CapRI -Final Results of the Open-label, Multi-center,

Randomized Phase III Trial of Adjuvant Chemoradiation Plus Interferon-2b (CRI)

versus 5-FU/FA for Patients with Resected Pancreatic Adenocarcinoma

Angela Märten, Jan Schmidt, Jürgen Debus, Sabine Harig, Thomas Herrmann, Katja Lindel, Justus Klein, Detlef Bartsch, Lorenzo Capussotti, Carl Zülke, Reiner Kunz, Ulrich Mansmann, Markus W. Büchler

University of Heidelberg, GermanyHospital of Bielefeld, Germany

University of Regensburg, Germany Istituto per la Ricerca e la Cura del Cancro, Torino, Italy

St. Joseph Hospital, Berlin, Germany

Financial DisclosureRelated to the trial:

– Travel Grants from Essex Pharma

Unrelated to the trial– Boehringer Ingelheim (employment since 2009)– Roche (research funding)– Novartis (research funding)– Amgen (advisor)– Morphotek (advisor)– Bayer (honoraria)– …

This trial was supported by – Manfred-Lautenschläger Foundation, Germany

Virginia MasonVirginia MasonESPAC-1 ESPAC-1 chemotherapychemotherapy

Neoptolemos et al., 2004, NEJMPicozzi et al., 2003, Am J Surg

aadjuvant CChemoRRadioIImmunotherapy of ppancreatic carcinoma

CapRICapRI

Rationale

5-FU/Cisplatin/RT/IFN-5-FU/Cisplatin/RT/IFN-

5-FU5-FU

Study type Open, prospective, randomized, controlled, multi-center IIT

Recruitment August 2004-December 2007Sample size 110 (=0.05; power = 80%)Primary endpoint Overall survival in both armsSec. endpoints Safety, DFS, QoL, Screening for predictive

markersStudy centers Heidelberg, Berlin, Torino, Bielefeld,

RegensburgData Manage-ment/Biometrics

Institutes for Medical Biometrics, Universities of Heidelberg and Munich

DSMB Two oncologists, 1 biometricianOn-site monitoring

Independent CRO

Study Design

Inclusion Criteria• R0 or R1 pancreatic adenocarcinoma• Treatment start within 12 weeks after surgery• Performance status: Karnofsky 70• Creatinine 1.5 mg/dL, CrCl ≥ 60 ml/min

Exclusion Criteria• Residual metastatic or incompletely resected local disease• Former radiotherapy in respective region• Patients with severe pulmonary disease• Patients with significant cardiovascular disease • Patients with immunodeficiencies or autoimmune diseases• Presence or history of severe depression

Eligibility

study-arm A

study-arm B

week 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

FA 20 mg/m² as bolus injection, followed by5‑FU 425 mg/m² as short infusion 5 days/week

X X X X X X

All patients are treated as outpatients

Cisplatin 30 mg/m² over 60‘ IFN-2b s.c. 3 Mio Units 3/week (total 17x)

EBRT 50.4 Gy in 28 fractions

5-FU 200 mg/m²/day CI

Knaebel et al., BMC Cancer 2005

R

x x x x x x-------------------

Treatment Scheme

O

low dose Interferon(LDI) prior to therapy

cycle 1 CRI

*Screening-log was only kept at Heidelberg

Allocated to intervention 67Received allocated intervention 57Did not receive allocated intervention 10

-not meeting inclusion criteria 3-Withdrawal 7

Allocated to intervention 65Received allocated intervention 53Did not receive allocated intervention 12

-not meeting inclusion criteria 5-Withdrawal 7

Analyzed 53Excluded from analysis 0

Assessed for eligibility510 patients*

Lost to follow-up 0Discontinued intervention 7

Lost to follow-up 1Discontinued intervention 9

Analyzed 57Excluded from analysis 0

Excluded: 378*-Not meeting incl. crit.: 227*

Histology 167General condition 48Others 12

-Refused to participate: 151*Distance 62Concers about trial 62Other trials 17Others 15

Arm BArm A

  A B both arms p-valueage 63 [37;74) 63 [33;77] 63 [33;77] 0.95femalemale

19 (36%)34 (64%)

31 (54%)26 (46%)

50 (45%)60 (55%) 0.09

R0R1

29 (55%)24 (45%)

37 (66%)19 (34%)

66 (61%)43 (39%) 0.25

T1T2T3T4

1 (2%)2 (4%)

49 (92%)1 (2%)

0 (0%)1 (2%)

55 (96%)1 (2%)

1 (1%)3 (3%)

104 (95%)2 (2%) 0.71

N0N1

11 (21%)42 (79%)

12 (21%)45 (79%)

