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This is a Phase 1, open-label, dose-escalation, and multidose study, aiming to investigate the safety, tolerability and pharmacokinetics(PK) 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 recurrent or metastatic cervical cancer.
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 1 year). There will be a lead-in period on Day -28 for each dose escalation cohort in which the single-dose pharmacokinetics 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 and immune-related response criteria irRECIST), 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.
The study was divided into two stages. After the recommended phase II dose (RP2D) is determined in the first stage, the sample size will be amplified with RP2D in the second stage. When a total of 15 cases are included in the two stages, an interim analysis will be conducted to decide whether to expand the total number of cases to 60 based on the results of the analysis. If more than 2 cases of response will be observed in 15 cervical cancer subjects, 45 cases (with a total sample size of 60 cases) could be included to further observe the safety and efficacy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ZKAB001 5mg/kg | Experimental | Three or six patients will be treated with the dose of 5 mg/kg/time of ZKAB001 IV bi-weekly. DLT will be observed within 28 days after administration. |
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| ZKAB001 10 mg/kg | Experimental | Three or six patients will be treated with the dose of 10 mg/kg/time of ZKAB001 IV bi-weekly. DLT will be observed within 28 days after administration. |
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| ZKAB001 15 mg/kg | Experimental | Three or six patients will be treated with the dose of 15 mg/kg/time of ZKAB001 IV bi-weekly. DLT will be 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 |
|
| Measure | Description | Time Frame |
|---|---|---|
| RP2D | Recommended phase II dose. | 28 days after first dose |
| Objective response rate | The proportion of subjects who achieved the best objective response rate (PR or CR). | 2 years |
| Tolerance | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Effect of ZKAB001 on T cell function and cytokine expression | The response of CD4+ and CD8+ cells to tumor at baseline and after each administration will be detected by flow cytometry. | through study completion, an average of 2 years |
| The number of subjects presenting detectable anti drug antibodies (ADAs) |
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Inclusion Criteria:
1) Absolute neutrophil count(ANC)≥109/L 2) Platelets ≥100x109/L 3) Hemoglobin ≥9g/dL 4) Serum albumin ≥2.8g/dL 5) Bilirubin ≤1.5x Upper limit of normal(ULN) 6) ALT and AST ≤1.5xULN, if If liver metastases are present, alanine transaminase(ALT) and aspartate transaminase(AST) should be ≤5xULN 7) Creatinine clearance rate ≥50ml/min (Cockcroft-Gault equation) 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 | |
|---|---|---|---|---|
| lingying Wu, M.D | Contact | 13910865483 | wulingying@csco.org.cn | |
| hong Fang, master | Contact | 010-87788714 |
| Name | Affiliation | Role |
|---|---|---|
| lingying Wu, M.D | Tumor Hospital of the Chinese Academy of Medical Sciences | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Chinese Academy of Medical Sciences and Peking Union Medical College | Recruiting | Beijing | Beijing Municipality | 100000 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36136294 | Derived | An J, Tang J, Li BX, Xiong H, Qiu H, Luo L, Wang L, Wang D, Zhou Q, Xu Q, Song H, Zhang Y, Zhang H, Li Y, Yu X, Zhang J, Ng R, Zhao W, Wong M, Dai X, Li G, Wu L. Efficacy and Safety of the Anti-PD-L1 mAb Socazolimab for Recurrent or Metastatic Cervical Cancer: a Phase I Dose-Escalation and Expansion Study. Clin Cancer Res. 2022 Dec 1;28(23):5098-5106. doi: 10.1158/1078-0432.CCR-22-1280. |
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| ID | Term |
|---|---|
| D002583 | Uterine Cervical Neoplasms |
| ID | Term |
|---|---|
| D014594 | Uterine Neoplasms |
| D005833 | Genital Neoplasms, Female |
| D014565 | Urogenital Neoplasms |
| D009371 | Neoplasms by Site |
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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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To evaluated the number of subjects presenting detectable anti drug antibodies (ADAs). |
| through study completion, an average of 2 years |
| Receptor occupancy | Monocytes will be isolated from peripheral blood before each cycle of administration, and the receptor occupancy of PD-L1 on CD3+T cells will be determined. | through study completion, an average of 2 years |
| PD-L1 expression | Detection of PD-L1 expression in tumor tissues. | through study completion, an average of 2 years |
| progression free survival(PFS) | Evaluate the PFS of the study population | through study completion, an average of 2 years |
| overall survival | Evaluate the OS of the study population | through study completion, an average of 2 years |
| duration of response | Evaluate the DOR of the study population | through study completion, an average of 2 years |
| best of response | Evaluate the BOR of the study population | through study completion, an average of 2 years |
| D009369 |
| Neoplasms |
| D002577 | Uterine Cervical Diseases |
| D014591 | Uterine Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |