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

Primary Purpose

Malignant Pleural Effusions

Status
Completed
Phase
Phase 1
Locations
Australia
Study Type
Interventional
Intervention
SCB-313
Sponsored by
Clover Biopharmaceuticals AUS Pty Ltd
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Pleural Effusions

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Histologically or cytologically confirmed cancer of any primary tumor type.
  2. 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.
  3. 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.
  4. Life expectancy of at least 8 weeks.
  5. Age ≥18 years.
  6. Adequate hematologic function, defined as:

    1. Platelet count ≥75,000/μL;
    2. Prothrombin time and activated partial thromboplastin time ≤1.5 times the upper limit of normal (ULN);
    3. Absolute neutrophil count ≥1,500 μL;
    4. 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).
  7. Adequate renal function, defined as creatinine clearance >40 mL/minute.
  8. Adequate liver function, defined as:

    1. Aspartate aminotransferase and alanine aminotransferase ≤2.0 times ULN;
    2. Bilirubin ≤2.0 times ULN, unless patient has known Gilbert's syndrome.
  9. 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.

  10. Willing to attend follow-up visits on Days 10, and 21 after the first study drug administration.

Exclusion Criteria:

  1. Significantly loculated pleural effusions not amenable to drainage or patient is unlikely to benefit from intrapleural therapy.
  2. Concurrent use of any investigational product (IP) or investigational medicine within 28 days before Day 1 of study drug administration.
  3. 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).
  4. 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.
  5. Acute or chronic infection (such as tuberculosis) requiring antiviral or intravenous antibiotics within 2 weeks prior to enrollment.
  6. Clinical unstable or uncontrolled concomitant hematologic, cardiovascular, pulmonary, hepatic, renal, pancreatic, or endocrine diseases.
  7. History of gross hemoptysis (>2.5 mL).
  8. Residual adverse events (AEs) > Grade 2 from previous treatment.
  9. Evidence or suspicion of relevant psychiatric impairment, including alcohol or recreational drug abuse.
  10. 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.
  11. 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).
  12. Major surgery (open procedures) within 4 weeks prior to enrollment.
  13. Patient with ileus within 30 days prior to Screening.
  14. Positive serology test for human immunodeficiency virus type 1 and/or 2, or known history of other immunodeficiency disease.
  15. Live vaccine within 2 weeks prior to enrollment.
  16. Scheduled participation in another clinical study involving an investigational product or device during the DLT observation period of this study.
  17. Previous treatment with a TRAIL-based therapy or death receptor 4/5 agonist therapy.
  18. Known or suspected hypersensitivity to any component of SCB-313.
  19. Any further condition which, in the opinion of the Investigator, may result in undue risk of the patient by participating in the present study.
  20. Untreated central nervous system metastatic disease, leptomeningeal disease, or cord compression.

Sites / Locations

  • Liverpool Hospital
  • Orange Health Service
  • The Royal Melbourne Hospital
  • SCGH (Sir Charles Gairdner Hospital)

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

SCB-313

Arm Description

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.

Outcomes

Primary Outcome Measures

Occurrence of DLT
Occurrence of dose limiting toxicity (DLT)

Secondary Outcome Measures

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
Immunogenicity
Occurrence of binding and neutralizing anti-SCB-313 antibodies
Pleural effusion response rate at Day 21
Based on chest radiographs at Day 21, compared to Baseline.
Pleural effusion drainage-free rate at Day 21
Defined as the probability of being effusion-drainage free at Day 21
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.
Blood oxygen levels
To compare blood oxygen levels during the study
Overall survival
The time from the first dose of SCB-313 until death from any cause.
Pharmacokinetics (Cmax)
Maximum SCB-313 concentration
Pharmacokinetics(Cmax/D)
Dose-normalized Cmax of SCB-313
Pharmacokinetics(Tmax)
Time to Cmax of SCB-313
Pharmacokinetics ([AUC]0-24)
Area under SCB-313 concentration time curve from zero to 24 hours after dosing
Pharmacokinetics (AUC0-24/D)
Dose-normalized AUC0-24
Pharmacokinetics ((AUC0-last))
Area under the SCB-313 concentration-time curve from time zero to the last quantifiable concentration time point
Pharmacokinetics (Ctrough)
Trough concentration (Ctrough) at each predose time point and at 24 hours after the last dose
Amount of drug in pleural effusion
Amount of SCB-313 in pleural effusion at 24 hours after each dose
Pharmacokinetics (AUC 0-inf)
Area under the curve from time zero extrapolated to infinity
Pharmacokinetics (AUC0-inf/D)
Dose-normalized AUC0-inf
Pharmacokinetics (t1/2)
Terminal half-life
Pharmacokinetics (CL/F serum only)
Apparent systemic clearance after intrapleural dosing
Pharmacokinetics (Vz/F serum only)
Apparent volume of distribution after intrapleural dosing
Pharmacokinetics (λz)
Terminal rate constant
Tumor response
Tumor response in patients with measurable disease using RECIST v1.1 as applicable.
Carcinoembryonic antigen (CEA)
Changes in serum tumor markers
CA-125
Changes in serum tumor markers
CA-19-9
Changes in serum tumor markers
Changes in 24-hour urine volume
Measured urine volume at baseline and postdose
Changes in GFR
The changes in glomerular filtration rate
Changes in tumor cell count in pleural effusion samples
The changes in tumor cell count
Caspase-cleaved CK18
Changes in serum PD biomarker
KRAS mutation
Predictive biomarker analysis (assessed using archival tumor specimens )
MMR defects
Predictive biomarker analysis (assessed using archival tumor specimens )
Bcl2 overexpression
Predictive biomarker analysis (assessed using archival tumor specimens )
TRAIL resistance
Predictive biomarker analysis (assessed using pleural effusion samples)

