NCT06878222

Iparomlimab and Tuvonralimab Combined With Paclitaxel and Cisplatin as Neoadjuvant Therapy for CC

Iparomlimab and Tuvonralimab Combined With Paclitaxel and Cisplatin as Neoadjuvant Therapy for Cervical Cancer: a Phase 2 Umbrella Trial

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 35 (estimated)
• Sponsor: Obstetrics & Gynecology Hospital of Fudan University · Academic / Other
• Sex: Female
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

Currently, the survival rate of locally advanced cervical cancer is low, posing a significant challenge in the treatment of cervical cancer. Radical chemoradiotherapy is considered the standard treatment for patients with locally advanced cervical cancer. However, 23.3% to 34.4% of patients still experience recurrence or subsequent metastasis. Radical surgery following neoadjuvant chemotherapy is an alternative to concurrent chemoradiotherapy, but it also has limitations: for approximately 9.8% to 30.6% of patients who do not respond to neoadjuvant chemotherapy, effective local treatment may be delayed. Additionally, more than 30% of patients still require adjuvant radiotherapy or chemoradiotherapy after surgery, significantly increasing the risk of complications. Therefore, there is an urgent need to explore alternative or improved treatment methods for neoadjuvant chemotherapy in locally advanced cervical cancer. An increasing number of women are being diagnosed with cervical cancer during their childbearing years, many of whom have a desire to preserve their fertility. For selected patients with stage IB2 cervical cancer, options include abdominal radical trachelectomy or radical trachelectomy following neoadjuvant chemotherapy. However, compared to conservative surgeries such as conization or partial cervical resection, radical trachelectomy is associated with less favorable fertility rates and pregnancy outcomes, with significantly higher rates of infertility, miscarriage, and preterm birth. For patients with stage IB3 or IIA1-IIA2 cervical cancer, the current standard surgical approach is radical hysterectomy, which does not preserve fertility. Current research suggests that neoadjuvant chemotherapy can shrink tumor size, decrease lymph node and distant metastases, and reduce the need for postoperative adjuvant radiotherapy. This offers hope for young cervical cancer patients who wish to preserve fertility, as it may reduce tumor size, thereby allowing for less extensive fertility-sparing surgery, improving pregnancy outcomes, or even making fertility-sparing surgery a viable option. In recent years, immunotherapy has gradually become a research hotspot in cancer treatment. Anti-PD-1/PD-L1 monoclonal antibodies, as a type of immunotherapy drug, have demonstrated promising anti-tumor efficacy and low side effects in clinical trials. Iparomlimab and Tuvonralimab is a novel therapeutic biological product targeting both PD-1 and CTLA-4. It is composed of two engineered monoclonal antibodies (anti-PD-1 and anti-CTLA-4) expressed in a fixed ratio and has shown significant efficacy in cervical cancer patients. Therefore, given the urgent need to improve neoadjuvant therapy for locally advanced cervical cancer and fertility-preserving neoadjuvant therapy for early-stage cervical cancer patients, this study is being conducted to explore and evaluate the efficacy and safety of Iparomlimab and Tuvonralimab combined with paclitaxel and cisplatin as neoadjuvant therapy for cervical cancer. Additionally, the study aims to investigate the relationship between tumor-related biomarkers and the risk of recurrence.

