third international study · 2 lch-iii report sept 2008 3 subcenter start of protocol usa/canada...
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LCH-III Report Sept 2008 1
START: 01.04.2001
LCH-IIITHIRD INTERNATIONAL STUDY
EVALUATION: September 2008
LCH-III Report Sept 2008 2
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
LCH-III Report Sept 2008 3
SUBCENTER Start of protocolUSA/CANADA April 2001 ITALY April 2001SCANDINAVIA April 2001GPOH April 2001ARGENTINA April 2001FRANCE January 2002SPAIN February 2002UK August 2002
LCH-III
LCH-III Report Sept 2008 4
RECRUITMENT OF MS-PATIENTS
3
LCH-III Report Sept 2008 5
RECRUITMENT
1131602529All
21615Brazil
381622Spain
1193980Argentina
51-51France
480327153GPOH
311219Scandinavia
893752Italy
251139112USA
512625UK
ALLSSMS
LCH-III Report Sept 2008 6
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
LCH-III Report Sept 2008 7
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)
continuation treatmentfor 12 months (LR12)
Randomisation
Randomisation
yes no
LCH-III Report Sept 2008 8
MULTI-SYSTEM
518529266269252260All
15159966Brazil
2222991313Spain
798052522728Argentina
515128282323France
14315373767077GPOH
1919441515Scandinavia
525224242828Italy
11211258585454USA
2525991616UK
< 11.2007All< 11.2007All< 11.2007All
AllRiskLR
5
LCH-III Report Sept 2008 9
RISK PATIENTS
MS-LCH with involvementof „RISK“ organs
(hematopoetic system, liver, spleen orlungs)
LCH-III Report Sept 2008 10
RECRUITMENT OF RISK PATIENTS
6
LCH-III Report Sept 2008 11
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 Report Sept 2008 12
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
LCH-III Report Sept 2008 13
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
LCH-III Report Sept 2008 14
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
LCH-III Report Sept 2008 15
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
LCH-III Report Sept 2008 16
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
LCH-III Report Sept 2008 17
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
LCH-III Report Sept 2008 18
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
LCH-III Report Sept 2008 19
RISK PATIENTSPRIMARY STUDY ENDPOINT
NON-RESPONSE IN RISK ORGANSAT WEEK 12
PDN+VB vs. PDN+VBL+MTX
LCH-III Report Sept 2008 20
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
LCH-III Report Sept 2008 21
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
LCH-III Report Sept 2008 22
RISK PATIENTSPRIMARY ENDPOINT
Response in Risk Organs at Week 6/12
234 pts. randomised
204 (87%) with information
at wk 6/12
12
LCH-III Report Sept 2008 23
RISK PATIENTSPRIMARY ENDPOINT
Response in Risk Organs at Week 6/12
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%
LCH-III Report Sept 2008 24
RISK PATIENTSPRIMARY ENDPOINT
Response in Risk Organs at Week 6/12
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
LCH-III Report Sept 2008 25
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
accept alternative hypotheses
LCH-III Report Sept 2008 26
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
LCH-III Report Sept 2008 27
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
LCH-III Report Sept 2008 28
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
LCH-III Report Sept 2008 29
Follow up of Survivors
LCH-III Report Sept 2008 30
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
85%76%54413Scandinavia
61%63%573613Italy
61%53%452456USA
57%44%36168UK
%
01.09.2008last followup
Survivors last
year
Months from
randomization to
16
LCH-III Report Sept 2008 31
Overall Survival in RISK
median observation time 2.7 years
0.80±0.0419119B
0.87±0.0313115A
3-yrs. pSUDeathsPatients
p=0.236
LCH-III Report Sept 2008 32
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
LCH-III Report Sept 2008 33
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
LCH-III Report Sept 2008 34
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
LCH-III Report Sept 2008 35
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%
LCH-III Report Sept 2008 36
Risk patients
26827Total
11912Arm B
11515Arm A
340not randomized
2-CDA+ARA C pts.