Full Information

First Posted
March 1, 2019
Last Updated
February 1, 2022
Sponsor
Clover Biopharmaceuticals AUS Pty Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT03869697
Brief Title
Study With SCB-313 (Recombinant Human TRAIL-Trimer Fusion Protein) for Treatment of Malignant Pleural Effusions
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
November 20, 2019 (Actual)
Primary Completion Date
November 4, 2021 (Actual)
Study Completion Date
November 23, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Clover Biopharmaceuticals AUS Pty Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Pleural Effusions

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
SCB-313
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
SCB-313
Other Intervention Name(s)
recombinant human TRAIL-Trimer fusion protein
Intervention Description
5 mg or 20 mg lyophilized powder in a single-use glass vial
Primary Outcome Measure Information:
Title
Occurrence of DLT
Description
Occurrence of dose limiting toxicity (DLT)
Time Frame
Up to 21 days after start of treatment
Secondary Outcome Measure Information:
Title
SAEs or TEAEs
Description
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
Time Frame
Up to 21 days after start of treatment
Title
Immunogenicity
Description
Occurrence of binding and neutralizing anti-SCB-313 antibodies
Time Frame
Up to 21 days after start of treatment
Title
Pleural effusion response rate at Day 21
Description
Based on chest radiographs at Day 21, compared to Baseline.
Time Frame
At Day 21 after start of treatment
Title
Pleural effusion drainage-free rate at Day 21
Description
Defined as the probability of being effusion-drainage free at Day 21
Time Frame
At Day 21 after start of treatment
Title
The changes in effusion volume and flow rate after SCB-313 treatment , and at next drainage over the baseline daily effusion flow rate.
Description
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.
Time Frame
Up to 6 months after start of treatment
Title
Blood oxygen levels
Description
To compare blood oxygen levels during the study
Time Frame
Up to 21 days after start of treatment
Title
Overall survival
Description
The time from the first dose of SCB-313 until death from any cause.
Time Frame
Up to 6 months after start of treatment
Title
Pharmacokinetics (Cmax)
Description
Maximum SCB-313 concentration
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics(Cmax/D)
Description
Dose-normalized Cmax of SCB-313
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics(Tmax)
Description
Time to Cmax of SCB-313
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics ([AUC]0-24)
Description
Area under SCB-313 concentration time curve from zero to 24 hours after dosing
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics (AUC0-24/D)
Description
Dose-normalized AUC0-24
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics ((AUC0-last))
Description
Area under the SCB-313 concentration-time curve from time zero to the last quantifiable concentration time point
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics (Ctrough)
Description
Trough concentration (Ctrough) at each predose time point and at 24 hours after the last dose
Time Frame
Up to 4 days after start of treatment
Title
Amount of drug in pleural effusion
Description
Amount of SCB-313 in pleural effusion at 24 hours after each dose
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics (AUC 0-inf)
Description
Area under the curve from time zero extrapolated to infinity
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics (AUC0-inf/D)
Description
Dose-normalized AUC0-inf
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics (t1/2)
Description
Terminal half-life
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics (CL/F serum only)
Description
Apparent systemic clearance after intrapleural dosing
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics (Vz/F serum only)
Description
Apparent volume of distribution after intrapleural dosing
Time Frame
Up to 4 days after start of treatment
Title
Pharmacokinetics (λz)
Description
Terminal rate constant
Time Frame
Up to 4 days after start of treatment
Title
Tumor response
Description
Tumor response in patients with measurable disease using RECIST v1.1 as applicable.
Time Frame
Up to 6 months after start of treatment
Title
Carcinoembryonic antigen (CEA)
Description
Changes in serum tumor markers
Time Frame
Up to 21 days after start of treatment
Title
CA-125
Description
Changes in serum tumor markers
Time Frame
Up to 21 days after start of treatment
Title
CA-19-9
Description
Changes in serum tumor markers
Time Frame
Up to 21 days after start of treatment
Title
Changes in 24-hour urine volume
Description
Measured urine volume at baseline and postdose
Time Frame
Up to 4 days after start of treatment
Title
Changes in GFR
Description
The changes in glomerular filtration rate
Time Frame
Up to 4 days after start of treatment
Title
Changes in tumor cell count in pleural effusion samples
Description
The changes in tumor cell count
Time Frame
Up to 4 days after start of treatment
Title
Caspase-cleaved CK18
Description
Changes in serum PD biomarker
Time Frame
Up to 10 days after start of treatment
Title
KRAS mutation
Description
Predictive biomarker analysis (assessed using archival tumor specimens )
Time Frame
Baseline
Title
MMR defects
Description
Predictive biomarker analysis (assessed using archival tumor specimens )
Time Frame
Baseline
Title
Bcl2 overexpression
Description
Predictive biomarker analysis (assessed using archival tumor specimens )
Time Frame
Baseline
Title
TRAIL resistance
Description
Predictive biomarker analysis (assessed using pleural effusion samples)
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Liverpool Hospital
City
Liverpool
State/Province
New South Wales
ZIP/Postal Code
2170
Country
Australia
Facility Name
Orange Health Service
City
Orange
State/Province
New South Wales
ZIP/Postal Code
2800
Country
Australia
Facility Name
The Royal Melbourne Hospital
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
SCGH (Sir Charles Gairdner Hospital)
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia

12. IPD Sharing Statement

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

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