INVIGORATE: A Study of QL1706 and Bevacizumab in Advanced First-Line Ovarian Clear Cell Carcinoma

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

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.

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, such as use of disease-modifying drugs, corticosteroids, or immunosuppressants, within 2 years before the first dose. Replacement therapies, such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency, are not considered systemic treatment. Note: Patients with cataracts, Graves' disease, or psoriasis not requiring systemic treatment within the past 2 years are not excluded.

• Systemic infection requiring systemic antibiotic treatment or other severe infections within 2 weeks before randomization, or unexplained fever >38.0°C during the screening period or before enrollment, and inability to discontinue aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) for more than 5 days.

• Severe illness or concomitant non-tumor diseases, such as neurological disorders, psychiatric disorders, infectious diseases, or laboratory abnormalities, that may increase the risk of participating in the study or taking study drugs, and which the investigator deems would make the patient unsuitable for the study.

• Pregnant or lactating women.

• Clinically significant cardiovascular diseases, including but not limited to:

  1. Myocardial infarction or unstable angina within 6 months before the first dose.
  2. Stroke or transient ischemic attack within 6 months before the first dose.
  3. Hypertension not controlled by optimal antihypertensive therapy, defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg.
  4. Poorly controlled arrhythmias. Patients who have stabilized before the first dose and have been stable for ≥14 days may be enrolled.
  5. Congestive heart failure, New York Heart Association (NYHA) functional class II-IV.
  6. Myocarditis.

• Expectation of needing any other form of anti-tumor therapy during the study period.

• Receipt of traditional Chinese medicines with anti-tumor indications or immunomodulatory drugs, including but not limited to thymosin, interferon, interleukin-2, etc., within 2 weeks before the first dose.

• HIV-positive patients.

• Known history of anti-tuberculosis treatment within one year before the first administration of study treatment.

• Hepatitis B surface antigen (HBsAg) positive and hepatitis B virus DNA (HBV DNA) ≥2000 IU/mL or 10^4 copies/mL; HCV antibody positive and HCV RNA positive.

• Pre-existing peripheral neuropathy of grade ≥2 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

• Current or recent, within 10 days before the first dose of study drug, continuous use of full-dose oral or parenteral anticoagulants or thrombolytic agents for 10 days. Note: Prophylactic use of low-dose anticoagulants is permitted, including low-dose warfarin (≤1 mg/day), low-dose heparin (≤12,000 U/day), or low-dose aspirin (≤100 mg/day), provided the prothrombin time international normalized ratio (INR) is ≤1.5.

• Hereditary bleeding tendency or coagulation dysfunction, or history of thrombosis, or imaging showing tumor invasion/infiltration of major blood vessels, or investigator or radiologist assessment of bleeding tendency.

• Known history of severe allergy to macromolecular protein preparations, or to any component of QL1706 or other investigational drugs, or severe allergic history to chemotherapeutic drugs such as carboplatin, paclitaxel, nab-paclitaxel, or their premedications.

• Currently participating in interventional clinical research treatment, or receiving any other investigational drug or research device treatment within 4 weeks before the first dose. Patients who failed screening for other clinical trials may be included in this study.

• Patients deemed unsuitable for participation in this study by the investigator.