23 (21%)87 (79%) 1.00

G1G2G3

1 (2%)34 (64%)18 (34%)

1 (2%)40 (70%)16 (28%)

2 (2%)74 (68%)33 (31%) 0.77

pp WhippleWhippleleft resection

35 (66%)4 (8%)

14 (26%)

39 (69%)11 (19%)

7 (12%)

74 (67%)15 (14%)21 (19%) 0.06

treatment start [days] 58.8 ± 14.2 57.3 ± 15.2 58.0 ± 14.7 0.50CA 19.9 preop [U/ml] 991 +/- 2574 409 ± 613 693 ± 1865 0.58Diabetes Mellitus-pankreopriv -no

16 (30%)9 (17%)

28 (53%)

17 (30%)3 (5%)

31 (54%)

33 (30%)12 (11%)59 (54%) 0.54

BMI <20BMI <25BMI <30BMI >30

7 (13%)32 (60%)12 (23%)2 (4%)

10 (18%)27 (47%)16 (28%)4 (7%)

17 (16%)59 (54%)28 (26%)6 (6%) 0.58

Patient’s Demographics

External ValiditySelection bias Are the populations representative?

–Eligibility criteria are limited to the (unavoidable) restrictions for safety reasons and clinical restrictions

–CapRI patients do not differ from the ‘average patient’.–No evidence of recruiting bias

Performance bias Are the interventions feasible under ‚real world’ conditions?

–Only in specialized centers

Attrition bias Are under ‘real world conditions’ similar drop-outs to be expected?

–Rather more. Therefore, no impact on transferability into ‘real world’.

Detection bias Are the endpoints relevant?

–Definitely

External validity is given

Sorg et al., Pancreas, 2009

Drug-Administration

Dose administeredcycle 1 arm

Acycle 2-3

arm A arm B% patients that received total dose 5.7% 11.3% 56.1%

% of administered drugIFN-2b 95 ±12%

5-FU 72 ± 23% 81 ± 26% 86 ± 23%

Cisplatin 75 ± 19%

Radiation 98 ± 7%

Toxicitycycle 1 arm AN = 53

cycle 2 arm AN = 51

cycle 3 arm AN = 46

arm B N = 57

Pts experienced CTC grade ¾ 17 (32.1%) 2 (3.9%) 2 (4.3%) 9 (15.8%) Grade 3 toxicities in >5% of patients:

Neutropenia 28 (52.8%) - - -

Hypovolemia / electrolyte disturbances*

8 (15.1%) - - -

Nausea / vomiting 8 (15.1%) - - -

Anaemia 3 (5.7%) - - -

Diarrhoea 3 (5.7%) - - 6 (10.5%)

Thrombopenia 3 (5.7%) - - -

Grade 4 toxicities 11 (20.8%) - - 1 (1.8%)Acute renal insufficiency 1 (1.9%) - - -

Neutropenia 7 (13.2%) - - -

Hypovol. / electrolytes 1 (1.9%) - - -

Hand Foot Syndrome 1 (1.9%) - - -

Nausea / vomiting 1 (1.9%) - - -

Diarrhoea - - - 1 (1.8%)

*Hoffmann et al., BMC Cancer 2006

EORTC QLQ C30

0

10

20

30

40

50

60

70

80

90

100

day 0day 15

day 38

day 64

day 120

FU 1FU 2

FU 3FU 4

FU 5FU 6

FU 7FU 8

scor

e

Physical functioning - A Physical functioning - B Role functioning Arm ARole functioning Arm B Emotional functioning - A Emotional functioning - BCognitive functioning - A Cognitive functioning - B Social functioning - ASocial functioning - B Global Health Status - A Global Health Status - B

Follow-up every 3 monthscycle 2-3cycle 1

• Decrease in QoL during cycle 1 • Recovery after end of cycle 1• Similar to better QoL during follow-up (p = 0.02)

CES-D Depression Scale

• Increase of depression score during IFN-therapy

• Complete recovery after end of cycle 1

0

2

4

6

8

10

12

14

16

18

20

day 0 day 15 day 38 day 64 day 120 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8

scor

e

arm Aarm B

Depression

Follow-up (every 3 months)

cycle 2-3cycle 1

No at riskArm A 53 53 47 39 33 24 16 12 8 6 3Arm B 57 56 45 35 29 23 17 11 7 5 3

Median Follow-up: 26.9 mo

Overall Survival

MedianMedian 95% CI95% CIpp--

valuevalueArm A 32.1 [22.8; 42.2] 0.490

Arm B 28.4 [19.5; 38.6]

