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This is a Phase 1+2, open-label, dose-escalation, and multidose study, aiming to investigate the safety, tolerability and pharmacokinetics of ZKAB001 (a fully human monoclonal antibody targeting the Programmed Death - Ligand 1 (PD-L1) membrane receptor on T lymphocytes and other cells of the immune system) administered every 14 days in subjects with limited stage of high-grade osteosarcoma of maintenance therapy after adjuvant chemotherapy.
The study will consist of 4 periods: Screening (up to 28 days), Lead-in period (Day -28), Treatment (up to 24 cycles or 1 year, whichever occurs first), and Follow-up (up to 2 years). There will be a lead-in period on Day -28 for each dose escalation cohort in which the single-dose pharmacokinetics(PK) of ZKAB001 will be characterized prior to initiation of continuous dosing in the first cycle of treatment. The lead-in period duration, PK time-points, doses and/or regimens used in subsequent cohorts may be modified based on the exposure (AUC) observed during the lead-in period (although the number of PK samples will not be increased). Treatment of continuous dosing is up to 24 cycles or 1 year, until as per investigator's opinion, subjects experience disease progression (evaluated by RECIST 1.1), no clinical benefit, or intolerable toxicity. If investigators suspect subjects experience pseudoprogression or has evidence to prove "mixed response", subjects can continue to accept treatment as investigator decided.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ZKAB001 5 mg/kg/time | Experimental | Three or six patients will treated with the dose of 5 mg/kg/time of ZKAB001 IV bi-weekly. DLT was observed within 28 days after administration. |
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| ZKAB001 10 mg/kg/time | Experimental | Three or six patients will treated with the dose of 10 mg/kg/time of ZKAB001 IV bi-weekly. DLT was observed within 28 days after administration. |
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| ZKAB001 15 mg/kg/time | Experimental | Three or six patients will treated with the dose of 15 mg/kg/time of ZKAB001 IV bi-weekly. DLT was observed within 28 days after administration. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ZKAB001 5mg/kg | Drug | 5mg/kg/times bi-week IV administration of ZKAB001 |
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| Measure | Description | Time Frame |
|---|---|---|
| Dose limiting toxicity (DLT) | Adverse events of level 3 or above related to the study drug occurring within 28 days after the first dose as assessed by CTCAE v4.0. | 28 days after first dose |
| Measure | Description | Time Frame |
|---|---|---|
| Maximal tolerable dose(MTD) | DLT occurs in less than 1/6 subjects, this lower dose is defined as MTD. | 28 days after first dose |
| EFS(event-free survival) | The rate of 3-year event-free survival |
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Inclusion Criteria:
1)neutrophil count (ANC) absolutely acuity≥1.5 x 109 / L; 2)platelet count≥80 x 109 / L; 3)hemoglobin≥90 g/L; 4)serum albumin≥28 g/L; 5)bilirubin≤1.5 x ULN(upper limit of normal); 6)Alanine transaminase (ALT)and AST≤1.5 x ULN, serum Cr≤1.25 x ULN; 7) endogenous creatinine clearance≥50 ml/min (according Gault Cockcroft formula).
7.Female reproductive subjects should take effective contraception during the study period and within 3 months after the study treatment period. The serum or urine human chorionic gonadotropin(HCG) examination must be negative within 7 days before the subject is enrolled.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| yang Yao, master | Contact | 18930177737 | yangyao_6@hotmail.com |
| Name | Affiliation | Role |
|---|---|---|
| yang Yao, master | 600 yishan road, Shanghai | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Shanghai Sixth People's Hospital | Recruiting | Shanghai | Shanghai Municipality | 200233 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31401903 | Derived | Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14. |
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| ID | Term |
|---|---|
| D012516 | Osteosarcoma |
| ID | Term |
|---|---|
| D018213 | Neoplasms, Bone Tissue |
| D009372 | Neoplasms, Connective Tissue |
| D018204 | Neoplasms, Connective and Soft Tissue |
| D009370 | Neoplasms by Histologic Type |
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| ZKAB001 10mg/kg | Drug | 10mg/kg/times bi-week IV administration of ZKAB001 |
|
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| ZKAB001 15mg/kg | Drug | 15mg/kg/times bi-week IV administration of ZKAB001 |
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| through study completion, an average of 3 years |
| AUC(0-t) | Area under curve 0-t | 24 periods or 1 year |
| AUC(INF) | Area under curve INF | 24 periods or 1 year |
| Cmax | Peak concentration | 24 periods or 1 year |
| Tmax | Peak time | 24 periods or 1 year |
| T1/2 | Half life | 24 periods or 1 year |
| Vss | Steady-state apparent volume of distribution based on plasma concentration | 24 periods or 1 year |
| total body clearance(CLT) | total body clearance | 24 periods or 1 year |
| Cmin | The trough value at steady state | 24 periods or 1 year |
| the percentage of the receptors of PD-L1 in CD14+ monocytes and CD3+T cells | To detected the percentage of the receptors of PD-L1 in CD14+(cluster of differentiation 14+ ) monocytes and CD3+(cluster of differentiation 3+)T cells. | through study completion, an average of 3 years |
| the number of subjects presenting detectable anti drug antibodies (ADAs) | To evaluated the number of subjects presenting detectable anti drug antibodies (ADAs). | through study completion, an average of 3 years |
| D009369 | Neoplasms |
| D012509 | Sarcoma |