Study With SCB-313 (Recombinant Human TRAIL-Trimer Fusion Protein) for Treatment of Malignant Pleural Effusions

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, preliminary efficacy, and PK/PD of SCB-313 (recombinant human TRAIL-Trimer fusion protein) administered once via intrapleural injection (SAD) and once daily over 2 to 3 days (MAD)for the treatment of cancer patients with symptomatic malignant pleural effusions requiring drainage.

Official Title
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A Phase I Study Evaluating the Safety, Tolerability, Efficacy, and Pharmacokinetics of SCB-313, a Fully-Human TRAIL-Trimer Fusion Protein, for the Treatment of Malignant Pleural Effusions

Conditions
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Malignant Pleural Effusions

Intervention / Treatment
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* Drug: SCB-313


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed cancer of any primary tumor type. Malignant pleural effusion causing respiratory symptoms requiring drainage that is histologically or cytologically confirmed; or pleural effusion with radiologically proven pleural malignancy as diagnosed in normal clinical practice on thoracic computed tomography in the absence of histocytological or cytological proof. Eastern Cooperative Oncology Group (ECOG) performance status: 0 to 2. Patients with an ECOG performance status of 3 may be included if the Investigator determines that removal of pleural fluid would improve their performance status to 2 or better. Life expectancy of at least 8 weeks. Age ≥18 years. Adequate hematologic function, defined as: Platelet count ≥75,000/μL; Prothrombin time and activated partial thromboplastin time ≤1.5 times the upper limit of normal (ULN); Absolute neutrophil count ≥1,500 μL; Hemoglobin ≥8 g/dL (transfusion and erythropoietic agents are allowed). In case there is existence of active bleeding or other persistent condition of either increased destruction or impaired production of erythrocytes, which may require repeated transfusion or erythropoietic treatment, the eligibility must be discussed with the Sponsor on a case-by-case basis prior to randomization). Adequate renal function, defined as creatinine clearance >40 mL/minute. Adequate liver function, defined as: Aspartate aminotransferase and alanine aminotransferase ≤2.0 times ULN; Bilirubin ≤2.0 times ULN, unless patient has known Gilbert's syndrome. Female patients of childbearing potential (excluding women who have undergone surgical sterilization or are menopausal, defined as no menstrual periods for 1 year or more without any other medical reasons) are eligible if they have negative serum pregnancy test result 7 days before the first dose of SCB-313 and are willing to use an effective method of birth control/contraception to prevent pregnancy until 6 months after discontinuation of SCB-313. Both men and women of reproductive potential must agree to use effective contraception during the study and for 6 months after discontinuation of SCB-313. Note: Contraceptive methods that are considered highly effective areas follows: total abstinence, intrauterine device, double barrier method (such as condom plus diaphragm with spermicide), contraceptive implant, hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices, or injections with prolonged release), or vasectomized partner with confirmed azoospermia. Willing to attend follow-up visits on Days 10, and 21 after the first study drug administration. Exclusion Criteria: Significantly loculated pleural effusions not amenable to drainage or patient is unlikely to benefit from intrapleural therapy. Concurrent use of any investigational product (IP) or investigational medicine within 28 days before Day 1 of study drug administration. Radiotherapy outside the chest field within 2 weeks, or radical radiotherapy to pleural or lung lesions within 8 weeks prior to enrollment (Note: palliative radiotherapy to the chest is allowed). Start a new systemic anticancer therapy, including chemotherapy, targeted therapy, immuno-oncology (I-O) therapy regimen, within 28 days before Day 1 of study drug administration or during DLT observation period. Acute or chronic infection (such as tuberculosis) requiring antiviral or intravenous antibiotics within 2 weeks prior to enrollment. Clinical unstable or uncontrolled concomitant hematologic, cardiovascular, pulmonary, hepatic, renal, pancreatic, or endocrine diseases. History of gross hemoptysis (>2.5 mL). Residual adverse events (AEs) > Grade 2 from previous treatment. Evidence or suspicion of relevant psychiatric impairment, including alcohol or recreational drug abuse. Myocardial infarction within 6 months prior to treatment and/or prior diagnoses of congestive heart failure (New York Heart Association Class III or IV), unstable angina, unstable cardiac arrhythmia requiring medication, and/or long QT syndrome or QT/QTc interval >480 msec at Baseline. Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg confirmed upon repeated measures (note: no more than 3 repeated measures allowed). Major surgery (open procedures) within 4 weeks prior to enrollment. Patient with ileus within 30 days prior to Screening. Positive serology test for human immunodeficiency virus type 1 and/or 2, or known history of other immunodeficiency disease. Live vaccine within 2 weeks prior to enrollment. Scheduled participation in another clinical study involving an investigational product or device during the DLT observation period of this study. Previous treatment with a TRAIL-based therapy or death receptor 4/5 agonist therapy. Known or suspected hypersensitivity to any component of SCB-313. Any further condition which, in the opinion of the Investigator, may result in undue risk of the patient by participating in the present study. Untreated central nervous system metastatic disease, leptomeningeal disease, or cord compression.

