Please select the eligibility criteria that correspond to the clinical trial below.
Title: 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)
Brief Summary: 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.


Options:
A: Inclusion Criteria:

1. Histologically-confirmed inoperable colorectal adenocarcinoma excluding vermiform appendix cancer and anal canal cancer.
2. Age ≥20 years at the time of informed consent
3. ECOG performance status (PS) of 0-2
4. Written informed consent prior to study-specific screening procedures
5. Life expectancy of at least 90 days
6. Withdrawal from first-line chemotherapy (regardless of containing molecular-targeted drugs) for metastatic colorectal cancer due to intolerable toxicity or progressive disease, or relapse within 180 days after the last dose of adjuvant chemotherapy.
7. Adequate organ function according to following laboratory values obtained within 14 days before enrolment (excluding patients who received blood transfusions or hematopoietic growth factors within 14 days before the laboratory test) Neutrophil count: ≥1500/mm3 Platelet count: ≥10.0 x 104/mm3 Hemoglobin: ≥9.0 g/dL Total bilirubin: ≤1.5 mg/dL AST, ALT: ≤100 IU/L (≤200 IU/I if liver metastases present) Serum creatinine: ≤1.5 mg/dL

Exclusion Criteria:

1. History of other malignancy with a disease-free interval \<5 years (other than curatively treated cutaneous basal cell carcinoma, curatively treated carcinoma in situ of the cervix, and gastroenterological cancer confirmed to be cured by endoscopic mucosal resection)
2. With massive pleural effusion or ascites requiring intervention
3. Radiological evidence of brain tumor or brain metastases
4. Active infection including hepatitis
5. Any of the following complication:

   i) Gastrointestinal bleeding or gastrointestinal obstruction (including paralytic ileus) ii) Symptomatic heart disease (including unstable angina, myocardial infarction, and heart failure) iii) Interstitial pneumonia or pulmonary fibrosis iv) Uncontrolled diabetes mellitus v) Uncontrolled diarrhea (that interferes with daily activities despite adequate therapy)
6. Any of the following medical history:

   Myocardial infarction: History of one episode within one year before enrollment or two or more lifetime episodes i) Serious hypersensitivity to any of the study drugs ii) History of adverse reaction to fluoropyrimidines suggesting dihydropyrimidine dehydrogenase (DPD) deficiency
7. Previous treatment with irinotecan hydrochloride
8. Current treatment with atazanavir sulfate
9. Previous treatment with tegafur, gimeracil, and oteracil potassium within seven days before enrollment
10. Pregnant or lactating females, and males and females unwilling to use contraception
11. Requires continuous treatment with systemic steroids
12. Psychiatric disability that would preclude study compliance
13. Otherwise determined by the investigator to be unsuitable for participation in the study
14. Concurrent gastrointestinal perforation or history of gastrointestinal perforation with 1 year before enrollment
15. History of pulmonary hemorrhage/hemoptysis ≥ Grade 2 (defined as bright red blood of at least 2.5mL) within 1 month prior to enrollment.
16. History of laparotomy, thoracotomy, or intestinal resection within 28 days before enrollment
17. Unhealed wound (except suture wounds from implantation of a central venous port), gastrointestinal ulcer, or traumatic fracture
18. Current or recent (within 1 year) thromboembolism or cerebrovascular disease
19. Currently receiving or requires anticoagulation therapy (\> 325 mg/day of aspirin)
20. Bleeding diathesis, coagulopathy, or coagulation factor abnormality (INR ≥1.5 within 14 days before enrollment)
21. Uncontrolled hypertension
22. Urine dipstick for proteinuria \>+2
B: Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the colon or rectum in patients who are presenting with metastatic disease
* One and only one prior chemotherapy regimen for metastatic disease consisting of the combination of a fluoropyrimidine-based chemotherapy and an oxaliplatin-based chemotherapy. Prior adjuvant chemotherapy used prior to the onset of metastatic disease is permitted
* At least one uni dimensionally measurable lesion per modified RECIST criteria. All sites of disease must be evaluated \<= 28 days before randomization
* Radiographically documented disease progression per modified RECIST criteria either while receiving or \<= 6 months after the last dose of prior chemotherapy regimen for metastatic disease
* ECOG performance status of 0 or 1
* Man or woman \>= 18 years of age
* Adequate end organ assessments by laboratory studies (hematological and chemistries)
* Life expectancy \>= 3 months

Exclusion Criteria:

* Exclude subjects with a history of prior malignancy, except:

  * Malignancy treated with curative intent and with no known active disease present for \>= 3 years before enrollment and felt to be at low risk for recurrence by treating physician
  * Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease
  * Adequately treated cervical carcinoma in situ without evidence of disease
  * Prostatic intraepithelial neoplasia without evidence of prostate cancer
* Prior irinotecan therapy
* Systemic chemotherapy, hormonal therapy, or immunotherapy \<= 21 days prior to randomization
* Experimental or approved proteins/antibodies (eg, bevacizumab) \<= 30 days prior to randomization
* Clinically significant cardiac disease within 12 months prior to randomization, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent
* Known allergy or hypersensitivity to irinotecan, 5 FU (known dihydropyrimidine dehydrogenase deficiency) or leucovorin
* Active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as \>= CTC grade 2 \[CTCAE version 3.0\])
C: Inclusion Criteria:

* Histology and staging disease

  * Histologically proven CRC; advanced disease, not amenable to curative surgery;
  * Of Note: In case of a single metastasis, histological or cytological proof of colorectal carcinoma should be obtained prior to randomisation.
  * Measurable or evaluable disease; Serum CEA as the only parameter for disease activity is not allowed.
* General conditions

  * Written informed consent;
  * Age 18 years and above;
  * WHO performance status 0-2;
  * Adequate bone marrow function(WBC \> 3.0 x 109/L, platelets \> 100 x 109/L, Hb \> 6 mmol/L);
  * Adequate hepatic function: total bilirubin \< 1. 5 x upper normal limit, ASAT and ALAT \< 3 x upper normal limits; in case of liver metastases \< 5 x upper normal limits
  * Adequate renal function: creatinin \< 1. 5 x upper normal limits.
* Other - Expected adequacy of follow-up.

Exclusion Criteria:

* General conditions

  * Pregnancy or lactation;
  * Patients (M/F) with reproductive potential not implementing adequate contraceptives measures.
* Prior or current history

  * Prior chemotherapy for advanced disease; prior adjuvant chemotherapy is allowed provided that the last administration was given \> 6 months prior to randomisation.
  * Serious concomitant diseases preventing the safe administration of chemotherapy or likely to interfere with the study assessments;
  * Serious active infections;
  * Inflammatory bowel disease or other diseases associated with chronic diarrhoea;
  * Previous extensive irradiation of the pelvis or abdomen;
  * Other malignancies in the past 5 years with the exception of adequately treated carcinoma in situ of the cervix or squamous or basal cell carcinoma of the skin.
* Concomitant treatments

  * Concomitant (or within 4 weeks before randomisation) administration of any other experimental drug under investigation;
  * Concurrent treatment with any other anti-cancer therapy.
D: 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

Answer: D