No at riskArm A 53 53 45 36 29 20 14 10 7 6 3Arm B 57 56 43 32 26 18 11 6 5 3 1

Disease Free Survival

MedianMedian 95% CI95% CI pp-value-valueArm AArm A 24.8 [19.3; 32.1] 0.4302

Arm BArm B 22.1 [17.5; 29.3]

Localisation of relapse

Arm AN = 41

Arm BN = 45

TotalN = 86 p-value

Local 12 (29.3%) 25 (55.6%) 37 (43.0%) 0.014

Liver 17 (41.5%) 10 (22.2%) 27 (31.4%) NS

Lung 5 (12.2%) 2 (4.4%) 7 (8.1%) NS

Lymph node 1 (2.4%) 5 (11.1%) 6 (7.0%) NS

Peritoneal carcinoma

5 (12.2%) 1 (2.2%) 6 (7.0%) NS

Unknown 1 (2.4%) 2 (4.4%) 3 (3.5%) NS

Resection margins

Arm A: R0 --- R1 ---Arm B: R0 --- R1 ---

R1 N Median 95% CI p-ValueArm AArm A 24 33.0 [18.6; ] 0.1317

Arm BArm B 19 16.8 [10.4; 27.9]

Treatment start

--- < 8 weeks--- > 8 weeksp = 0.023

--- arm A > 8 weeks--- arm B > 8 weeksp = 0.12

Comparison

ESPAC-1 No CTCONKO 001 BSC ESPAC-1 CT

CONKO 001 GemESPAC-3 5-FUESPAC-3 Gem

Virginia Mason-CRI

CapRI-CRI

CapRI- 5FU

ESPAC1 5-FU

CONKO-1 Gem

ESPAC3 5-FU/Gem

CapRI 5-FU

CapRI CRI

V. Mason CRI

Recruit. 2/94-6/00 7/98-12/04 7/00-1/07 8/04-12/07 8/04-12/07 7/95-12/02

2ys 39% 48% 50% 52% 62% 64%mOS 20 23 23 28 32 44

MonocytesCD40+Dendritic CellsNK cell lysis

IL-12TNF-

CD8:CD4Effector memory T cells

MUC-1 specific T cellsDendritic Cells

Zhu et al., JIT, 2008Hoffmann et al., Antican Res, 2008Märten et al., JIT, 2010

Translational ResearchSignificant specific and unspecific immune responses

Ma et al., WJG, 2005Schmidt et al., CII, 2006Zhu et al., JIT, 2007Schmidt et al., JIT, 2007

Predictive Markers

Patients with a pronounced increase in cytotoxicity after 1st IFN- challenge had a significant longer DFS

arm A

0%

10%

20%

30%

40%

10:1 20:1 40:1 80:1

effector to target ratio

lysi

s of

K56

2 ce

llspre LDI

24hrs after LDI

pre 1st cycle

after 1st day oftherapypre 2nd cycle

--- increase of cytotoxicity after 1st IFN- > 7%--- < 7%

DFS

p = 0.03NK cell mediated cytotoxicity increased within 24hrs after IFN-administration

No change in arm Barm B

0%

10%

20%

30%

40%

10:1 20:1 40:1 80:1

effector to target ratio

lysi

s of

K56

2 ce

lls

pre 1st cyclepre 2nd cyclepre 3rd cycle

No change in arm B

Predictive MarkersDecrease of CD4 cells

(>6.8 percentage points) and decrease of CD4+CD152+ cells

were associated with significant longer OS

--- no decrease --- decrease in CD4+CD152+ cells after 1st IFN-

p = 0.018p = 0.037

--- slight or no decrease in CD4+ cells --- pronounced decrease in CD4+ cells

Summary• The CapRI regimen is toxic• However, toxicity is definitely manageable• Decrease in QoL during cycle 1 but patient recover completely• Primary endpoint not reached; no significant difference in mOS• However, no overlapping curves underpowered trial?• And, best survival data even for classical CT • Trend for better control of R1 resected patients • Association between immune response to IFN- and survival• Confirmatory phase III trial needed

Thanks to

• Our patients

• Manfred Lautenschläger

• The lab team

And to the InvestigatorsSurgery Oncology Radiooncology Biometry/DM

Jan Schmidt Sabine Harig Jürgen Debus Ulrich Mansmann

Markus Büchler Thomas

Herrmann Katja Lindel Ulrich Abel

Detlef Bartsch Dirk JägerRobert

Krempien Karin Hörner Lorenzo

Capussotti Manfred Görner Justus Klein

Carsten Zülke Katrin Hoffmann Peter Hirnle DSMB

Reiner Kunz Florian Lordick Marc MünterMarie von Lilienfeld-

Toal

Paolo Massucco Sabine Kümmel Carsten Ziske

Christin Tjaden Fabio Leone Lutz Edler

… … ….