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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
101
5mg/kg/times bi-week IV administration of ZKAB001
10mg/kg/times bi-week IV administration of ZKAB001
15mg/kg/times bi-week IV administration of ZKAB001
Chinese Academy of Medical Sciences and Peking Union Medical College
Beijing, Beijing Municipality, China
RECRUITINGRP2D
Recommended phase II dose.
Time frame: 28 days after first dose
Objective response rate
The proportion of subjects who achieved the best objective response rate (PR or CR).
Time frame: 2 years
Tolerance
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: 2 years
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.
Time frame: through study completion, an average of 2 years
The number of subjects presenting detectable anti drug antibodies (ADAs)
To evaluated the number of subjects presenting detectable anti drug antibodies (ADAs).
Time frame: 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.
Time frame: through study completion, an average of 2 years
PD-L1 expression
Detection of PD-L1 expression in tumor tissues.
Time frame: through study completion, an average of 2 years
progression free survival(PFS)
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Evaluate the PFS of the study population
Time frame: through study completion, an average of 2 years
overall survival
Evaluate the OS of the study population
Time frame: through study completion, an average of 2 years
duration of response
Evaluate the DOR of the study population
Time frame: through study completion, an average of 2 years
best of response
Evaluate the BOR of the study population
Time frame: through study completion, an average of 2 years