CapOx given concurrently to neoadjuvant RT improved pathologic response and tumor regression2 in phase II trials. Synergy of cetuximab and RT has been demonstrated, e.g. with improved overall survival compared to RT alone in squamous cell cancer of head and neck.This trial was initiated to evaluate the feasibility and efficacy of adding cetuximab to our previously described preoperative concurrent regimen of RT with CapOx in advanced RC1.Determination of the maximal tolerated dose (MTD) was the endpoint of phase I whereas phase II endpoint was to determinate efficacy in terms of pathohistologic complete response (pCR).

Method: Patients (pts) had to have resectable adenocarcinoma of the rectum (max. 16 cm from anal verge), T3,4 and/or N+ disease, synchronous distant metastases were allowed. Tumor staging: CT scan with endoscopic ultrasound or MRI.

Cetuximab, Capecitabine and Oxaliplatin (Cet-CAPOX) with Concurrent Radiotherapy (RT) in Advanced Rectal Cancer: Final Results of a Phase I/II Trial

ASCO 2007, Abstract #4042

Rationale

Phase I/II cohort; n=60

Median age, years [range] 61.5 [35-83]

Male / Female 63% / 37%

ECOG 0 / 1 80% / 20%

• Cetuximab can be safely added to CapOx-RT without dose

compromise to either chemotherapy or concurrent RT.

• Toxicity profile and post-surgical complication rates are

comparable to CapOx-RT alone.

• In our study, the addition of cetuximab produced down-staging and

downsizing, but a relatively low rate of pathologic responses and

therefore did not meet statistical hypothesis criteria.

• Further preclinical and clinical research is necessary to clarify the

mechanism and define the reason of this phenomenon.

Acknowledgements:

This trial was supported by Merck KGaA, Sanofi-Aventis and Roche Pharma AG, Germany

Dirk Arnold1, Matthias Hipp2, Torsten Liersch3, Kathrin Dellas1, Oliver Kölbl2, Werner Hohenberger4, Florian Lordick5, Heiko Sülberg6, Rolf Sauer4, Claus Rödel41Martin Luther University, Halle; 2University of Regensburg; 3Georg August University, Göttingen; 4Friedrich Alexander University, Erlangen; 5Technical University, Munich; 6WiSP Langenfeld; all: Germany

Schedule

Phase I doses

LevelCetuximab*

mg/m²

Oxaliplatin

mg/m²

Capecitabine

mg/m²/day Pts.

included

I (400)/ 250 50 1000 7

II (400)/ 250 50 1300 3

III (400)/ 250 50 1650 3

Patient characteristics

Response

Conclusions* Cetuximab: Initial dose 400 mg/m2 given one week prior to RT followed by 250 mg/m2 weekly

1Rödel C, Liersch T, Hermann RM, Arnold D, Reese T, Hipp M, Fürst A, Schwella N, Bieker M, Hellmich G, Ewald H, Haier J, Lordick F, Flentje M, Sülberg H, Hohenberger W, Sauer R.Multicenter phase II trial of chemoradiation with Oxaliplatin for rectal cancer. J Clin Oncol 2007; 25:110-117

2Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative chemoradiation. Int J Colorectal Dis 1997; 12(1):19-23

References

Initial Tumor stage and localisation; n = 60

Clinical staging (CT + endoscopic US or MRI)

Primary tumour (n / %)

T2 N+ 1 pt. (2%)

T3 N0 7 pts. (12%)

T3 N+ 43 pts. (72%)

T4 N0 2 pts. (3%)

T4 N+ 7 pts. (12%)

Distant metastases

Yes 11 pts. (20%)

Distance of lower tumor margin to anal verge

Range (cm) 0 – 14

Lower third (<6cm) 27 (45%)

Middle third (6-12cm) 27 (45%)

Upper third (>12cm) 6 (10%)

DayCapecitabineLevel I-III

CetuximabRT*28 x 1.8 Gy

Twice dailydose every day

Twice dailydose every day

Twice dailydose every day

Twice dailydose every day

-7

1

8

15

22

29

36

* RT: 3D conformation technique, a dummy run was organized between the different centers

Oxaliplatin50 mg/m²

400 mg/m²

250 mg/m²

250 mg/m²

250 mg/m²

250 mg/m²

250 mg/m²

250 mg/m²

Dose administration

Toxicity: Phase II analysis

Toxicity (NCI CTC v.2.0); n = 48 @ phase II cohort (dose level 3)

CTC grade 1, 2 3 4

Leukocytopenia

Thrombocytopenia

Infection

35%

21%

21%

4%

2%

6%

2%*

2%*

2%*

Diarrhea

Liver enzymes

Proctitis

Radiation dermatitis

Hypersensitivity reaction

Acne-like rash

56%

52%

14%

42%

10%

68% / 28%

17%

6%

2%

8%

2%

4%

2%*

--

--

--

--

--

Pathologic staging of T- and N-status compared to preoperative clinical staging (N=45)

ypT0 ypT1 ypT2 ypT3 ypT4

cT3: N=39 4 12 21 2

cT4: N= 6 2 3 1

ypN0 ypN1 ypN2

cN0: N= 9 7 1 1

cN+: N=36 21 5 10

Tumor regression grading (Dworak3); n = 45

TRG 0 (No regression) 4%

TRG 1 (< 25%) 22%

TRG 2 (25 – 50%) 27%

TRG 3 (>50%) 38%

TRG 4 (complete regression) 9%

Resections in phase II cohort: 45 (48) pts.

Anterior / low anterior resection

31 pts.

Intersphincter resection 4 pts.

Abdominoperineal resection 10 pts.

R0 rate 93%

any complications 36%

Wound heeling 16%

Anastomotic leakage 11%

Ileus 4%

Bleeding 4%

Re-operation necessary 11%

Surgical parameters

DLT (Diarrhea grade 3-4) occured in 1 pt. at dose level 1. No further DLTs were observed on dose levels 2 and 3.

Dose level 3 (with the same dose as in our phase II without cetuximab) was chosen for phase II evaluation.

47 more patients were included for phase II to a total of 50 pts. at the recommended dose level.

48 are evaluable for phase II population (1 withdrawal from further treatment, 1 unrelated death)

*Pt. died from multiorgan failure, with underlying DPD deficiency. 1 more pt. died for unrelated reason. 1 pt. with hypersensitivity was excluded from further cetuximab administration

T-level „downsizing“: 21/45 (47%)

N-level „downstaging“: 21/36 (58%)