Cetuximab + Capecitabine + Irinotecan (CCI) Versus Cetuximab + Capecitabine + Oxaliplatin (CCO) as 1st-Line Therapy for Patients With Metastatic

Colorectal Cancer (CRC): Randomized Phase II Trial of the AIO CRC Study

Group.

V. HeinemannUniversity of Munich – Klinikum Großhadern, Munich, Germany

Recruiting CentresRecruiting Centres

Abenhardt Onkologische Praxis München

Decker Onkologische Praxis Weingarten

Dietzfelbinger Privatklinik Herrsching

Eggers Kreiskrankenhaus Torgau

Fischer von Weikersthal Klinikum St. Marien Amberg

Fleck DRK Krankenhaus Luckenwalde

Fuchs St. Antonius Hospital Eschweiler

Gabius Onkologische Praxis Rosenheim

Haberl Klinikum St. Elisabeth Straubing

Heinemann Klinikum Großhadern München

Heni Kreiskrankenhaus Biberach

Hitz Onkologische Schwerpunktpraxis München

Jung Onkologische Praxis Traunstein

Kappauf Onkologische Praxis Starnberg

Klein Klinikum Bayreuth GmbH

Kubin Klinikum Traunstein

Lambertz Klinikum Garmisch-Partenkirchen

Mahl Onkologische Praxis Schrobenhausen

Maubach Onkologische Praxis Ingolstadt

Mittermüller Onkologische Praxis Germering

Nusch Onkologische Praxis Velbert

Oruzio Zentralklinikum Augsburg

Perker Onkologische Praxis Weilheim-Schongau

Puchtler Klinikum Rosenheim

Schlag Onkologische Praxis Würzburg

Schulze Onkologische Praxis Zittau

Seipelt Onkologische Praxis Bad Soden

Slawik Onkologische Praxis Augsburg

Stauch Onkologische Praxis Kronach

Stötzer Onkologische Praxis München

Vehling-Kaiser Onkologische Praxis Landshut

Wagner Klinik für Chirurgie, Chemnitz gGmbH

Walther Marienhospital Stuttgart

Weiß Onkologische Praxis Weiden

Zellmann Schlossbergklinik Oberstaufen

Treatment RegimensTreatment RegimensDay: 1 8 15 21

Arm A: (*)Irinotecan200mg/m², 30min i.v.Cetuximab (**)250mg/m², 60min i.v. Capecitabine800mg/m² p.o., twice daily

Arm B:Oxaliplatin130mg/m², 120min i.v.Cetuximab (**)250mg/m², 60min i.v. Capecitabine 1000mg/m² p.o., twice daily

(*): 20% dose reduction for patients > 65 years, arm A

(**): Cetuximab loading dose (only week 1): 400mg/m², 120minq 3 weeks

Primary Endpoint: Response rate.

Secondary Endpoints: Time to progression

Disease stabilisation rate (CR+PR+SD)

Tolerability

Grade 3/4- toxicities.

Recruitment and EvaluationRecruitment and Evaluation

Total CCI CCOPatients recruited 137* 69 68Patients evaluable for toxicity

74 37 37

Patients evaluable for response 52 27 25Evaluable cycles 357 198 159

* The recruitment goal was extended with an amendment of the protocol

Patient CharacteristicsPatient Characteristics

ParameterTotal

(n = 74)CCI

(n = 37)CCO

(n = 37)

Age (years, median + range) 61 (38-74) 63 (38-72) 59 (38-74)

Gender (m/f) 2.5 : 1 2.4 : 1 2.7 : 1

Karnofsky PFS 70% 8.1% 10.8% 5.4%

80% 25.7% 32.4% 18.9%

90% 27.0% 24.3% 29.7%

100% 39.2% 32.4% 46.0%

Localisation (colon/rectum) 1.7 : 1 1.3 : 1 2.2 : 1

Metastatic sites: 1 39.2% 32.4% 46.0%

2 29.7% 32.4% 27.0%

3 17.6% 18.9% 16.2%

>3 10.8% 10.8% 10.8%

unknown 2.7% 5.4% -

Type of Adjuvant PretreatmentType of Adjuvant Pretreatment

Total (%)(n = 74)

CCI (%)(n = 37)

CCO (%)(n = 37)

Adjuvant chemotherapy 17.6 18.9 16.2

Adjuvant 5-FU 6.8 8.1 5.4

Adjuvant 5-FU+FA 9.5 10.8 8.1

Unknown 1.4 - 2.7

Prior radiotherapy 13.5 16.2 10.8

Location of MetastasesLocation of Metastases

LocalisationTotal

(n = 74)CCI

(n = 37)CCO

(n = 37)

