EMD 525797 in Combination With Cetuximab and Irinotecan in K-ras Wild Type Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and clinical activity of the experimental drug EMD 525797 (study drug), a monoclonal antibody targeting alfa integrins, in combination with irinotecan and cetuximab in K-ras wildtype metastatic colorectal cancer patients.

Official Title
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An Open-label, Randomized, Controlled, Multicenter, Phase I/II Trial Investigating 2 EMD 525797 Doses in Combination With Cetuximab and Irinotecan Versus Cetuximab and Irinotecan Alone, as Second-line Treatment for Subjects With K-ras Wild Type Metastatic Colorectal Cancer (mCRC)

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: EMD 525797 250 mg
* Drug: EMD 525797 500 mg
* Drug: EMD 525797 750 mg
* Drug: EMD 525797 1000 mg
* Drug: Cetuximab
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with histologically confirmed kras wildtype (WT) colorectal carcinoma (CRC) with documented distant metastasis Prior oxaliplatin/fluoropyrimidine-containing regimen for the first-line treatment of metastatic disease Failed an oxaliplatin regimen for metastatic colorectal carcinoma (mCRC). Failure is defined as either progressive disease (PD) (clinical or radiologic) within 6 months of the last dose of any agent of an oxaliplatin-based regimen or intolerance to an oxaliplatin regimen. Intolerance to an oxaliplatin regimen is defined as discontinuation due to any of the following: severe allergic reaction, persistent severe neurotoxicity, or delayed recovery from toxicity preventing retreatment At least 1 radiographically documented measurable lesion in a previously non irradiated area according to Response Evaluation Criteria In Solid Tumors (RECIST, Version 1.0), i.e., this lesion must be adequately measurable in at least 1 dimension (longest diameter to be recorded) as greater than or equal to (>=) 2 centimeter (cm) by conventional techniques or >=1 cm by spiral computed tomography (CT) scan Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, or Karnofsky performance status (KPS) >= 80 percent (%) Absolute Neutrophil Count (ANC) >=1.5 x 10^9/Liter Platelets >=100 x 10^9/Liter Hemoglobin >=9 gram per deciliter (g/dL) (without transfusions) Bilirubin less than or equal to (<=) 1.5 x upper limit normal (ULN) Aspartate transaminase (AST) <=5 x ULN and alanine transaminase (ALT) <=5 x ULN Serum creatinine <=1.25 x ULN and/or creatinine clearance >=50 milliliter per minute (mL/min) International Nationalized Ratio (INR), and partial thromboplastin time (PTT) within normal limits Sodium and potassium within normal limits or <=10% above or below (supplementation permitted) Exclusion Criteria: Previous treatment with any inhibitor of Epidermal Growth Factor Receptor (EGFR) Known brain metastasis and/or leptomeningeal disease Radiotherapy (except localized radiotherapy for pain relief), major surgery, or any investigational drug in the 30 days before the start of trial treatment entry; planned major surgery during the trial Concurrent chronic systemic immune or hormone therapy not indicated in this trial protocol (except for physiologic replacement; steroids up to 10 mg 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), clinically relevant cardiomyopathy, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia Uncontrolled hypertension defined as systolic blood pressure >=160 millimeter of mercury (mmHg) and/or diastolic blood pressure >=100 mmHg under resting conditions History of coagulation disorder associated with bleeding or recurrent thrombotic events History of recent peptic ulcer disease (endoscopically proven gastric, duodenal or esophageal ulcer) within 6 months of trial treatment start Chronic inflammatory bowel disease, or acute/chronic ileus Active infection (requiring i.v. antibiotics), including active tuberculosis, active or chronic Hepatitis B or C, or ongoing HIV infection

