Locally Advanced, Uterine Cervical Neoplasms
Conditions
Keywords
Locally advanced cervical cancer, QL1706, Neoadjuvant chemoimmunotherapy, Pathological complete response, Phase II Single-arm Prospective study, QUARTZ-CC
Brief summary
Purpose: To evaluate the efficacy and safety of neoadjuvant treatment with iparomlimab and tuvonralimab (QL1706), a dual PD1and CTLA4 bispecific antibody, in combination with paclitaxel and either cisplatin or carboplatin (TP/TC regimen) for patients with locally advanced cervical cancer. Eligibility Criteria: Women aged 18 to 70 years with newly diagnosed, histologically confirmed cervical cancer (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma), FIGO stage IB3 or IIA2, with no evidence of significant lymph node involvement (pelvic and paraaortic lymph nodes \<1.5 cm in short diameter), and who have not received any prior anticancer therapy. Study Procedures: Participants will receive up to 4 cycles of QL1706 plus TP/TC chemotherapy (once every 3 weeks) prior to surgery. After 2 cycles, clinical assessment will be performed to evaluate tumor response. If tumor shrinkage is observed, treatment may continue for 2 additional cycles, followed by imaging evaluation. Depending on the response, participants with complete or partial response may undergo less extensive surgery (cervical conization plus sentinel lymph node biopsy) rather than standard radical hysterectomy. After surgery, participants who achieve a major pathological response will receive QL1706 maintenance therapy as a single agent for up to 8 additional cycles (once every 3 weeks). For participants with insufficient tumor response, standard radical hysterectomy will be performed. Postoperative adjuvant therapy (radiation or chemotherapy) will follow standard clinical guidelines. Primary and Secondary Objectives: The primary endpoint is the pathological complete response (pCR) rate in the resected tissue following neoadjuvant treatment. Secondary endpoints include safety (treatment related adverse events), objective response rate (ORR), 3 years overall survival, 3 years disease free survival, and quality of life. Study Duration: Total participation time depends on treatment response and surgical scheduling, with an expected duration of approximately 9 to 12 months (including neoadjuvant treatment, surgery, and potential maintenance therapy).
Detailed description
Detailed Description Background Cervical cancer remains the fourth most common malignancy among women worldwide. In 2022, approximately 660,000 new cases and 350,000 deaths were reported globally, with the heaviest burden observed in developing regions, particularly Asia, which accounts for nearly 60% of global cases and deaths. China alone contributes 22.8% of global incidence and 16% of global mortality. Locally advanced cervical cancer (LACC, FIGO stages IB3 and IIA2) constitutes approximately 50% of all cervical cancer cases in China. Current standard of care is concurrent chemoradiotherapy (CCRT); however, 23.3%-34.4% of patients still experience disease recurrence or metastasis. Neoadjuvant chemotherapy (NACT) followed by radical surgery has been investigated as an alternative strategy, yet 9.8%-30.6% of patients fail to respond to NACT, potentially delaying effective local treatment. Moreover, over 30% of patients who undergo surgery require adjuvant radiotherapy, raising concerns regarding treatment burden and health economics.In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Anti-PD-1/PD-L1 and anti-CTLA-4 antibodies exert complementary mechanisms of action. Emerging evidence supports the combination of neoadjuvant chemotherapy and immunotherapy for LACC. In the PACS study (presented at ASCO 2024), the pathological complete response (pCR) rate was 36.2%, and the optimal pathological response rate (residual tumor \<3 mm) was 53.2%. Other studies, including NACI, MITO CERV3, and NATCI, have reported similarly encouraging pCR rates. Given the unmet medical need for more effective and less toxic neoadjuvant regimens, further evaluation of novel immunotherapy combinations such as the dual PD-1/CTLA-4 bispecific antibody iparomlimab and tuvonralimab (QL1706) in combination