Liver 63 (85.1%) 28 (75.7%) 35 (94.6%)

Lungs 28 (37.8%) 15 (40.5%) 13 (35.1%)

Lymph Nodes 23 (31.1%) 12 (32.4%) 11 (29.7%)

Peritoneum 11 (14.9%) 6 (16.2%) 5 (13.5%)

Intestine 4 (5.4%) 3 (8.1%) 1 (2.7%)

Bones 1 (1.4%) 1 (2.7%) -

Pleura 1 (1.4%) 1 (2.7%) -

Brain 1 (1.4%) 1 (2.7%) -

Others 12 (16.2%) 6 (16.2%) 6 (16.2%)

Unknown 2 (2.7%) 2 (5.4%) -

EGF-Receptor StatusEGF-Receptor Status

Total(n = 74)

CCI(n = 37)

CCO(n = 37)

EGFR detectable 71.62 % 70.27 % 72.97 %

EGFR not detectable 27.03 % 27.03 % 27.03 %

unknown 1.35 % 2.70 % -

Dose Reductions / Delayed CyclesDose Reductions / Delayed Cycles

Total (%)(357 cycles)

CCI (%)(198 cycles)

CCO (%)(159 cycles)

Dose reductions * 32.5 24.2 42.8

Delayed cycles ** 18.8 21.7 15.9

LocalisationTotal

(n = 74)CCI

(n = 37)CCO

(n = 37)

Liver 63 (85.1%) 28 (75.7%) 35 (94.6%)

Lungs 28 (37.8%) 15 (40.5%) 13 (35.1%)

Lymph Nodes 23 (31.1%) 12 (32.4%) 11 (29.7%)

Peritoneum 11 (14.9%) 6 (16.2%) 5 (13.5%)

Intestine 4 (5.4%) 3 (8.1%) 1 (2.7%)

Bones 1 (1.4%) 1 (2.7%) -

Pleura 1 (1.4%) 1 (2.7%) -

Brain 1 (1.4%) 1 (2.7%) -

Others 12 (16.2%) 6 (16.2%) 6 (16.2%)

Unknown 2 (2.7%) 2 (5.4%) -

Allergic Reactions Related to Allergic Reactions Related to CetuximabCetuximab

(Manifestation at First Application) (Manifestation at First Application)

Non-Hematological ToxicityNon-Hematological Toxicity per patient analysis

%

10,8

8,1

10,8

0,0 0,0 0,00,0

5,4

2,7

0,0

2,7

0,0

0

2

4

6

8

10

12

Ane

mia

Leuk

open

ia

Neu

trop

enia

Thr

ombo

peni

a

Fev

er

Neu

trop

.

Fev

er

CCI

CCO

Hematological ToxicityHematological Toxicity per patient analysis

%13,5

18,9

2,70,0

2,7 2,7

18,9

10,8

0,0

16,2

21,6

0,0 0,02,7

18,9

29,7

5,4 5,4

0

5

10

15

20

25

30

35

Na

use

a/V

om

itin

g

Dia

rrh

oe

Ob

stip

atio

n

Sto

ma

titis

Alo

pe

cia

Ne

uro

toxi

city

Ski

n T

oxi

city

Pa

in

Fa

tigu

e

CCI

CCO

Best Response During TreatmentBest Response During Treatment

CCI CCOp-value

n % n %

evaluable patients 27 100 25 100

CR 2 7.4 2 8.0 1.0

PR 9 33.3 15 60.0 0.094

SD 13 48.2 6 24.0 0.090

PD 3 11.1 2 8.0 1.0

CR + PR 11 40.7 17 68.0 0.058

CR + PR + SD 24 88.9 23 92.0 1.0

Conclusions:Conclusions:• Both treatment arms – CCI and CCO – are feasible and highly effective.

• In the CCI arm, most common Grade 3-4 toxicities were diarrhea (19%), skin toxicity (19%), nausea and vomiting (14%), pain (11%), and anemia (11%).

• In the CCO arm, most common Grade 3-4 toxicities were skin toxicity (30%), diarrhea (22%), neurotoxicity (19%) and nausea and vomiting (16%).

• Non-hematological toxicity appears to be greater in the CCO arm, possibly also related to the higher dose of capecitabine used in this arm.

• Hematological toxicity appears to be greater in the CCI arm.

• Disease control rates are equally high: 88.9% in the CCI arm and 92.0% in the CCO arm (p=1.0).

• The accrual of the CIOX-trial is ongoing.