Back to resultsRecombinant Human Arginase 1 (rhArg1) in Patients With Advanced Arginine Auxotrophic Solid Tumors
Primary Purpose
Melanoma, Prostate Adenocarcinoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
PEG-BCT-100
Sponsored by
About this trial
This is an interventional treatment trial for Melanoma focused on measuring arginine auxotrophic tumors, PEG-BCT-100, arginase
Eligibility Criteria
Inclusion Criteria:
- Confirmed diagnosis of Stage IIIb/IV malignant melanoma or castration resistant adenocarcinoma of prostate (CRPC).
- Advanced cancer not candidate for treatment with modality or agents that are approved or have established efficacy. Candidates who cannot tolerate standard treatment or whose cancers have progressed on current standard of care.
- Males or females 18 years-old and above.
- Ability to understand and willingness to provide written informed consent;
- Karnofsky performance status (see Appendix 13.3) of 80% or above and expected survival of more than 12 weeks.
- Negative urine pregnancy test, if female, and willingness to use an effective method of contraception during the entire study period whether the patient is male or female.
Exclusion Criteria:
- Has received cancer treatment, e.g. chemotherapy, targeted biologic or enzymes, either approved or investigational, within 4 weeks prior to the start of the PEG-BCT-100;
- Advancing liver failure indicated by uncontrolled ascites, pleural effusions, or encephalopathy.
- Child-Pugh score of B and C (see Appendix 13.4).
- Significant hepatic, renal or bone marrow dysfunction indicated by: total bilirubin >2.0 mg/dL, evidence of bile duct obstruction, serum albumin <2.5 g/dL, serum ALT or AST >2.5 x upper limit of normal, serum creatinine ≥1.5 mg/dL, ANC ≥1.5 x 109/L, platelets <100 x 109/L, or INR >2.0.
- Significant cardiac or pulmonary disease defined by New York Heart Association (NYHA) Class III or IV (see Appendix 13.5), left ventricular ejection fraction (LVEF) lower than institutional normal limits by echo or MUGA, history of myocardial infarction within the past 6 months, significant unstable arrhythmia or evidence of ischemia on ECG.
- Pregnant or nursing women. NOTE: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- Significant active infection including HIV requiring oral or parenteral anti-infective therapies.
- Use of investigational drug(s) within 4 weeks of enrollment.
- Prior treatment with arginine depleting agent.
Sites / Locations
- California Cancer Associates for Research and Excellence, cCARE
- John Wayne Cancer Institute
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Cohort 5
Cohort 6
Arm Description
PEG-BCT-100 at 0.5 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 0.5 mg/kg on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 0.5 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 0.5 mg/kg until disease progression at the discretion of the investigator.
PEG-BCT-100 at 1.0 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 1.0 mg/kg on days 22 (week4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 1.0 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 1.0 mg/kg until disease progression at the discretion of the investigator.
PEG-BCT-100 at 1.7 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 1.7 mg/kg on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 1.7 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 1.7 mg/kg until disease progression at the discretion of the investigator.
PEG-BCT-100 at 1.7 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 2.7 mg/kg on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 2.7 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 2.7 mg/kg until disease progression at the discretion of the investigator.
PEG-BCT-100 at 1.7 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 4.0 mg/kg on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 4.0 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 4.0 mg/kg until disease progression at the discretion of the investigator.
PEG-BCT-100 at a dose to be determined administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT-100 will be administered at at a dose to be determined on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at at a dose to be determined. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at at a dose to be determined until disease progression at the discretion of the investigator.
Outcomes
Primary Outcome Measures
Number of patients undergoing adverse events (AEs) or serious adverse events (SAEs)
Optimal Biological Dose
The optimal biological dose (OBD) of PEG-BCT-100 will be calculated based on the pharmacodynamics (PD) endpoint of plasma arginine depletion relative to plasma pharmacokinetics (PK) of PEG-BCT-100
Secondary Outcome Measures
Maximum Tolerated Dose and Dosing Schedule
Overall response
Evaluate objective tumor responses by RECIST (Response Evaluation Criteria In Solid Tumors)
Pharmacokinetics (PK)-PEG-BCT-100 concentration
Determine the dose-related peak to trough concentrations of plasma PEG-BCT-100 over time
Pharmacodynamics (PD)
To determine the magnitude of plasma arginine depletion (AD) relative to the dose of PEG-BCT-100
PK-PEG-BCT-100 plasma clearance
the plasma clearance of PEG-BCT-100
PD-duration of AD
the time and duration of effective AD assessed by plasma arginine <8 µM relative to the plasma peak and time to clearance over the range of PEG-BCT-100 doses
PD-relationship between AD and PEG-BCT-100 dose
the temporal and quantitative relationships of depleted plasma arginine to dose and plasma concentrations of PEG-BCT-100
PD-relationship between PEG-BCT-100 dose and tumor markers
the temporal and quantitative relationships of depleted plasma arginine to dose and plasma concentrations of PEG-BCT-100; and, The relationship of PEG-BCT-100 dose and its resultant effective AD to changes in AFP/PSA and/or tumor symptoms and measurements.