with platinum-based chemotherapy is warranted. Detailed Treatment and Response-Adapted Algorithm Following neoadjuvant treatment (up to 4 cycles of paclitaxel plus cisplatin or carboplatin combined with QL1706), patients undergo clinical assessment after 2 cycles. If tumor shrinkage is observed, patients continue for 2 additional cycles followed by imaging evaluation. Based on imaging response: complete response leads to cervical conization plus sentinel lymph node biopsy or pelvic lymph node dissection; partial response leads to radical hysterectomy or trachelectomy plus sentinel lymph node biopsy or pelvic lymph node dissection. Patients achieving optimal pathological response (defined as pathological complete response or residual tumor depth ≤3 mm) receive 2 additional cycles of the same regimen followed by QL1706 maintenance therapy for 8 cycles. Non-optimal responders receive adjuvant therapy per NCCN guidelines. Patients who cannot tolerate surgery or have contraindications receive radical radiotherapy. Sample Size Justification and Statistical Framework The sample size was calculated using Simon's two-stage optimal design (one-sided alpha=0.05, power=80%; null hypothesis pCR=30% vs. alternative pCR=43%). The first stage enrolls 33 patients; if 10 or more pCR events are observed, enrollment continues to a total of 94 evaluable patients. Accounting for 10% dropout, total target enrollment is 103 patients. Data and Safety Monitoring An independent Data Monitoring Committee will oversee patient safety and conduct periodic reviews. The Committee may recommend early termination for efficacy, futility, or safety concerns. The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, with written informed consent obtained from all participants.
Interventions
250 mg administered intravenously over at least 30 minutes on Day 1 of each 21-day cycle for up to 4 cycles as neoadjuvant therapy, and up to 8 cycles as maintenance therapy (for patients achieving optimal pathological response).
DRUGPaclitaxel
150-175 mg/m² administered intravenously over at least 3 hours on Day 1 of each 21-day cycle for up to 4 cycles, with standard premedication to prevent hypersensitivity.
DRUGCisplatin
70-75 mg/m² administered intravenously over at least 1 hour, split over two consecutive days (Day 1 and Day 2) of each 21-day cycle for up to 4 cycles. Cisplatin or Carboplatin according to investigator's choice
DRUGCarboplatin
AUC=5 administered intravenously over at least 1 hour on Day 1 of each 21-day cycle for up to 4 cycles. Cisplatin or Carboplatin according to investigator's choice
Sponsors
Sun Yat-sen University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single-arm, open-label, Simon's two-stage optimal design. In the first stage, 33 patients will be enrolled. If 10 or more patients achieve pathological complete response (pCR), the study will proceed to the second stage, enrolling additional patients to reach a total of 94 evaluable patients (accounting for 10% dropout, total enrollment target is 103). The primary endpoint is pCR rate
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18 to 70 years. 2. Histologically or cytologically confirmed cervical cancer, FIGO stage IB3 or IIA2. 3. Imaging findings showing pelvic lymph node short-axis diameter \< 1.5 cm and para-aortic lymph node short-axis diameter \< 1.5 cm. 4. Pathological diagnosis of cervical squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. 5. No prior anti-tumor therapy. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
Exclusion criteria
1. Presence of other concurrent malignancies. 2. Pregnant or peripartum women. 3. History of myocardial infarction or stroke, unstable angina, decompensated heart failure, or deep vein thrombosis. 4. Presence of NCI-CTCAE version 5.0 grade ≥2 arrhythmia, any grade of atrial fibrillation, or clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention. 5. Active unresolved hepatitis, defined as progressive decrease in appetite, general weakness, nausea, acid reflux, aversion to oily foods, abdominal distension, or abnormal liver function with jaundice (e.g., scleral or urinary jaundice); for hepatitis B, HBV DNA \> 1000 IU/mL. 6. Hepatic insufficiency (aspartate aminotransferase/alanine aminotransferase \> 2.5 × upper limit of normal). 