Donafenib for Recurrent Cervical Cancer

Study Overview
=================
Brief Summary
-----------------
This study is to evaluate the safety and tolerability of Donafenib combined with paclitaxel and platinum ± programmed death 1 monoclonal antibody (PD-1 antibody) in patients with recurrent cervical cancer.

Detailed Description
-----------------
This is a single center, non-randomized, open-label Phase II clinical study to investigate the efficacy and tolerability of Donafenib combined with paclitaxel and platinum ± PD-1 antibody in patients with recurrent cervical cancer. In total 20 patients will receive Donafenib (200mg, bid) combined with paclitaxel (135mg/m2) and cisplatin (creatinine clearance rate > 60ml/min, 50 mg/m2) or paclitaxel (175 mg/m2) and carboplatin AUC=5 (40ml/min < creatinine clearance rate < 60ml/min) ± PD-1 antibody every 3 weeks. Actual Study Start Date: March 27, 2022 Estimated Primary Completion Date: December 27, 2023 Estimated Study Completion Date: June 27, 2024 Arms There is only one arm, i.e., group of Donafenib combined with paclitaxel and platinum ± PD-1 antibody. Each treatment period was 21 days. Patients will be treated with 4-6 cycles of Donafenib plus TP or TC ± PD-1 antibody. After completion of the combination, patients will be maintained on Donafenib until disease progression or unacceptable toxicity occurs (up to 12 months) Donafenib was taken orally at 200 mg twice on an empty stomach (1 hour before or > 2 hours after meal) in the morning and evening of each administration day, with an interval of about 12 hours. Maintain the same dose until disease progression, death, toxicity intolerance, withdrawal of informed consent, initiation of new antineoplastic therapy, or termination of treatment for other reasons specified in the protocol, for a maximum of 12 months. Paclitaxel and platinum: If creatinine clearance rate > 60ml/min: on Day 1 of each 21-day cycle, participants receive an intravenous (IV) infusion of paclitaxel 135 mg/m2plus cisplatin 50 mg/m2. If 40ml/min < creatinine clearance rate < 60ml/min:on Day 1 of each 21-day cycle, participants receive an intravenous (IV) infusion of paclitaxel 175 mg/m2 plus carboplatin AUC=5. PD-1 antibody: PD-1 antibody is not mandatory, intravenous infusion on the first day of each cycle, every 3 weeks for a cycle until disease progression, death, toxicity intolerance, withdrawal of informed consent, initiation of new antitumor therapy, or termination of treatment for other reasons specified in the protocol, the longest treatment period is 12 months. The primary outcome measure is progression-free survival. The secondary outcome measures include overall survival, objective response rate, etc.

Official Title
-----------------
Efficacy and Safety of Donafenib Combined With Paclitaxel and Platinum in Patients With Recurrent, Metastatic, and Persistent Advanced Cervical Cancer: A Single-arm, Phase II Study

Conditions
-----------------
Targeted Therapy, Chemotherapy, Recurrent Cervical Carcinoma, Metastatic Cervical Carcinoma, Persistent Advanced Cervical Carcinoma, Survival Outcomes, Adverse Effect

Intervention / Treatment
-----------------
* Combination Product: Donafenib combined with paclitaxel and platinum ± PD-1 antibody


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria Written informed consent obtained. Age 18 75, female. Histologically confirmed cervical squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma. Patients with cervical cancer recurred for the first time, and did not receive any treatment after recurrence. Patients must have measurable disease per RECIST 1.1. ECOG performance status 0 or 1, expected lifetime ≥ 3 months. No targeted drugs containing VEGF were used before, including but not limited to anlotinib, apatinib, bevacizumab, etc. Adequate organ function: Absolute neutrophil count (ANC) ≥ 1.5x109/L, Platelets ≥ 100x109/L, Hemoglobin (Hb) ≥ 90g/L, Bilirubin ≤ 1.5 times the upper limit of normal, ALT/AST ≤ 3x ULN (for patient with liver metastasis ALT/AST ≤ 5x ULN), Serum bilirubin ≤1.5x ULN, Serum creatinine ≤ 1.5 times the upper limit of normal, and creatinine clearance ≥ 40ml/min (calculated by Cockcroft-Gault formula); International normalized ratio (INR) ≤1.5 Exclusion Criteria: Histopathologic diagnoses of tumors other than squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma. With second primary malignant diseases. Pregnancy or children bearing potential. With uncontrolled auto-immune diseases, interstitial pneumonia, ulcerative colitis, or patients who should receive long-term glucocorticoid treatment (>10mg/d prednisone). With uncontrollable complications. Conditions which impact on pill taking (dysphagia, chronic diarrhea, bowel obstruction). Known hypersensitivity reaction to any of the study drugs or components. Other unsuitable conditions determined by investigators. Hepatitis B virus (HBV) >2000 IU/ml or DNA ≥ 1×10^4/ml; or hepatitis C virus (HCV) RNA ≥ 1×10^3/ml). Has received a live vaccine within 4 weeks prior to the first dose of trial treatment. Note: Injection of inactivated viral vaccines against seasonal influenza are allowed. Has pleural effusion and ascites that require punctured and drained. However, an exception includes patients with pleural effusion and ascites who have no symptoms. Any other medical, psychiatric, or social condition deemed by the investigator to be likely to interfere with a subject's rights, safety, welfare, or ability to sign informed consent, cooperate, and participate in the study or would interfere with the interpretation of the results.

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

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with recurrent cervical cancer<br>Eligible patients according to inclusion and exclusion criteria. | Combination Product: Donafenib combined with paclitaxel and platinum ± PD-1 antibody<br>* Patients will receive Donafenib (200mg, bid) combined with paclitaxel (135mg/m2) and cisplatin (creatinine clearance rate > 60ml/min, 50 mg/m2) or paclitaxel (175 mg/m2) and carboplatin AUC=5 (40ml/min < creatinine clearance rate < 60ml/min) ± PD-1 antibody every 3 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS defined as the time the duration from date of enrollment to the first documented disease progression, or death due to any cause, whichever occurs first. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival is defined as the duration from date of enrollment to the date of death from any cause. | 36 months | 
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants in the analysis population who have a complete or partial remission. | 24 months | 
| Duration of Response (DCR) | DCR is defined as the percentage of participants in the analysis population who have a complete or partial remission, or stable disease (SD). | 24 months | 
| Adverse Events | Adverse event (AE)、Treatment emergent adverse event (TEAE)、Serious adverse event (SAE). | 24 months |