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety part: EMD 525797 250 mg + Standard of Care (SoC)<br>EMD 525797 250 mg in combination with cetuximab and irinotecan | Drug: EMD 525797 250 mg<br>* EMD 525797 will be administered at a target dose of 250 mg as a 1-hour intravenous infusion for every 2 week until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent .<br>Drug: Cetuximab<br>* Safety part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until DLT. Randomized part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>Drug: Irinotecan<br>* Safety part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>|
| Experimental: Safety part: EMD 525797 500 mg + SoC<br>EMD 525797 500 mg in combination with cetuximab and irinotecan | Drug: EMD 525797 500 mg<br>* Safety part: EMD 525797 will be administered at a target dose of 500 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: EMD 525797 will be administered at a target dose of 500 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>Drug: Cetuximab<br>* Safety part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until DLT. Randomized part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>Drug: Irinotecan<br>* Safety part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>|
| Experimental: Safety part: EMD 525797 750 mg + SoC<br>EMD 525797 750 mg in combination with cetuximab and irinotecan | Drug: EMD 525797 750 mg<br>* EMD 525797 will be administered at a target dose of 750 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent .<br>* Other names: Abituzumab;Drug: Cetuximab<br>* Safety part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until DLT. Randomized part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>Drug: Irinotecan<br>* Safety part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>|
| Experimental: Safety part: EMD 525797 1000 mg + SoC<br>EMD 525797 1000 mg in combination with cetuximab and irinotecan | Drug: EMD 525797 1000 mg<br>* Safety part: EMD 525797 will be administered at a target dose of 1000 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: EMD 525797 will be administered at a target dose of 1000 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>* Other names: Abituzumab;Drug: Cetuximab<br>* Safety part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until DLT. Randomized part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>Drug: Irinotecan<br>* Safety part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>|
| Experimental: Randomized part: EMD 525797 500 mg + SoC<br>EMD 525797 500 mg in combination with cetuximab and irinotecan | Drug: EMD 525797 500 mg<br>* Safety part: EMD 525797 will be administered at a target dose of 500 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: EMD 525797 will be administered at a target dose of 500 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>Drug: Cetuximab<br>* Safety part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until DLT. Randomized part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>Drug: Irinotecan<br>* Safety part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>|
| Experimental: Randomized Part: EMD 525797 1000 mg + SoC<br>EMD 525797 1000 mg (or dose as defined by safety monitoring committee (SMC)] in combination with cetuximab and irinotecan. | Drug: EMD 525797 1000 mg<br>* Safety part: EMD 525797 will be administered at a target dose of 1000 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: EMD 525797 will be administered at a target dose of 1000 mg as a 1-hour intravenous infusion for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>* Other names: Abituzumab;Drug: Cetuximab<br>* Safety part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until DLT. Randomized part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>Drug: Irinotecan<br>* Safety part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>|
| Other: Randomized Part: SoC<br>Cetuximab and irinotecan | Drug: Cetuximab<br>* Safety part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until DLT. Randomized part: Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m^2) on Day 1 Cycle 1 (Week 1) as IV infusion for 2 hours, and then at a dose of 250 mg/m^2 on Day 8 (Week 2) once weekly until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>Drug: Irinotecan<br>* Safety part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent . Randomized part: Irinotecan will be administered at a dose of 180 mg/m^2 as IV infusion for 30-90 minutes for every 2 weeks until radio-graphically documented PD (as assessed by the investigator), unacceptable toxicity or eligibility for curative resection (investigator's assessment), or withdrawal of consent.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Part: Number of Subjects Experiencing DLTs (Dose Limiting Toxicity) | DLT was defined as any Grade 4 hematologic toxicity or Grade 3/4 non-hematologic toxicity assessed as related to trial treatment by the Investigator and/or Sponsor and confirmed by the safety monitoring committee (SMC) to be relevant to the combination treatment within the first cycle of therapy. Any Grade 3 or 4 non haematological toxicity, any Grade 4 hematological toxicity, treatment related deaths within the first 2 weeks of therapy. Toxicities excluded from DLT: alopecia, rash, nausea, vomiting and hypomagnesemia of Grade 3 or 4 severity, Grade 4 neutropenia or leukopenia lasting for =< 5 days and not associated with fever; Single laboratory values out of normal range without any clinical correlation and resolve within 7 days; Grade 3 or 4 diarrhoea without adequate supportive care. Adequate supportive care has been administered and Grade 4 diarrhea persists (investigator decision); isolated Grade 4 lymphocytopenia and thrombocytopenia without clinical correlation. | Time from the first dose of study drug up to 2 weeks | 
| Randomized Part: Progression Free Survival (PFS) | PFS was defined as the time from the randomization date to first documented sign of objective radio-graphic disease progression (PD) as per Response Evaluation Criteria In Solid Tumors version 1. (RECIST 1.0) or death from any cause if reported within 12 weeks from the last tumor assessment. PD per RECIST v 1.0 was defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as the reference the smallest sum of longest diameters recorded since treatment started, or unequivocal progression of existing non-target lesion or appearance of new lesions. Subjects who did not progress or died at the time of analyses, or subjects who died without previously radio-graphically documented PD and death was observed after more than 12 weeks of last tumor assessment without progression, these subjects were censored at their last tumor assessment date or date of randomization, whichever occurred last. | Time from randomization until progressive disease or death; assessed up to 18 months (i.e data cut-off date: 09 Oct 2013) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Time | OS was defined as the time from the date of randomization to the date of death from any cause. For subjects who were still alive at the analysis cut off date or lost to follow up, survival was censored at the last recorded date the subject was known to be alive or at the analysis cut off date, whichever occurred first. | Time from randomization until death assessed up to 18 months (i.e data cut-off date: 09 Oct 2013) | 
| Time to Progression (TTP) | TTP was defined as the time from the date of randomization to the date of objective radiographic disease progression (PD). PD per RECIST v 1.0 was defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as the reference the smallest sum of longest diameters recorded since treatment started, or unequivocal progression of existing non-target lesion or appearance of new lesions. For subjects who did not progress or who were without any post baseline tumor assessment, TTP was censored at their last tumor assessment date, or at the randomization date, whichever occurred last. | Time from randomization until disease progression assessed up to 18 months (i.e data cut-off date: 09 Oct 2013) | 
| Number of Subjects With Tumor Response | Tumor response was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) as judged by RECIST version 1.0. CR was defined for target lesions (TLs) as the disappearance of all lesions, and for non-target lesions (NTLs) as the disappearance of all non-target non-measurable lesions and/or normalization of serum levels of tumor markers. PR was defined for TLs as at least a 30 percent (%) decrease from baseline (BL) in the sum of longest diameter (SLD) of TLs. | Time from randomization up to 18 months (i.e data cut-off date: 09 Oct 2013) | 
| Time to Treatment Failure (TTF) | TTF was defined as the time from randomization to treatment discontinuation for any reason. For subjects on drug at the analysis cut off date or lost to follow up, TTF was censored at the trial discontinuation date or at the analysis cut off date, whichever occurred first. | Time from randomization until discontinuation assessed up to 18 months (i.e data cut-off date: 09 Oct 2013) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EMD 525797, Cetuximab, Irinotecan, metastatic colorectal cancer