QL1604 Plus Chemotherapy Versus Chemotherapy in Subjects With Stage ⅣB, Recurrent, or Metastatic Cervical Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of PD-1 Inhibitor (QL1604) plus chemotherapy in patients with Stage Ⅳ, recurrent, or metastatic cervical cancer. Possible chemotherapy regimens include: paclitaxel plus cisplatin and paclitaxel plus carboplatin.

Detailed Description
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The study will be conducted in 2 parts.The first stage is a single-arm clinical trial, and the second stage is a controlled clinical trial.

Official Title
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A Study of QL1604 Plus Chemotherapy Versus Chemotherapy Plus Placebo With Stage ⅣB, Recurrent, or Metastatic Cervical Cancer

Conditions
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Cervical Cancer

Intervention / Treatment
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* Drug: QL1604
* Drug: Paclitaxel injection
* Drug: Cisplatin/Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years and ≤ 75 years Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Life expectancy of at least 12 weeks. At least one measurable lesion (according to RECIST v1.1) Cervical squamous cell carcinoma, adenocarcinoma and adenosquamous cell carcinoma diagnosed by histopathology and confirmed by imaging as recurrent or stage ⅣB cervical cancer. No brain metastasis, or no meningeal metastasis. Patients must have normal function as defined: ANC≥1.5*10^9/L; PLT≥90*10^9/L, Hb≥90 g/L, Total Bilirubin (TBIL)≤1.5*Upper Limit of Normal(ULN), Alanine Transaminase (ALT)and Aspartate Aminotransferase(AST)≤2.5*ULN.For liver metastasis patients, ALT and AST≤5*ULN, Cr≤ 1.5*ULN, or creatinine clearance rate ≥50 mL/min, Proteinuria <2+，if proteinuria≥ 2+ and 24 hours total urine protein < 1.0 g LVEF≥ 50%. Any unresolved AEs ≤ CTCAE Grade 1 (except alopecia). Negative pregnancy test for females of child-bearing potentials. Patients with reproductive function agreed to take effective contraceptive measures during the treatment and in 6 months after the end of administration. Patients must be able to understand and volunteer to sign the informed consent. Exclusion Criteria: Has received more than 2 courses of palliative chemotherapy for treatment of cervical cancer. Has received prior chemoradiotherapy within 3 months before enrollment,or has received prior radiotherapy within 2 weaks before enrollment. Has received prior surgery therapy within 2 weaks before enrollment,or has not recovered from the effects of surgery therapy. Is currently participating in or has participated in a study of an investigational agent within 4 weeks before enrollment. Has any active autoimmune diseases or a history of autoimmune diseases (such as the following, but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, vasculitis, nephritis, thyroid hyperfunction; patients with vitiligo; complete remission of asthma in childhood, can be included without any intervention after adulthood; asthma patients who require bronchodilators for medical intervention cannot be included). Is using immunosuppressive agents or systemic hormonal therapy to achieve immunosuppressive purposes (agents amount > 10 mg / day of prednisone or other therapeutic hormones), and continue to use within 2 weeks before enrollment. Known history of hypersensitivity to macromolecular protein preparation or any components of the QL1604 formulation, or any components of the study drugs. Has uncontrolled clinically significant cardiac and cerebral vascular diseases within 6 months before enrollment, including but not limited to the following: myocardial infarction, severe or unstable angina, coronary artery/peripheral artery bypass grafting, congestive heart failure, cerebrovascular accident (including transient ischemic attack). Symptomatic congestive heart failure (New York Heart Association Grade II-IV), or NCI-CTCAE v5.0 ≥ 2 arrhythmia, atrial fibrillation of any grade, or clinically significant supraventricular arrhythmia or ventricular arrhythmia requirement for treatment or intervention. Has active infection or an unexplained fever > 38.5°C during screening visits( subjects with tumor fever may be enrolled at the discretion of the investigator). Hepatitis b surface antigen (HBsAg) positive and/or hepatitis b core antibody (HBcAb) positive and HBVDNA>103copies/ml, hepatitis c virus antibody positive . Known history of human immunodeficiency virus (HIV) infection, or other acquired or congenital immunodeficiency diseases,or has a history of organ transplantation (except corneal transplantation). Has been vaccinated with live anti-tumor