Assess Safety and Tolerability of ART-123 + FOLFOX + Bevacizumab in Metastatic Colorectal Cancer Patients

To compare the safety and tolerability of ART-123 to placebo in patients with metastatic colorectal cancer who receive oxaliplatin-containing chemotherapy and bevacizumab

• thrombomodulin alfa (Drug), also known as ART-123: Weight based dose of reconstituted treatment
• Placebo (Drug): Weight based dose of reconstituted treatment

Primary outcomes

• Number and Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) [From start of first IMP dose (Cycle 1, Day 1) through End of Treatment (EOT) visit; planned for 6 weeks]: Number and percentage of participants experiencing one or more adverse events which occurred or worsened in severity after the start of the first dose of investigational medicinal product (IMP)
• Number and Percentage of Participants with Serious TEAEs [From start of first IMP dose (Cycle 1, Day 1) through EOT visit; planned for 6 weeks]: Number and percentage of participants experiencing one or more serious adverse events which occurred or worsened in severity after the start of the first dose of IMP
• Number and Percentage of Participants with TEAEs Leading to Death [From start of first IMP dose (Cycle 1, Day 1) through EOT visit; planned for 6 weeks]: Number and percentage of participants with TEAEs that resulted in death
• Number and Percentage of Participants with TEAEs Leading to IMP Discontinuation [From start of first IMP dose (Cycle 1, Day 1) through planned third IMP dose; planned for 4 weeks]: Number and percentage of participants with TEAEs that lead to discontinuation of IMP
• Number and Percentage of Participants with Bleeding Events [From start of first IMP dose (Cycle 1, Day 1) through EOT visit; planned for 6 weeks]: Number and percentage of participants experiencing bleeding events
• Number and Percentage of Participants with Serious Bleeding Events [From start of first IMP dose (Cycle 1, Day 1) through EOT visit; planned for 6 weeks]: Number and percentage of participants with bleeding events that represent serious adverse events
• Number and Percentage of Participants with Dose Limiting Toxicity (DLT) [From start of first IMP dose (Cycle 1, Day 1) until the start of the third IMP dose; planned for 4 weeks]: Number and percentage of participants experiencing DLT
• Number and Percentage of Participants with Abnormal Complete Blood Count (CBC) Results [6 weeks]: Descriptive statistics will summarize the following by cohort: red blood cell count, hemoglobin, hematocrit, white blood cell count, white blood cell differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelet count
• Number and Percentage of Participants with Abnormal Serum Chemistry Results [6 weeks]: Descriptive statistics will summarize the following by cohort: aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, lactate dehydrogenase, total bilirubin, total protein, albumin, blood urea nitrogen, creatinine, glucose, and electrolytes (sodium, potassium, chloride)
• Number and Percentage of Participants with Abnormal Coagulation Panel Results [6 weeks]: Descriptive statistics will summarize the following by cohort: international normalized ratio (INR), activated partial thromboplastin time (APTT)
• Number and Percentage of Participants with Abnormal Qualitative Urinalysis Results [6 weeks]: Qualitative summary of the following by cohort: protein, glucose, and occult blood
• Number and Percentage of Participants with Abnormal Vital Signs [6 weeks]: Descriptive statistics will summarize the following by cohort: body temperature, pulse, and blood pressure
• Number and Percentage of Participants with Anti-ART-123 Antibodies [6 weeks]: Number and Percentage of Participants with detectable anti-ART-123 antibodies; samples testing positive for anti-ART-123 antibodies will be tested for the presence of neutralizing antibodies

Secondary outcomes

• Plasma Concentrations of Thrombomodulin [Cycle 1, Day 1 (each cycle is 14 days)]: Plasma concentrations of thrombomodulin associated with Cycle 1 dosing (each cycle is 14 days)
• Plasma Concentrations of 5-fluorouracil (5-FU) [Cycle 1, Day 1 (each cycle is 14 days)]: Plasma concentrations of 5-FU associated with Cycle 1 dosing (each cycle is 14 days)
• Plasma Concentrations of Oxaliplatin [Cycle 1, Day 1 and Cycle 3, Day 1 (each cycle is 14 days)]: Plasma concentrations of oxaliplatin associated with Cycle 1 and Cycle 3 dosing (each cycle is 14 days)
• Serum Concentrations of Bevacizumab [Cycle 1, Day 1 and Cycle 3, Day 1 (each cycle is 14 days)]: Serum concentrations of bevacizumab associated with Cycle 1 and Cycle 3 dosing (each cycle is 14 days)

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* 18 years of age or older
* Metastatic colorectal cancer; pathologically confirmed adenocarcinoma of the colon or rectum
* ECOG performance status of 0 or 1
* The most recent laboratory findings (including for liver and kidney) within 14 days prior to randomization remain within acceptable ranges Willingness of the patient and the sexual partner to use a highly effective contraceptive method during the course of the study
* Able to sufficiently understand the clinical study and give written informed consent

Exclusion Criteria:

* History of major hemorrhage
* High risk of hemorrhage
* History of other malignancies
* Active ulcer
* Patients using anti-coagulants and fibrinolytic drugs
* Active Hepatitis B, or known HBs antigen positive
* Prior treatment history with thrombomodulin alfa
* Administration of another investigational medicinal product within 30 days prior to randomization
* Patient is pregnant (positive urine human chorionic gonadotropin) or breastfeeding or intends to get pregnant during the Treatment period
* Patients otherwise deemed as inappropriate to participate in the study by the Investigator

• Libbie McKenzie, MD FASN, Study director, Veloxis Pharmaceuticals