A Randomized, Open-label, Active-controlled, Multicenter Phase 3 Trial Evaluating QL1706 With Bevacizumab Versus Standard Platinum-Based Chemotherapy With or Without Bevacizumab as First-line Treatment for Advanced Ovarian Clear Cell Carcinoma

Official Summary

The goal of this phase 3 clinical trial is to evaluate whether QL1706 plus bevacizumab can effectively treat adult female patients (18 to \<75 years old) with newly diagnosed FIGO stage IC-IV ovarian clear cell carcinoma. The main questions it aims to answer are: 1. Does QL1706 plus bevacizumab, compared with standard platinum-based chemotherapy with or without bevacizumab, prolong patients' progression-free survival (PFS)? 2. What is the safety profile of QL1706 followed by QL1706 plus bevacizumab, such as what medical problems (adverse events) do participants experience? Researchers will compare QL1706 followed by QL1706 plus bevacizumab (experimental arm) with standard platinum-based chemotherapy consisting of paclitaxel plus carboplatin with or without bevacizumab (control arm) to see whether QL1706-based immunotherapy is more effective in the first-line treatment of advanced ovarian clear cell carcinoma. Participants will: 1. Be randomly assigned to receive either QL1706 alone during Cycle 1 followed by QL1706 plus bevacizumab from Cycle 2, or paclitaxel plus carboplatin with or without bevacizumab according to prespecified high-risk criteria. 2. Visit the research center regularly for drug infusions, medical examinations (such as vital signs, physical exams, laboratory tests), and tumor imaging assessments. 3. Complete quality of life questionnaires as required.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 75 Years
• Sex: FEMALE

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 226 participants

Study Arms

• Experimental Arm: QL1706 + Bevacizumab (EXPERIMENTAL)
  QL1706 5 mg/kg Q3W (D1)+Bevacizumab 15mg/kg Q3W (D1) (QL1706/Bevacizumab treatment for a maximum of 2 years/22 cycles)
• Control Arm: Paclitaxel + Carboplatin ± Bevacizumab (ACTIVE_COMPARATOR)
  Paclitaxel 175 mg/m² Q3W (D1) + Carboplatin AUC 5 Q3W (D1), for 6 cycles, with or without Bevacizumab 15 mg/kg Q3W (D1) according to prespecified high-risk criteria. Bevacizumab may be continued until disease progression, unacceptable toxicity, or completion of a maximum of 22 cycles.

Interventions

• DRUG: QL1706 (bispecific antibody targeting PD-1 and CTLA-4) — QL1706: 5 mg/kg intravenously every 3 weeks until disease progression or intolerable toxicity, with a maximum duration of 2 years.
• DRUG: Bevacizumab — Bevacizumab : 15 mg/kg intravenously every 3 weeks until disease progression or intolerable toxicity, with a maximum duration of 22 cycles.
• DRUG: carboplatin — Carboplatin: AUC=5, intravenously every 3 weeks until disease progression or intolerable toxicity, with a maximum duration of 6 cycles
• DRUG: Paclitaxel — Paclitaxel: 175 mg/m\^2 intravenously every 3 weeks until disease progression or intolerable toxicity, with a maximum duration of 6 cycles

Primary Outcomes

• Progression-Free Survival (PFS) (Up to 4 years)

Secondary Outcomes

• Overall Survival (OS) (Up to 4 years)
• Progression-Free Survival 2 (PFS2) (Up to 4 years)
• Time to First Subsequent Therapy (TFST) (Up to 4 years)
• Time to Second Subsequent Therapy (TSST) (Up to 4 years)
• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] (Up to 4 years)

Eligibility Criteria

Inclusion Criteria:

* Voluntary participation in the study and signed informed consent form.
* Age ≥ 18 years and \< 75 years, female.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Expected survival ≥ 3 months.
* Histologically or cytologically newly diagnosed FIGO stage IC-IV ovarian clear cell carcinoma.
* Patients are planned to undergo primary debulking surgery (PDS), regardless of whether satisfactory debulking is achieved, and have complete surgical records and residual disease assessment results (R0 vs R1/R2).
* No prior first-line postoperative systemic antitumor therapy for the current ovarian clear cell carcinoma, including chemotherapy, targeted therapy, immunotherapy, etc.
* Adequate organ function confirmed by the following requirements:

Hematological (no use of any blood components or cell growth factors within 7 days prior to initiation of study treatment):

i. Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L (1,500/mm\^3). ii. Platelet count ≥ 100 × 10\^9/L (100,000/mm\^3). iii. Hemoglobin ≥ 90 g/L.