19
LCH-III Report Sept 2008 37
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
LCH-III Report Sept 2008 38
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
LCH-III Report Sept 2008 39
Reactivations
LR
Risk
0.34±0.081346120.57±0.09245660.35±0.071969B0.29±0.061975A3-yrs. pReactEventsPatients
LCH-III Report Sept 2008 40
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
LCH-III Report Sept 2008 41
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
NNNNNNN.YNNNN1.28420061505641
NNNNYNNNYNNNN0.62120051507024
NNNNNNNNYNNNN0.68420051507010
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
NNNNNNNNYNNNN0.32320021506001
OTHSTTMucous
HYPO
SKINNERVES
LYMPH
DIBONE
HEMA
SPLEEN
LUNG
LIVER
afterNAD
yearHSUPN
LCH-III Report Sept 2008 42
Reactivations Arm B
NNNNNNN.YNNNN2.07820081507080
NNNNNNYNYNNNN2.18520071506632
NNNNYNNNNNNNN2.0720071506621
NNYNYNN.NNNNN0.40820071505678
...NYN...N.NY0.45720071503094
NNNNYNNYYNNNN2.28120071502155
NNNNNNN.YNNNN0.07720061507085
NNNNNNN.YNNNN1.30320061507078
NNNNNNN.YNNNN0.28720061502083
.........Y.YN0.8320051503048
NNNNYNN.NNYYY0.58620051502098
NNNNYNN.YNNNN0.21620041507040
NNNYNNNYYNNNN1.5520041506003
....Y...Y...N0.98320041503013
.....N.YY....1.07320041503009
NNNNYNN.NNNNY0.13420031508001
NNNNNNNNYNNNN0.2320031505448
NNNNNNN.YNNYN0.61920031505068
..Y...Y...Y.Y0.41920021503001
OTHSTTMucous
HYPO
SKINNERVES
LYMPH
DIBONE
HEMA
SPLEEN
LUNG
LIVER
afterNAD
yearHSUPN
22
LCH-III Report Sept 2008 43
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
LCH-III Report Sept 2008 44
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
LCH-III Report Sept 2008 45
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
LCH-III Report Sept 2008 46
LOW RISK PATIENTS
MS-LCH without involvement of „RISK“ organs(hematopoetic system, liver, spleen or lungs)
24
LCH-III Report Sept 2008 47
RECRUITMENT OF LOW RISK PATIENTS
LCH-III Report Sept 2008 48
Low Risk Group
initial response at week 6
NAD/AD better Intermediate/worse
continuation treatmentfor 6 months (LR6)
continuation treatmentfor 12 months (LR12)
Randomisation
25
LCH-III Report Sept 2008 49
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
LCH-III Report Sept 2008 50
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
LCH-III Report Sept 2008 51
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
LCH-III Report Sept 2008 52
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
LCH-III Report Sept 2008 53
LOW RISK PATIENTS
observed expectedPatients 234 239Randomised 172 172Randomised and not ineligible 158Randomisation-rate** 68% 72%
Results August 2007
LCH-III Report Sept 2008 54
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
LCH-III Report Sept 2008 55
HISTOLOGICAL CONFIRMATION
91%16918690%233260All
100%33100%66Brazil
78%7969%913Spain
91%212393%2628Argentina
100%2222100%2323France
91%323586%6677GPOH
100%99100%1515Scandinavia
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
13 days16 daysmedian
Dx-therapy start
2326unknown
0 days – 2.3 years0 days-2.2yrs.min-max
64 days51 daysmedian
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
LCH-III Report Sept 2008 57
LOW RISK PATIENTSPRIMARY STUDY ENDPOINT
REACTIVATION AFTER 6 MONTHS
with
6 months vs. 12 months therapy
LCH-III Report Sept 2008 58
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
LCH-III Report Sept 2008 59
Follow up of randomised pts.
not evaluable for the primary endpoint
LCH-III Report Sept 2008 60
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
LCH-III Report Sept 2008 61
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
LCH-III Report Sept 2008 62
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
LCH-III Report Sept 2008 63
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.
LCH-III Report Sept 2008 64
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
accept alternative hypotheses
accept alternative hypotheses
33
LCH-III Report Sept 2008 65
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
LCH-III Report Sept 2008 66
Reactivations after NAD
LR
Risk
0.34±0.081346120.57±0.09245660.35±0.071969B0.29±0.061975A3-yrs. pReactEventsPatients