Iparomlimab and Tuvonralimab Plus Paclitaxel and Platinum as Neoadjuvant Therapy for Locally Advanced Cervical Cancer

Official title

Iparomlimab and Tuvonralimab Plus Paclitaxel and Platinum as Neoadjuvant Therapy for Locally Advanced Cervical Cancer: A Prospective Single-Arm Phase II Trial

Overview

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

• Drug Iparomlimab and Tuvonralimab (QL1706)
  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).
• Drug Paclitaxel
  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.
• Drug Cisplatin
  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
• Drug Carboplatin
  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

Primary outcome measures

• Pathological Complete Response (pCR) Rate [Time frame: At the time of surgery, following completion of neoadjuvant treatment (each cycle is 21 days; patients receive 2 to 4 cycles)]

Secondary outcome measures (7)

• Major Pathological Response (MPR) Rate [Time frame: At the time of surgery, following completion of neoadjuvant treatment (each cycle is 21 days)]
• Objective Response Rate (ORR) [Time frame: After 4 cycles of neoadjuvant treatment (each cycle is 21 days)]
• 3-Year Overall Survival (OS) Rate [Time frame: From date of first dose to date of death from any cause, assessed up to 36 months]
• 3-Year Disease-Free Survival (DFS) Rate [Time frame: From date of surgery to date of recurrence or death, assessed up to 36 months]
• Treatment-Related Adverse Events (TRAEs) [Time frame: 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).]
• Patient-Reported Outcomes (PROs)-Change in Quality of Life as Measured by the EORTC QLQ-C30 [Time frame: 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).]
• Patient-Reported Outcomes (PROs)-Change in Cervical Cancer-Specific Symptoms as Measured by the EORTC QLQ-CX24 [Time frame: 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).]

Eligibility criteria

Inclusion criteria

• Age 18 to 70 years.
• Histologically or cytologically confirmed cervical cancer, FIGO stage IB3 or IIA2.
• Imaging findings showing pelvic lymph node short-axis diameter < 1.5 cm and para-aortic lymph node short-axis diameter < 1.5 cm.
• Pathological diagnosis of cervical squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma.
• No prior anti-tumor therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

Exclusion criteria

• Presence of other concurrent malignancies.
• Pregnant or peripartum women.
• History of myocardial infarction or stroke, unstable angina, decompensated heart failure, or deep vein thrombosis.
• 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.
• 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.
• Hepatic insufficiency (aspartate aminotransferase/alanine aminotransferase > 2.5 × upper limit of normal).
• Renal insufficiency (serum creatinine > 2 × upper limit of normal).
• History of chronic pulmonary disease with restrictive respiratory dysfunction.
• History of major organ transplantation or autoimmune disease.
• History of severe mental illness or cerebral dysfunction.
• History of substance abuse or drug addiction.
• 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.
• 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).
• Congenital or acquired immunodeficiency (e.g., HIV infection).
• Receipt of inactivated vaccine within 30 days prior to the first dose of study treatment.
• Inability or unwillingness to provide written informed consent or comply with study requirements.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Sun Yat-sen University Cancer Center — Guangzhou

Publications

• Lou H, Zhou Y, Li D, et al. 251 Efficacy and safety of iparomlimab and tuvonralimab in previously treated patients with recurrent or metastatic cervical cancer: a multicenter, open-label, single-arm, phase 2 clinical trial (DUBHE-C- 206). Int J Gynecol Cancer. 2024;34(Suppl 1):A5.1.
• Pan YC, Dai Z, Ma H, Zheng J, Leng J, Xie C, Yuan Y, Yang W, Yalikun Y, Song X, Han CB, Shang C, Yang Y. Self-powered and speed-adjustable sensor for abyssal ocean current measurements based on triboelectric nanogenerators. Nat Commun. 2024 Jul 20;15(1):6133. doi: 10.1038/s41467-024-50581-w. PMID 39033189
• Cui B, Xian C, Han B, Shu C, Qian Y, Ouyang Z, Wang X. High-resolution emission inventory of biogenic volatile organic compounds for rapidly urbanizing areas: A case of Shenzhen megacity, China. J Environ Manage. 2024 Feb;351:119754. doi: 10.1016/j.jenvman.2023.119754. Epub 2023 Dec 10. PMID 38071916
• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9. PMID 2702835

Identifiers

NCT: NCT07646301 · B2026-154-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