days – 2.3 years0 days-2.2yrs.min-max


First Symptom-Dx

43%3844%43< 2years

2 months-18 years1

4 months – 18yrs. min-maxmissing

2.4 years2.3 yearsmedian

Age at random.

33unknown

49%4241%39female

51%4459%55male

Sex

LR1212 months

n=89

LR66 months

n=97

29


LOW RISK PATIENTSPRIMARY STUDY ENDPOINT

REACTIVATION AFTER 6 MONTHS

with

6 months vs. 12 months therapy


LR6

LR12

week 6 6 months 12 months

Low Risk PatientsReactivations within 6 months

week6 – month6

NO DIFFERENCE BETWEEN RANDOMISED ARMS

REACTIVATIONS

WITHIN 6 MONTHS:

CANNOT BE ATTRIBUTED TO DIFFERENCES BETWEEN ARMS

NOT INCLUDED IN

ANALYSIS

EXPECTED

6-month reactivation rate 5%

OBSERVED

6 months reactivation rate 6%(±2%)

30


Follow up of randomised pts.

not evaluable for the primary endpoint


Completeness of Follow up

59%64%4428186AllAllAllAll 61%61%44278912 12 12 12 monthsmonthsmonthsmonths 60%62%4528976 6 6 6 monthsmonthsmonthsmonths 48%35%34123BrazilBrazilBrazilBrazil 63%58%40239SpainSpainSpainSpain 78%76%503823ArgentinaArgentinaArgentinaArgentina 52%63%352222FranceFranceFranceFrance 76%67%463135GPOHGPOHGPOHGPOH 67%51%37199ScandScandScandScand.... 49%56%522923ItalyItalyItalyItaly 50%60%452749USAUSAUSAUSA 50%54%392113UKUKUKUK lastlastlastlast%%%%01.09.200801.09.200801.09.200801.09.2008last last last last followfollowfollowfollow upupupupSurvivorsSurvivorsSurvivorsSurvivors RandomizationRandomizationRandomizationRandomization totototo

31


LOW RISK PATIENTSPRIMARY ENDPOINT

Reactivation free survival

• Events: reactivation(=progression in any organ) or death

• Interval start: 6 months after therapystart

• patients with reactivations within 6 months will be excluded in analysis


LOW RISK PATIENTSPOWER CONSIDERATIONS

Null hypothesis: 1-year RFS=65% in both armsAlternative hypothesis: LR12 ⇒ 1-year RFS=85%

Two-sided α=5%, power=80% ⇒ 36 events

40 LR patients/year expected85% (34 pts) with initial response at week 6

randomization rate = 85% ⇒ 29 randomization/year5% Events and 10% LFU within 24 weeks of treatment

⇒ 24 patients/year will enter the analysis⇒⇒⇒⇒

6-years recruitment period/sample size=148 pts.given group sequential design and LFU after 24 weeks

32


LR6

LR12

week 6 6 months 12 months

Low Risk PatientsReactivations

14 pts.

(randomised

and not

ineligible)

excluded

-13 too early

-10 reactivations (< 6 months)

135 evaluable pts

108 with FU-information after 6 months (79%)

21% without FU-information beyond 6 months

INFORMATIVE PERIOD

for primary study endpoint

172 pts.


Group Sequential Design according to O‘Brien Fleming

-5-4-3-2-1012345

0% 20% 40% 60% 80% 100%

no

min

al

cri

tical

po

int

accept H0



33


LOW RISK Reactivations after NAD/ADB

2-yrs 3-yrs after Tx-Start

6 months n=34/74 0.43±0.08 0.50±0.08

12 months n=18/64 0.26±0.06 0.35±0.08 p=0.019


Reactivations after NAD

LR

Risk

0.34±0.081346120.57±0.09245660.35±0.071969B0.29±0.061975A3-yrs. pReactEventsPatients

34


LCH-III

STUDY REFERENCE CENTER VIENNAGADNER H.GROIS N.

MINKOV M.

PÖTSCHGER U.

THIEM E.

DATA SAFETY MONITORING BOARDFALDUM A.OTTEN J.

TUBERGEN D.

third international study · 2 lch-iii report sept 2008 3 subcenter start of protocol usa/canada...

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