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SCB-313<br>Cohorts in SAD phase: 5 mg, 10mg, 20mg, 40mg, 80 mg. Cohort in MAD phase: biological effective dose determined from SAD phase. 1 intrapleural injection of SCB-313 on Day 1 for the SAD cohorts, and 3 intrapleural injections of SCB-313 on Days 1, 2 and 3 for the MAD cohort. | Drug: SCB-313<br>* 5 mg or 20 mg lyophilized powder in a single-use glass vial<br>* Other names: recombinant human TRAIL-Trimer fusion protein;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of DLT | Occurrence of dose limiting toxicity (DLT) | Up to 21 days after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SAEs or TEAEs | Occurrence of serious adverse events (SAEs) and/or treatment-emergent adverse events (TEAEs) regardless of causality or relationship to SCB-313, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 | Up to 21 days after start of treatment | 
| Immunogenicity | Occurrence of binding and neutralizing anti-SCB-313 antibodies | Up to 21 days after start of treatment | 
| Pleural effusion response rate at Day 21 | Based on chest radiographs at Day 21, compared to Baseline. | At Day 21 after start of treatment | 
| Pleural effusion drainage-free rate at Day 21 | Defined as the probability of being effusion-drainage free at Day 21 | At Day 21 after start of treatment | 
| The changes in effusion volume and flow rate after SCB-313 treatment , and at next drainage over the baseline daily effusion flow rate. | The baseline daily effusion flow rate will be measured. Effusion flow rate will be calculated from the effusion volume drained over the time elapsed between drainages. Effusion flow rate at next pleural drainage will be calculated from the volume over the time elapsed between drainages. | Up to 6 months after start of treatment | 
| Blood oxygen levels | To compare blood oxygen levels during the study | Up to 21 days after start of treatment | 
| Overall survival | The time from the first dose of SCB-313 until death from any cause. | Up to 6 months after start of treatment | 
| Pharmacokinetics (Cmax) | Maximum SCB-313 concentration | Up to 4 days after start of treatment | 
| Pharmacokinetics(Cmax/D) | Dose-normalized Cmax of SCB-313 | Up to 4 days after start of treatment | 
| Pharmacokinetics(Tmax) | Time to Cmax of SCB-313 | Up to 4 days after start of treatment | 
| Pharmacokinetics ([AUC]0-24) | Area under SCB-313 concentration time curve from zero to 24 hours after dosing | Up to 4 days after start of treatment | 
| Pharmacokinetics (AUC0-24/D) | Dose-normalized AUC0-24 | Up to 4 days after start of treatment | 
| Pharmacokinetics ((AUC0-last)) | Area under the SCB-313 concentration-time curve from time zero to the last quantifiable concentration time point | Up to 4 days after start of treatment | 
| Pharmacokinetics (Ctrough) | Trough concentration (Ctrough) at each predose time point and at 24 hours after the last dose | Up to 4 days after start of treatment | 
| Amount of drug in pleural effusion | Amount of SCB-313 in pleural effusion at 24 hours after each dose | Up to 4 days after start of treatment | 
| Pharmacokinetics (AUC 0-inf) | Area under the curve from time zero extrapolated to infinity | Up to 4 days after start of treatment | 
| Pharmacokinetics (AUC0-inf/D) | Dose-normalized AUC0-inf | Up to 4 days after start of treatment | 
| Pharmacokinetics (t1/2) | Terminal half-life | Up to 4 days after start of treatment | 
| Pharmacokinetics (CL/F serum only) | Apparent systemic clearance after intrapleural dosing | Up to 4 days after start of treatment | 
| Pharmacokinetics (Vz/F serum only) | Apparent volume of distribution after intrapleural dosing | Up to 4 days after start of treatment | 
| Pharmacokinetics (λz) | Terminal rate constant | Up to 4 days after start of treatment | 
| Tumor response | Tumor response in patients with measurable disease using RECIST v1.1 as applicable. | Up to 6 months after start of treatment | 
| Carcinoembryonic antigen (CEA) | Changes in serum tumor markers | Up to 21 days after start of treatment | 
| CA-125 | Changes in serum tumor markers | Up to 21 days after start of treatment | 
| CA-19-9 | Changes in serum tumor markers | Up to 21 days after start of treatment | 
| Changes in 24-hour urine volume | Measured urine volume at baseline and postdose | Up to 4 days after start of treatment | 
| Changes in GFR | The changes in glomerular filtration rate | Up to 4 days after start of treatment | 
| Changes in tumor cell count in pleural effusion samples | The changes in tumor cell count | Up to 4 days after start of treatment | 
| Caspase-cleaved CK18 | Changes in serum PD biomarker | Up to 10 days after start of treatment | 
| KRAS mutation | Predictive biomarker analysis (assessed using archival tumor specimens ) | Baseline | 
| MMR defects | Predictive biomarker analysis (assessed using archival tumor specimens ) | Baseline | 
| Bcl2 overexpression | Predictive biomarker analysis (assessed using archival tumor specimens ) | Baseline | 
| TRAIL resistance | Predictive biomarker analysis (assessed using pleural effusion samples) | Baseline |