vaccine, or have received anti-tumor immunotherapy, or may receive other systemic anti-tumor treatments during the study period. Peripheral neuropathy≥ CTCAE Grade 2. History of psychotropic substance abuse, alcoholism or drug abuse. Has a clear history of neurological or mental disorders, including epilepsy or dementia. Patients with other malignancies witnin 5 years( except cured basal cell carcinoma of skin cancer, papillary thyroid carcinoma). At the discretion of the investigator, there are patients with serious concomitant disease that compromises patient safety or affects the patient's completion of the study,such as unable to be controlled within normal level following treatment of anti-hypertension agents (systolic blood pressure > 160 mmHg, diastolic blood pressure > 110 mmHg), serious diabetes, thyroid diseases, etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The first stage is a single-arm clinical trial, and the second stage is a controlled clinical trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>On Day 1 of each 21-day cycle, participants receive an intravenous (IV) infusion of QL1604 200 mg plus Investigator choice of chemotherapy (paclitaxel 175 mg/m^2 plus cisplatin 70 mg/m^2 or paclitaxel 175 mg/m^2 plus carboplatin Area Under the Curve (AUC) 6) | Drug: QL1604<br>* Intravenous Infusion<br>* Other names: PD-1 monoclonal antibody;Drug: Paclitaxel injection<br>* Intravenous Infusion<br>Drug: Cisplatin/Carboplatin<br>* Intravenous Infusion<br>|
| Experimental: Cohort B-arm1<br>On Day 1 of each 21-day cycle, participants receive an IV infusion of QL1604 200 mg plus Investigator choice of chemotherapy (paclitaxel 175 mg/m^2 plus cisplatin 70 mg/m^2 or paclitaxel 175 mg/m^2 plus carboplatin AUC 6) | Drug: QL1604<br>* Intravenous Infusion<br>* Other names: PD-1 monoclonal antibody;Drug: Paclitaxel injection<br>* Intravenous Infusion<br>Drug: Cisplatin/Carboplatin<br>* Intravenous Infusion<br>|
| Experimental: Cohort B-arm2<br>On Day 1 of each 21-day cycle, participants receive an IV infusion of placebo plus Investigator choice of chemotherapy (paclitaxel 175 mg/m^2 plus cisplatin 70 mg/m^2 or paclitaxel 175 mg/m^2 plus carboplatin AUC 6) | Drug: Paclitaxel injection<br>* Intravenous Infusion<br>Drug: Cisplatin/Carboplatin<br>* Intravenous Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with adverse events | The incidence and severity of adverse events (AE),serious adverse events (SAE) and treatment-emergent adverse events (TEAEs) according to CTCAE V5.0 | Up to 90 days from last dose | 
| Objective response rate (ORR) as assessed by investigator based on RECIST v1.1 and iRECIST | Objective response rate (ORR) as assessed by investigator based on RECIST v1.1 and iRECIST | approximately 6 months | 
| Progression-free survival (PFS) as assessed by investigator based on RECIST v1.1 and iRECIST and as assessed by independent radiology review based on RECIST v1.1 | Progression-free survival (PFS) is defined as time from the date of randomization to the date of first documentation of disease progression or death due to any cause(whichever occurs earlier) | approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival(OS) | Overall survival(OS) is defined as the time from randomization to death due to any cause | approximately 2 years | 
| Objective response rate (ORR) | Objective response rate (ORR) as assessed by independent radiology review based on RECIST v1.1 | approximately 2 years | 
| Duration of response(DOR) | Duration of response(DOR) as assessed by investigator based on RECIST v1.1 and iRECIST,as assessed by independent radiology review based on RECIST v1.1 | approximately 2 years | 
| Time to progress (TTP) | Time to progress (TTP) as assessed by investigator based on RECIST v1.1 and iRECIST,as assessed by independent radiology review based on RECIST v1.1 | approximately 2 years | 
| AUC of QL1604 | Area under curve from zero to infinity | approximately 1 years | 
| Cmax of QL1604 | Peak concentration | approximately 1 years | 
| Cmin of QL1604 | The trough value at steady state | approximately 1 years | 
| Tmax of QL1604 | Time to Cmax | approximately 1 years | 
| T1/2 of QL1604 | Half life | approximately 1 years | 
| Vss of QL1604 | Steady-state apparent volume of distribution based on plasma concentration | approximately 1 years | 
| CLT(total body clearance) of QL1604 | Total body clearance | approximately 1 years | 
| Immunogenicity | The titer of anti-drug antibodies (ADA)and neutralizing antibodies(Nab) | approximately 1 years | 
| Biomarkers | Explore the correlation between curative effect and different biomarkers, such as PD-L1, TMB | before the first dose |