7. Renal insufficiency (serum creatinine \> 2 × upper limit of normal). 8. History of chronic pulmonary disease with restrictive respiratory dysfunction. 9. History of major organ transplantation or autoimmune disease. 10. History of severe mental illness or cerebral dysfunction. 11. History of substance abuse or drug addiction. 12. Use of immunosuppressive agents or systemic corticosteroids for immunosuppressive purposes (dose \> 10 mg prednisone or equivalent) within 2 weeks prior to enrollment, with ongoing use. 13. Coagulation abnormality (INR \> 2.0, PT \> 16 seconds), bleeding tendency, or ongoing thrombolytic or anticoagulant therapy (prophylactic low-dose aspirin and low-molecular-weight heparin are permitted). 14. Congenital or acquired immunodeficiency (e.g., HIV infection). 15. Receipt of inactivated vaccine within 30 days prior to the first dose of study treatment. 16. Inability or unwillingness to provide written informed consent or comply with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) Rate | At the time of surgery, following completion of neoadjuvant treatment (each cycle is 21 days; patients receive 2 to 4 cycles) | Proportion of patients with no residual invasive tumor cells in the surgically resected primary tumor specimen following neoadjuvant therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response (MPR) Rate | At the time of surgery, following completion of neoadjuvant treatment (each cycle is 21 days) | Proportion of patients with residual tumor depth ≤3 mm in the surgically resected primary tumor specimen following neoadjuvant therapy. |
| Objective Response Rate (ORR) | After 4 cycles of neoadjuvant treatment (each cycle is 21 days) | Proportion of patients achieving complete response (CR) or partial response (PR) according to RECIST 1.1 criteria on imaging after neoadjuvant therapy. |
| 3-Year Overall Survival (OS) Rate | From date of first dose to date of death from any cause, assessed up to 36 months | Overall survival rate at 3 years from study enrollment. |
| 3-Year Disease-Free Survival (DFS) Rate | From date of surgery to date of recurrence or death, assessed up to 36 months | Disease-free survival rate at 3 years from study enrollment. |
| Treatment-Related Adverse Events (TRAEs) | From first dose of study treatment until 90 days after last dose (each cycle is 21 days; up to 6 neoadjuvant cycles + up to 8 maintenance cycles; total up to approximately 12 months). | Incidence, grade, and relationship of adverse events (both conventional and immune-related TRAEs) assessed by NCI-CTCAE v5.0. |
| Patient-Reported Outcomes (PROs)-Change in Quality of Life as Measured by the EORTC QLQ-C30 | Baseline (pre-treatment), and at 3, 6, 12, 24, and 36 months post-treatment. For assessments occurring during the treatment phase (each cycle is 21 days; up to 6 neoadjuvant cycles followed by up to 8 maintenance cycles). | Change from baseline in global health status/quality of life and functional/symptom scores measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). All scales range from 0 to 100. For the global health status and functional subscales, higher scores mean a better outcome. For the symptom subscales, higher scores mean a worse outcome. |
| Patient-Reported Outcomes (PROs)-Change in Cervical Cancer-Specific Symptoms as Measured by the EORTC QLQ-CX24 | Baseline (pre-treatment), and at 3, 6, 12, 24, and 36 months post-treatment. For assessments occurring during the treatment phase (each cycle is 21 days; up to 6 neoadjuvant cycles followed by up to 8 maintenance cycles). | Change from baseline in symptom and functional scores measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Cervical Cancer Module 24 (EORTC QLQ-CX24). All scales range from 0 to 100. For functional scales (including sexual activity), higher scores mean a better outcome. For symptom scales (including pain, lymphoedema, peripheral neuropathy, menopausal symptoms, and sexual worry), higher scores mean a worse outcome. |
Countries
China
Contacts
CONTACTJihong Liu, Ph.D.
CONTACTYun Zhou, M.D.
Outcome results
None listed