A Clinical Study to Test the Efficacy and Safety of CSL312 on Catheter-associated Blood Clot Formation in Subjects With Cancer Who Receive Chemotherapy Through a PICC Line

Study Overview
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Brief Summary
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Peripherally Inserted Central Catheters (PICCs) are commonly used in patients with cancer to administer chemotherapy and supportive care medication. However, PICCs and other medical devices that come into contact with blood increase the risk of blood clots (thrombosis) inside the blood vessels. Conventional blood thinners (anticoagulants) may reduce the risk of thrombosis but they also increase the risk of bleeding. CSL312, a monoclonal antibody that inhibits the activated blood clotting factor 12 (FXIIa) will be assessed for its potential to prevent thrombus formation in subjects with cancer at risk of PICC-associated thrombosis.

Official Title
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A Phase 1b, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety, and Pharmacokinetics of CSL312 in the Prevention of Peripherally Inserted Central Catheter (PICC)-Associated Thrombosis in Subjects With Cancer

Conditions
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PICC-associated Thrombosis

Intervention / Treatment
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* Drug: CSL312
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or older at the time of providing written informed consent Diagnosis of malignancy that requires placement of a PICC within the next 3 weeks for administration of chemotherapy (PICC anticipated to be required for at least 1 month) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 [Oken et al, 1982], and investigator's expectation that performance status will remain 0, 1, or 2 for the duration of the study Exclusion Criteria: Active bleeding or with a current clinically significant coagulopathy (eg, international normalized ratio [INR] > 1.5) or clinically significant risk for bleeding (eg, recent intracranial hemorrhage or bleeding peptic ulcer within the last 4 weeks) History of venous thrombosis, myocardial infarction or cerebrovascular event within 3 months, or a prothrombotic disorder (eg, antithrombin III, protein C or S deficiency) Life expectancy less than study duration (110 days) Platelet count of < 20 × 109/L on the day of dose 1 (Day 1) or within 7 days before first dosing Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 Treatment with antiplatelet or anticoagulant medication, including thrombosis prophylaxis, within 10 days prior to insertion of the PICC Chemotherapy regimen that would be expected to drop the platelet count to < 20 × 109/L Chemotherapy regimen with heparin mixed into IV bags (eg, dalteparin 2500 IU/day) Difficult IV access that would prevent infusion of the IP In situ central venous catheter (CVC) or PICC in the 3 months before the Screening Visit. The study PICC must be inserted in the contralateral side, which must be PICC / CVC naïve Undergoing dialysis or have another inserted intravascular foreign surface device Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) ≥ 4 × upper limit of normal

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: CSL312 Cohort 1 (Dose 1)<br>CSL312 administered as IV infusion | Drug: CSL312<br>* CSL312 administered as an IV infusion<br>* Other names: Garadacimab;|
| Experimental: CSL312 Cohort 2 (Dose 2)<br>CSL312 administered as IV infusion | Drug: CSL312<br>* CSL312 administered as an IV infusion<br>* Other names: Garadacimab;|
| Experimental: CSL312 Cohort 3 (Dose 3)<br>CSL312 administered as IV infusion | Drug: CSL312<br>* CSL312 administered as an IV infusion<br>* Other names: Garadacimab;|
| Experimental: CSL312 Cohort 4 (Dose 4)<br>CSL312 administered as IV infusion | Drug: CSL312<br>* CSL312 administered as an IV infusion<br>* Other names: Garadacimab;|
| Placebo Comparator: Placebo<br>Placebo administered as IV infusion | Drug: Placebo<br>* Solution of 70% 0.9% saline / 30% CSL312 diluent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with PICC-associated thrombosis | PICC-associated thrombosis which can be either: Asymptomatic PICC associated thrombosis detected by Duplex ultrasound (DUS) or venography at Day 15 or Day 29 after PICC insertion or Symptomatic PICC associated thrombosis up to Day 29 after PICC insertion, suspected clinically due to symptoms of the upper limb or neck, and objectively confirmed by DUS or venography | Up to 29 days after PICC insertion | 
| Percent of subjects with PICC-associated thrombosis | PICC-associated thrombosis which can be either: Asymptomatic PICC associated thrombosis detected by Duplex ultrasound (DUS) or venography at Day 15 or Day 29 after PICC insertion or Symptomatic PICC associated thrombosis up to Day 29 after PICC insertion, suspected clinically due to symptoms of the upper limb or neck, and objectively confirmed by DUS or venography | Up to 29 days after PICC insertion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall percentage of subjects with treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) |  | Up to 110 days after first dose of CSL312 | 
| Percent of subjects with related TEAEs |  | Up to 110 days after first dose of CSL312 | 
| Percent of subjects with TEAEs by severity |  | Up to 110 days after first dose of CSL312 | 
| Number of subjects treated with CSL312 with detectable antibodies to CSL312 |  | Up to 110 days after first dose of CSL312 | 
| Percent of subjects treated with CSL312 with detectable antibodies to CSL312 |  | Up to 110 days after first dose of CSL312 | 
| Maximum plasma concentration (Cmax) of CSL312 |  | Up to 110 days after first dose of CSL312 | 
| Area under the concentration-time curve (AUC0-t) of CSL312 |  | Up to 110 days after first dose of CSL312 | 
| Time of maximum plasma concentration (Tmax) of CSL312 |  | Up to 110 days after first dose of CSL312 | 
| Terminal elimination half-life (T1/2) of CSL312 |  | Up to 110 days after first dose of CSL312 | 
| Total systemic clearance (CLtot) of CSL312 |  | Up to 110 days after first dose of CSL312 | 
| Volume of distribution during the elimination phase (Vz) of CSL312 |  | Up to 110 days after first dose of CSL312 | 
| Accumulation Ratio (AR) of CSL312 |  | Up to 110 days after first dose of CSL312 | 
| Number of subjects with thrombosis-associated catheter occlusion |  | Up to 29 days after first dose of CSL312 | 
| Percent of subjects with thrombosis-associated catheter occlusion |  | Up to 29 days after first dose of CSL312 | 
| Number of subjects with PICC removal or replacement |  | Up to 29 days after first dose of CSL312 | 
| Percent of subjects with PICC removal or replacement |  | Up to 29 days after first dose of CSL312 | 
| Number of subjects with central line-associated blood stream infections (CLABSI) |  | Up to 29 days after first dose of CSL312 | 
| Percent of subjects with CLABSI |  | Up to 29 days after first dose of CSL312 |