Neoadjuvant Aitua (PD-1/CTLA-4 Bispecific) Plus Nab-Paclitaxel and Carboplatin for Advanced High-Grade Serous Ovarian Cancer

Background and Rationale: Ovarian cancer has the highest mortality rate among gynecological malignancies, with High-Grade Serous Carcinoma (HGSC) being the most common subtype. HGSC is characterized by a highly immunosuppressive Tumor Immune Microenvironment (TiME), often referred to as an "immune desert," which limits the efficacy of single-agent immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway.

Investigational Agent: Aitua Combination Antibody (QL1706) is a novel bifunctional antibody targeting both PD-1 and CTLA-4. Dual blockade of these pathways may synergistically activate anti-tumor immune responses: CTLA-4 inhibition promotes early T-cell activation in lymph nodes, while PD-1 inhibition reverses T-cell exhaustion within the tumor microenvironment. Previous studies in cervical cancer have shown that this bispecific antibody may offer improved efficacy with a manageable toxicity profile compared to combining two separate antibodies.

Chemotherapy Synergy: Albumin-bound paclitaxel (Nab-paclitaxel), a standard component of ovarian cancer treatment, avoids the need for corticosteroid pretreatment and has been shown to potentially enhance immune cell infiltration and regulate macrophage polarization. This study hypothesizes that combining Nab-paclitaxel/Carboplatin with the PD-1/CTLA-4 bispecific antibody will remodel the immune microenvironment and improve surgical outcomes.

Study Design: This is a single-center, open-label (with blinded assessment), randomized Phase II trial. Approximately 82 eligible patients will be stratified by FIGO stage (IIIC vs. IV) and randomized 1:1 to the experimental or control arm.

Neoadjuvant Phase: Patients receive 3 cycles of therapy (Q3W).

Surgical Phase: Patients with responsive or stable disease will undergo Interval Debulking Surgery (IDS). The primary endpoint is the R0 resection rate (no macroscopic residual disease).

Adjuvant Phase: Post-surgery, patients will continue treatment with the assigned regimen for additional cycles.

Translational Research: Tumor tissue, ascites, and peripheral blood will be collected at baseline, pre-surgery, and during therapy to analyze changes in immune cell subsets (e.g., via scRNA-seq, mIHC/mIF) and identify potential predictive biomarkers.

• Aitua Combination Antibody (Drug), also known as PD-1/CTLA-4 Bispecific Antibody, QL1706: Administered via intravenous infusion at a dose of 5 mg/kg on Day 1 of each 3-week cycle.
• Albumin-Bound Paclitaxel /nab-Paclitaxel (Drug): Administered via intravenous infusion at a dose of 260 mg/m\^2 on Day 1 of each 3-week cycle.
• Carboplatin (AUC 5) (Drug): Administered via intravenous infusion at a dose of AUC 5 on Day 1 of each 3-week cycle.
• Interval Debulking Surgery (Procedure): Performed after 3 cycles of neoadjuvant therapy. The goal is to achieve R0 resection (no macroscopic residual disease).

Primary outcomes

• Rate of R0 resection [At the time of surgery, up to 12 weeks]: Defined as the percentage of participants achieving optimal debulking surgery with no macroscopic residual disease (R0) after neoadjuvant therapy. This is assessed by the surgeon at the time of interval debulking surgery (IDS).

Secondary outcomes

• Pathological complete response (pCR) rate [At the time of surgery, up to 12 weeks]: Defined as the proportion of participants with no evidence of invasive cancer in the surgical specimens collected during interval debulking surgery (IDS).
• Objective response rate (ORR) [From baseline up to approximately 2 years]: Defined as the percentage of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on independent radiological review.
• Disease control rate (DCR) [From baseline up to approximately 2 years]: Defined as the percentage of participants who achieve a best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Progression-free survival (PFS) [From randomization up to approximately 2 years]: Defined as the time from randomization to the first documented disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause, whichever occurs first.
• Incidence and severity of adverse events (AEs) [Through 28 days after the last dose of study drug, up to approximately 2 years]: Safety will be assessed by monitoring the frequency and severity of adverse events (AEs) and serious adverse events (SAEs), graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This includes monitoring for immune-related adverse events (irAEs).

Other outcomes

• Change in tumor immune microenvironment (TiME) characteristics [At baseline, and at the time of surgery (up to 12 weeks)]: Exploratory analysis of immune cell subsets, such as cluster of differentiation 8 positive (CD8+) T cells, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), in tumor tissue and peripheral blood. This uses single-cell RNA sequencing (scRNA-seq), multiplex immunohistochemistry/immunofluorescence (mIHC/mIF), and flow cytometry to evaluate the immunomodulatory effects of the treatment.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

* Age ≥ 18 years.
* Histologically confirmed high-grade serous ovarian cancer (HGSC), fallopian tube cancer, or primary peritoneal cancer.
* International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
* Assessed by a multidisciplinary team (MDT) based on imaging (± laparoscopic exploration) as initially unable to achieve satisfactory tumor debulking (R0 resection).
* At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.
* Major organ function is basically normal.
* Willing to provide tumor tissue, peripheral blood, and ascites samples for translational research.

Exclusion Criteria:

* Pathological types other than high-grade serous carcinoma (HGSC).
* Prior receipt of any form of anti-tumor therapy.
* History of autoimmune disease or requiring immunosuppressive therapy.
* Known allergy to study drug components.
* Pregnant or lactating women.

• Ning Li, MD, Principal investigator, Cancer Institute and Hospital, Chinese Academy of Medical Sciences