Full Information
NCT ID
NCT02285101
First Posted
October 23, 2014
Last Updated
April 22, 2020
Sponsor
Bio-Cancer Treatment International Limited
Collaborators
Oncotherapeutics
1. Study Identification
Unique Protocol Identification Number
NCT02285101
Brief Title
Recombinant Human Arginase 1 (rhArg1) in Patients With Advanced Arginine Auxotrophic Solid Tumors
Official Title
Recombinant Human Arginase 1 (rhArg1) in Patients With Advanced Arginine Auxotrophic Solid Tumors: Dose Escalation, Safety and PK/PD
Study Type
Interventional
2. Study Status
Record Verification Date
April 2020
Overall Recruitment Status
Completed
Study Start Date
November 2014 (undefined)
Primary Completion Date
February 2019 (Actual)
Study Completion Date
February 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bio-Cancer Treatment International Limited
Collaborators
Oncotherapeutics
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The goal of this clinical research study is to evaluate the safety of PEG-BCT- 100 given as an infusion to treat patients who bear advanced solid tumors that are dependent on arginine (melanoma, renal cell carcinoma, prostate cancer and hepatocellular carcinoma), and who have progressed after receiving approved or established therapies. This is a Phase 1 study; PEG-BCT-100 is an enzyme that degrades arginine and is an investigational drug.
Detailed Description
This is a phase 1, multiple sites, open label and non-randomized study to evaluate the safety of PEG-BCT-100. Patient enrollment and sample size will follow a classical 3 + 3 dose-escalation design. The study will enroll a maximum of 36 patients. Cohorts of 3 patients will receive an initial single dose of PEG-BCT-100 beginning at 0.5 mg/kg. Single dose safety parameters including hematology and chemistry laboratory profiles will be monitored for 3 weeks. Patients not demonstrating a dose-limiting toxicity (DLT) following the single dose may then receive two additional doses of PEG-BCT-100 at the same dose level on Day 22 and Day 29. After these 2 additional doses, patients will undergo a full tumor and safety assessment after Day 29. Patients whose cancer is stable or responding may then receive weekly doses of PEG-BCT- 100 until disease progression. Dose escalations are planned for the next cohorts of 3 patients, which will be enrolled after Day 22 of the previous cohort, assuming that no single dose DLTs were reported. Each cohort of 3 patients may begin weekly administration if there is no DLTs by Day 22, and if the previous and lower dose cohort has successfully passed Week 4 of the study (doses on Days 1, and 22 + one week).
As of the beginning of 2018, an additional 22 patients will include only malignant melanoma patients. All newly enrolled patients will be enrolled at the dose level of Cohort Four (2.7 mg/kg) of PEG-BCT-100.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma, Prostate Adenocarcinoma
Keywords
arginine auxotrophic tumors, PEG-BCT-100, arginase
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
23 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
PEG-BCT-100 at 0.5 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 0.5 mg/kg on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 0.5 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 0.5 mg/kg until disease progression at the discretion of the investigator.
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
PEG-BCT-100 at 1.0 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 1.0 mg/kg on days 22 (week4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 1.0 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 1.0 mg/kg until disease progression at the discretion of the investigator.
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
PEG-BCT-100 at 1.7 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 1.7 mg/kg on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 1.7 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 1.7 mg/kg until disease progression at the discretion of the investigator.
Arm Title
Cohort 4
Arm Type
Experimental
Arm Description
PEG-BCT-100 at 1.7 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 2.7 mg/kg on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 2.7 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 2.7 mg/kg until disease progression at the discretion of the investigator.
Arm Title
Cohort 5
Arm Type
Experimental
Arm Description
PEG-BCT-100 at 1.7 mg/kg administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT- 100 will be administered at 4.0 mg/kg on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at 4.0 mg/kg. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at 4.0 mg/kg until disease progression at the discretion of the investigator.
Arm Title
Cohort 6
Arm Type
Experimental
Arm Description
PEG-BCT-100 at a dose to be determined administered as a single dose on day 1 (week 1); if not DLTs are observed, PEG-BCT-100 will be administered at at a dose to be determined on days 22 (week 4) and 29 (week 5). Patients responding to treatment or with stable disease may receive 8 additional weekly administrations of PEG-BCT-100 at at a dose to be determined. Beyond week 13, patients responding to treatment or with stable disease may continue to receive weekly PEG-BCT-100 at at a dose to be determined until disease progression at the discretion of the investigator.