Renal:

i. Calculated creatinine clearance (CrCl) ≥ 50 mL/min. CrCl will be calculated using the Cockcroft-Gault formula: CrCl (mL/min) = \[(140 - age) × weight (kg) × F\] / \[SCr (mg/dL) × 72\], where F = 0.85 for females and SCr = serum creatinine.

ii. Urine protein \< 2+ or 24-hour quantitative urine protein \< 1.0 g.

Hepatic:

i. Total serum bilirubin (TBil) ≤ 1.5 × ULN. ii. AST and ALT ≤ 2.5 × ULN.

Coagulation:

i. International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

\- For women of childbearing potential, a negative serum or urine pregnancy test within one week prior to enrollment, and effective contraceptive measures must be used after enrollment, for example, use of physical barrier contraception (condoms) or complete abstinence. Oral, injectable, or implantable hormonal contraceptives are not permitted. Or, women of non-childbearing potential, defined as: i. Naturally postmenopausal for at least 1 year. ii. Surgically sterile, including bilateral oophorectomy, bilateral salpingectomy, or hysterectomy.

iii. Serum follicle-stimulating hormone, luteinizing hormone, and plasma estradiol levels within the postmenopausal range for the study center's laboratory.

* Subject is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study requirements.
* Patient is willing to cooperate in completing quality of life questionnaires during the trial treatment and follow-up period, and agrees that these questionnaire results can be used for clinical research.

Exclusion Criteria:

* Histologically confirmed ovarian cancer of other epithelial origin or non-epithelial origin, other than ovarian clear cell carcinoma; ovarian tumors of low malignant potential, such as borderline tumors.
* Prior systemic preoperative antitumor therapy for the current ovarian clear cell carcinoma, including but not limited to neoadjuvant chemotherapy (NACT) or other types of neoadjuvant therapy, or planned neoadjuvant therapy followed by interval debulking surgery (IDS) during screening.
* Prior treatment with immune checkpoint inhibitors, such as PD-1/PD-L1 antibodies, or drugs targeting other T-cell receptors, such as CTLA-4, as well as immune checkpoint agonist antibodies, such as anti-ICOS, CD40, CD137, GITR, or OX40 antibodies, and immune cell therapy.
* Systemic use of corticosteroids or other immunosuppressive drugs, such as cyclophosphamide, azathioprine, methotrexate, thalidomide, or TNFα inhibitors, within 2 weeks before the first dose. Note: Inhaled or topical steroids, steroids as premedication for hypersensitivity reactions, such as CT scan contrast agent premedication or cytotoxic chemotherapy premedication, or adrenal replacement steroids, daily ≤10 mg prednisone or equivalent, are permitted in the absence of active autoimmune disease.
* Prior, within 5 years, or concurrent malignancies, with the exception of cured local tumors, such as basal cell skin cancer, squamous cell skin cancer, superficial bladder cancer, cervical carcinoma in situ, breast carcinoma in situ, etc., and breast cancer with no recurrence \>3 years after radical surgery.
* Patients with contraindications to bevacizumab, including but not limited to prior gastrointestinal perforation, surgery within 28 days before medication or incompletely healed wounds, severe bleeding or recent hemoptysis, or other situations where the investigator deems bevacizumab unsuitable.
* Receipt of live vaccine within 30 days before the first dose of study treatment, persisting until 90 days after the last dose of study treatment. Note: Live vaccines include but are not limited to measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccines. Seasonal influenza virus vaccines not containing live virus, inactivated COVID-19 vaccines, etc., are permitted.
* Active autoimmune disease requiring systemic treatment, su

Trial Locations

• Tongji Hospital, Wuhan, Hubei, China

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