Co-development decision

The purpose of this study is to evaluate the safety and efficacy of the experimental drug abituzumab (EMD525797) in combination with cetuximab and FOLFIRI in RAS wild-type, left-sided, metastatic colorectal cancer patients with high ανβ6 integrin expression.

Inclusion Criteria:

1. Signed and dated written informed consent prior to any study specific procedure;
2. Age: ≥18 years;
3. Evidence of newly diagnosed stage IV metastatic colorectal cancer. Primary tumor location on the left side of the Colon (including left splenic flexure) or rectum;
4. Demonstrated wild-type RAS mutation status in the tumor (primary tumor or metastasis) by local assessment;
5. Tumor tissue specimen shows high ανβ6 integrin expression, as determined by central laboratory assessment;
6. Tumor tissue specimen (formalin-fixed, paraffin-embedded block) preferably from primary resection and/or if available from a surgical sample from metastatic site must be available for central laboratory based ανβ6 integrin expression analysis. (No Fine Needle Aspiration [FNA] will be accepted);
7. At least 1 radiographically documented measurable lesion in a previously non-irradiated area according to RECIST (Version 1.1), i.e., this lesion must be adequately measurable in at least 1 dimension (longest diameter to be recorded) as ≥2 cm by conventional techniques or ≥1 cm by spiral CT scan;
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1;
9. Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study;

Exclusion Criteria:

1. Demonstrated any RAS or BRAF mutation;
2. Prior anti-EGFR or other targeted therapy;
3. Prior chemotherapy of the colorectal cancer, except for (neo) adjuvant therapy completed at least 6 months before randomization;
4. Radiotherapy (localized radiotherapy for pain relief is allowed to non-target lesions);
5. Investigational drug treatment for the treatment of malignancies in the past;
6. Concurrent participation in another interventional clinical study;
7. Pregnancy (exclusion confirmed with beta-hCG test) or lactation;
8. Any history or evidence of brain metastases or leptomeningeal metastases;
9. History of secondary malignancy within the past 5 years, except for basal cell carcinoma or carcinoma in situ of the cervix uteri, if treated with curative intent;
10. Concomitant chronic systemic immune or hormone therapy not indicated in this study protocol (except for physiologic replacement; steroids up to 10 mg per day of prednisone equivalent or topical and inhaled steroids are allowed);
11. Clinically relevant coronary artery disease (New York Heart Association [NYHA] functional angina classification III/IV), congestive heart failure (NYHA III/IV), or clinically relevant cardiomyopathy;
12. Uncontrolled hypertension defined as systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg under resting conditions;
13. History of myocardial infarction in the last 12 months, or a high risk of uncontrolled arrhythmia, coagulation disorder associated with bleeding or recurrent thrombotic events, with the exception of arterial fibrillation treated with anti-coagulants;
14. Recent peptic ulcer disease (endoscopically proven) within 6 months of randomization, chronic inflammatory bowel disease, or acute/chronic ileus;
15. Active infection (requiring IV antibiotics and/or antiviral therapy), including active tuberculosis, active or chronic Hepatitis B or C, or ongoing HIV infection, AIDS;
16. Presence of any contra-indications or known hypersensitivity to treatment with abituzumab, cetuximab, and FOLFIRI, or to any of the excipients of these drugs;
17. Concomitant treatment with prohibited medications;
18. Medical or psychological conditions that would not permit the patient to complete the study.