Study of Abituzumab in Combination With Cetuximab and FOLFIRI in Patients With Metastatic Colorectal Cancer.

Study Overview
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Brief Summary
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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.

Official Title
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AMELION: A Randomized, Double Blinded, Phase 2, Efficacy and Safety Study of Abituzumab (EMD 525797) in Combination With Cetuximab and FOLFIRI Versus Placebo in Combination With Cetuximab and FOLFIRI in First-line RAS Wild-type, Left-sided, Metastatic Colorectal Cancer Patients With High ανβ6 Integrin Expression.

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: abituzumab
* Combination Product: Placebo + Cetuximab + FOLFIRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent prior to any study specific procedure; Age: ≥18 years; 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; Demonstrated wild-type RAS mutation status in the tumor (primary tumor or metastasis) by local assessment; Tumor tissue specimen shows high ανβ6 integrin expression, as determined by central laboratory assessment; 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); 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; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1; 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: Demonstrated any RAS or BRAF mutation; Prior anti-EGFR or other targeted therapy; Prior chemotherapy of the colorectal cancer, except for (neo) adjuvant therapy completed at least 6 months before randomization; Radiotherapy (localized radiotherapy for pain relief is allowed to non-target lesions); Investigational drug treatment for the treatment of malignancies in the past; Concurrent participation in another interventional clinical study; Pregnancy (exclusion confirmed with beta-hCG test) or lactation; Any history or evidence of brain metastases or leptomeningeal metastases; 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; 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); 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; Uncontrolled hypertension defined as systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg under resting conditions; 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; Recent peptic ulcer disease (endoscopically proven) within 6 months of randomization, chronic inflammatory bowel disease, or acute/chronic ileus; Active infection (requiring IV antibiotics and/or antiviral therapy), including active tuberculosis, active or chronic Hepatitis B or C, or ongoing HIV infection, AIDS; Presence of any contra-indications or known hypersensitivity to treatment with abituzumab, cetuximab, and FOLFIRI, or to any of the excipients of these drugs; Concomitant treatment with prohibited medications; Medical or psychological conditions that would not permit the patient to complete the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abituzumab + Cetuximab + FOLFIRI<br>Cetuximab: 400 mg/m2 over 120 min followed by 250 mg/m2 weekly 60 min or 500 mg/m2 every two weeks, initially 120 min followed by 60 to 90 min (60 min [± 5 min] after completion of the cetuximab infusion) Abituzumab 1000 mg: every 2 weeks for 60 min (60 min [± 5 min] after completion of the abituzumab infusion) FOLFIRI: every 2 weeks Irinotecan 180 mg/m² IV, 30 - 90 min day 1 Folinic acid (racemic) 400 mg/m² IV, 120 min day 1 5-FU 400 mg/m² bolus day 1 5-FU 2400 mg/m² IV over a period of 46 h day 1-2 | Drug: abituzumab<br>* 1000 mg IV<br>* Other names: EMD525797;|
| Placebo Comparator: Placebo + Cetuximab + FOLFIRI<br>Cetuximab: 400 mg/m2 over 120 min followed by 250 mg/m2 weekly 60 min or 500 mg/m2 every two weeks, initially 120 min followed by 60 to 90 min (60 min [± 5 min] after completion of the cetuximab infusion) Placebo: every 2 weeks for 60 min (60 min [± 5 min] after completion of the placebo infusion) FOLFIRI: every 2 weeks Irinotecan 180 mg/m² IV, 30 - 90 min day 1 Folinic acid (racemic) 400 mg/m² IV, 120 min day 1 5-FU 400 mg/m² bolus day 1 5-FU 2400 mg/m² IV over a period of 46 h day 1-2 | Combination Product: Placebo + Cetuximab + FOLFIRI<br>* 400 mg/m2 over 120 min followed by 250 mg/m2 weekly 60 min or 500 mg/m2 every two weeks, initially 120 min followed by 60 to 90 min<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Progression free survival per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as determined by investigator. | 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The overall survival is defined as the time from randomization to death from any cause. | 68 months | 
| Objective Response Rate (ORR) | ORR will be estimated as the proportion of responders in each treatment arm, defined as a patient whose best overall response is PR or better during the treatment period according to RECIST 1.1. | 16 months | 
| Depth of Response (DPR) | Depth of response will be estimated as the maximum percent tumor shrinkage during treatment. | 16 months | 
| Early Tumor Shrinkage (ETS) | ETS will be estimated as the proportion of patients achieving a ≥20 % decrease from baseline in the sum of longest tumor diameters. | 68 months | 
| Secondary Resection Rate With a Potentially Curative Intent | Patients for whom the resectability of metastases becomes evident during the study therapy should undergo a surgical resection of the metastases. | 16 months | 
| Number of participants with treatment-related adverse events summarized by CTCAE severity grade (v5.0). | Adverse events will be summarized by body system, preferred term, severity, and relationship to treatment | 68 months |