Detailed description

In recent years, anti-PD-1/PD-L1 monoclonal antibodies, as a type of immunotherapy drug, have demonstrated promising anti-tumor efficacy in the treatment of cervical cancer patients. PD-1 (Programmed cell death protein 1) is a surface immune checkpoint protein that, by binding to its ligand PD-L1, inhibits the activation of T cells, thereby allowing tumor cells to evade immune system attacks. At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, a phase II clinical study was reported on the use of immunotherapy (sintilimab) combined with paclitaxel and cisplatin as neoadjuvant therapy for locally advanced cervical cancer. The results showed that the primary endpoint, pathological complete response (pCR), was 32.6% (14/43), and the best response rate (residual tumor infiltration depth less than 3 mm) was 51.2% (22/43). Iparomlimab and Tuvonralimab is a novel therapeutic biological product targeting both PD-1 and CTLA-4. It is composed of two engineered monoclonal antibodies (anti-PD-1 and anti-CTLA-4) expressed in a fixed ratio and produced as a single product from a single cell line. It offers the following advantages: 1. Dual immune targets of PD-1 and CTLA-4 monoclonal antibodies: The anti-PD-1 antibody relieves T cell killing inhibition, while the anti-CTLA-4 antibody relieves T cell activation inhibition, working synergistically to enhance efficacy. 2. Optimal 2:1 ratio of anti-PD-1 to anti-CTLA-4 antibodies: A dosing regimen of 5 mg/kg every 3 weeks ensures effective blood concentration, balancing efficacy and safety. 3. Flexible antibody subtype design: The anti-PD-1 antibody uses the IgG4 subtype, which lacks ADCC (antibody-dependent cellular cytotoxicity) effects and does not deplete effector T cells. The anti-CTLA-4 antibody uses the IgG1 subtype, which has ADCC effects and can eliminate regulatory T cells, further enhancing efficacy. 4. R255K mutation in the anti-CTLA-4 antibody: This mutation reduces the affinity of the anti-CTLA-4 antibody for the neonatal Fc receptor (FcRn), shortening its half-life to 1 week and lowering its blood concentration, thereby improving safety while maintaining efficacy. Currently, Iparomlimab and Tuvonralimab for recurrent or metastatic cervical cancer as a second-line or later treatment has shown an objective response rate (ORR) of 33.8% and a progression-free survival (PFS) of 5.4 months, with a favorable safety profile. When combined with chemotherapy as first-line treatment for recurrent or metastatic cervical cancer, the ORR was 75.9%, PFS was 15.1 months, and immune-related adverse events occurred in 16.7% of cases. These results indicate that Iparomlimab and Tuvonralimab, both as monotherapy and in combination therapy, demonstrates significant anti-tumor activity and safety, suggesting that dual-target antibodies are effective for advanced cancer patients. Therefore, given the urgent need to improve neoadjuvant therapy for locally advanced cervical cancer and neoadjuvant fertility-preserving therapy for early-stage cervical cancer, this study is being conducted to explore and evaluate the efficacy and safety of Iparomlimab and Tuvonralimab combined with paclitaxel and cisplatin as neoadjuvant therapy for locally advanced cervical cancer and fertility-preserving neoadjuvant therapy for cervical cancer. Additionally, the study aims to investigate the relationship between tumor-related biomarkers and the risk of recurrence, potentially offering new insights for optimizing fertility-preserving and non-preserving neoadjuvant therapies for cervical cancer.

Conditions

• Cervical Cancers

Interventions

Type	Name	Description
DRUG	Neoadjuvant Chemotherapy	paclitaxel, 135-175mg/m2, q3w, 3 cycles
DRUG	Neoadjuvant Chemotherapy	cisplatin, 75-80mg/m2, q3w, 3 cycles
DRUG	Immunotherapy	Iparomlimab and Tuvonralimab, 5mg/kg, q3w, 3cycles
PROCEDURE	Radical surgery	After 3 cycles of neoadjuvant therapy, patients who achieved CR/PR will undergo radical hysterectomy plus lymphadenectomy
PROCEDURE	Fertility-preserving surgery	After 3 cycles of neoadjuvant therapy, patients who achieved CR/PR will undergo Fertility-preserving surgery. For stage IB1/IB2 patients, conization or simple trachelectomy plus lymphadenectomy will be performed. For stage IIA1/IIA2 patients, radical trachelectomy plus lymphadenectomy will be performed.

Timeline

• Start date: 2025-03-15
• Primary completion: 2028-03-31
• Completion: 2030-03-31
• First posted: 2025-03-14
• Last updated: 2025-04-01

Locations

1 site across 1 country: China