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

Study Overview
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Brief Summary
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To evaluate the safety and tolerability of ART-123 in patients with metastatic colorectal cancer who receive oxaliplatin-containing chemotherapy and bevacizumab

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

Official Title
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Double-blind, Placebo-controlled, Randomized, Dose-escalating, Multi-center, Phase 1 Study to Assess the Safety and Tolerability of ART-123 With Leucovorin/5-fluorouracil/Oxaliplatin and Bevacizumab in Metastatic Colorectal Cancer Patients

Conditions
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Chemotherapy-induced Peripheral Neuropathy

Intervention / Treatment
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* Drug: thrombomodulin alfa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lowest Dose<br>Lyophilized ART-123 reconstituted with sterile water for injection and administered by intravenous infusion over approximately 30 minutes prior to chemotherapy on Day 1 of cycle (for up to 3 cycles including bevacizumab) | Drug: thrombomodulin alfa<br>* Weight based dose of reconstituted treatment<br>* Other names: ART-123;|
| Experimental: Low Dose<br>Lyophilized ART-123 reconstituted with sterile water for injection and administered by intravenous infusion over approximately 30 minutes prior to chemotherapy on Day 1 of cycle (for up to 3 cycles including bevacizumab) | Drug: thrombomodulin alfa<br>* Weight based dose of reconstituted treatment<br>* Other names: ART-123;|
| Experimental: Medium Dose<br>Lyophilized ART-123 reconstituted with sterile water for injection and administered by intravenous infusion over approximately 30 minutes prior to chemotherapy on Day 1 of cycle (for up to 3 cycles including bevacizumab) | Drug: thrombomodulin alfa<br>* Weight based dose of reconstituted treatment<br>* Other names: ART-123;|
| Experimental: High Dose<br>Lyophilized ART-123 reconstituted with sterile water for injection and administered by intravenous infusion over approximately 30 minutes prior to chemotherapy on Day 1 of cycle (for up to 3 cycles including bevacizumab) | Drug: thrombomodulin alfa<br>* Weight based dose of reconstituted treatment<br>* Other names: ART-123;|
| Experimental: Highest Dose<br>Lyophilized ART-123 reconstituted with sterile water for injection and administered by intravenous infusion over approximately 30 minutes prior to chemotherapy on Day 1 of cycle (for up to 3 cycles including bevacizumab) | Drug: thrombomodulin alfa<br>* Weight based dose of reconstituted treatment<br>* Other names: ART-123;|
| Placebo Comparator: Placebo<br>Lyophilized placebo reconstituted with sterile water for injection and administered by intravenous infusion over approximately 30 minutes prior to chemotherapy on Day 1 of cycle (for up to 3 cycles including bevacizumab) | Drug: Placebo<br>* Weight based dose of reconstituted treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) | 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) | 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 with Serious TEAEs | 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 | From start of first IMP dose (Cycle 1, Day 1) through EOT visit; planned for 6 weeks | 
| Number and Percentage of Participants with TEAEs Leading to Death | Number and percentage of participants with TEAEs that resulted in 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 Leading to IMP Discontinuation | Number and percentage of participants with TEAEs that lead to discontinuation of IMP | 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 Bleeding Events | Number and percentage of participants experiencing 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 Serious Bleeding Events | Number and percentage of participants with bleeding events that represent serious adverse events | From start of first IMP dose (Cycle 1, Day 1) through EOT visit; planned for 6 weeks | 
| Number and Percentage of Participants with Dose Limiting Toxicity (DLT) | Number and percentage of participants experiencing 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 with Abnormal Complete Blood Count (CBC) Results | 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 | 6 weeks | 
| Number and Percentage of Participants with Abnormal Serum Chemistry Results | 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) | 6 weeks | 
| Number and Percentage of Participants with Abnormal Coagulation Panel Results | Descriptive statistics will summarize the following by cohort: international normalized ratio (INR), activated partial thromboplastin time (APTT) | 6 weeks | 
| Number and Percentage of Participants with Abnormal Qualitative Urinalysis Results | Qualitative summary of the following by cohort: protein, glucose, and occult blood | 6 weeks | 
| Number and Percentage of Participants with Abnormal Vital Signs | Descriptive statistics will summarize the following by cohort: body temperature, pulse, and blood pressure | 6 weeks | 
| Number and Percentage of Participants with Anti-ART-123 Antibodies | 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 | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of Thrombomodulin | Plasma concentrations of thrombomodulin associated with Cycle 1 dosing (each cycle is 14 days) | Cycle 1, Day 1 (each cycle is 14 days) | 
| Plasma Concentrations of 5-fluorouracil (5-FU) | Plasma concentrations of 5-FU associated with Cycle 1 dosing (each cycle is 14 days) | Cycle 1, Day 1 (each cycle is 14 days) | 
| Plasma Concentrations of Oxaliplatin | Plasma concentrations of oxaliplatin associated with Cycle 1 and Cycle 3 dosing (each cycle is 14 days) | Cycle 1, Day 1 and Cycle 3, Day 1 (each cycle is 14 days) | 
| Serum Concentrations of Bevacizumab | Serum concentrations of bevacizumab associated with Cycle 1 and Cycle 3 dosing (each cycle is 14 days) | Cycle 1, Day 1 and Cycle 3, Day 1 (each cycle is 14 days) |