Intervention Type
Biological
Intervention Name(s)
PEG-BCT-100
Other Intervention Name(s)
pegylated recombinant human arginase
Primary Outcome Measure Information:
Title
Number of patients undergoing adverse events (AEs) or serious adverse events (SAEs)
Time Frame
at least 13 weeks
Title
Optimal Biological Dose
Description
The optimal biological dose (OBD) of PEG-BCT-100 will be calculated based on the pharmacodynamics (PD) endpoint of plasma arginine depletion relative to plasma pharmacokinetics (PK) of PEG-BCT-100
Time Frame
13 weeks
Secondary Outcome Measure Information:
Title
Maximum Tolerated Dose and Dosing Schedule
Time Frame
4 weeks of treatment
Title
Overall response
Description
Evaluate objective tumor responses by RECIST (Response Evaluation Criteria In Solid Tumors)
Time Frame
13 weeks
Title
Pharmacokinetics (PK)-PEG-BCT-100 concentration
Description
Determine the dose-related peak to trough concentrations of plasma PEG-BCT-100 over time
Time Frame
13 weeks
Title
Pharmacodynamics (PD)
Description
To determine the magnitude of plasma arginine depletion (AD) relative to the dose of PEG-BCT-100
Time Frame
13 weeks
Title
PK-PEG-BCT-100 plasma clearance
Description
the plasma clearance of PEG-BCT-100
Time Frame
13 weeks
Title
PD-duration of AD
Description
the time and duration of effective AD assessed by plasma arginine <8 µM relative to the plasma peak and time to clearance over the range of PEG-BCT-100 doses
Time Frame
13 weeks
Title
PD-relationship between AD and PEG-BCT-100 dose
Description
the temporal and quantitative relationships of depleted plasma arginine to dose and plasma concentrations of PEG-BCT-100
Time Frame
13 weeks
Title
PD-relationship between PEG-BCT-100 dose and tumor markers
Description
the temporal and quantitative relationships of depleted plasma arginine to dose and plasma concentrations of PEG-BCT-100; and, The relationship of PEG-BCT-100 dose and its resultant effective AD to changes in AFP/PSA and/or tumor symptoms and measurements.
Time Frame
13 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Confirmed diagnosis of Stage IIIb/IV malignant melanoma or castration resistant adenocarcinoma of prostate (CRPC).
Advanced cancer not candidate for treatment with modality or agents that are approved or have established efficacy. Candidates who cannot tolerate standard treatment or whose cancers have progressed on current standard of care.
Males or females 18 years-old and above.
Ability to understand and willingness to provide written informed consent;
Karnofsky performance status (see Appendix 13.3) of 80% or above and expected survival of more than 12 weeks.
Negative urine pregnancy test, if female, and willingness to use an effective method of contraception during the entire study period whether the patient is male or female.
Exclusion Criteria:
Has received cancer treatment, e.g. chemotherapy, targeted biologic or enzymes, either approved or investigational, within 4 weeks prior to the start of the PEG-BCT-100;
Advancing liver failure indicated by uncontrolled ascites, pleural effusions, or encephalopathy.
Child-Pugh score of B and C (see Appendix 13.4).
Significant hepatic, renal or bone marrow dysfunction indicated by: total bilirubin >2.0 mg/dL, evidence of bile duct obstruction, serum albumin <2.5 g/dL, serum ALT or AST >2.5 x upper limit of normal, serum creatinine ≥1.5 mg/dL, ANC ≥1.5 x 109/L, platelets <100 x 109/L, or INR >2.0.
Significant cardiac or pulmonary disease defined by New York Heart Association (NYHA) Class III or IV (see Appendix 13.5), left ventricular ejection fraction (LVEF) lower than institutional normal limits by echo or MUGA, history of myocardial infarction within the past 6 months, significant unstable arrhythmia or evidence of ischemia on ECG.
Pregnant or nursing women. NOTE: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
Significant active infection including HIV requiring oral or parenteral anti-infective therapies.
Use of investigational drug(s) within 4 weeks of enrollment.
Prior treatment with arginine depleting agent.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alberto Bessudo, MD
Organizational Affiliation
California Cancer Associates For Research and Excellence, cCARE
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Steven O'Day, MD
Organizational Affiliation
Saint John's Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
California Cancer Associates for Research and Excellence, cCARE
City
San Diego
State/Province
California
ZIP/Postal Code
92111
Country
United States
Facility Name
John Wayne Cancer Institute
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
29776373
Citation
De Santo C, Cheng P, Beggs A, Egan S, Bessudo A, Mussai F. Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma. J Hematol Oncol. 2018 May 18;11(1):68. doi: 10.1186/s13045-018-0612-6.
Results Reference
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Recombinant Human Arginase 1 (rhArg1) in Patients With Advanced Arginine Auxotrophic Solid Tumors
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