QL1706 Plus Chemotherapy as Neoadjuvant Therapy for Locally Advanced Cervical Cancer: A Phase II Trial

A Single-arm, Multicenter Phase II Clinical Study of QL1706 Plus Chemotherapy as Neoadjuvant Therapy for Locally Advanced Cervical Cance

Cervical cancer ranks as the second most common malignancy of the female genital tract. According to the World Health Organization, there are 530,000 new cases and approximately 250,000 cervical-cancer-related deaths worldwide each year, with 80% of these deaths occurring in women from developing countries. Early-stage disease can be managed surgically, whereas advanced or recurrent cervical cancer is treated with individualized multimodal therapy; nevertheless, the optimal management of locally advanced cervical cancer (FIGO 2018 stage IB3-IIA2) remains controversial. Chemoradiation is standard, but neoadjuvant chemotherapy followed by radical surgery after tumor down-staging is also used. More than 90% of cervical cancers are driven by persistent infection with high-risk human papillomavirus (HPV), which evades host immunity in part by up-regulating PD-L1 on tumor cells. Published series report PD-L1 positivity in 34.4-96% of cervical cancers, with even higher rates in squamous-cell histology, providing a rationale for PD-1/PD-L1 blockade. QL1706, a novel bispecific immunotherapeutic agent, has recently been approved as monotherapy for second-line treatment of advanced cervical cancer.QL1706, developed by Qilu Pharmaceutical using the proprietary MabPair™ platform, is the first bispecific antibody simultaneously targeting PD-1 and CTLA-4, showing synergistic anti-tumor activity and favorable tolerability.Unlike previous phase II/III trials of PD-1 monotherapy, this study does not restrict enrolment to patients with PD-L1-positive tumors, so QL1706 is expected to confer benefit in the second-line management of recurrent or metastatic cervical cancer. Therefore, investigating QL1706-based combination regimens as neoadjuvant treatment for treatment-naïve disease is also highly relevant and may improve outcomes in women with locally advanced cervical cancer.

Inclusion Criteria:

• (1) Has given written informed consent (or consent provided by an immediate family member if the subject is unable to do so) after full explanation of the study.

  (2) Female, aged ≥ 18 and ≤ 70 years on the date of informed-consent signature. (3) Histologically confirmed cervical cancer: A. Squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma; B. Previously untreated-no prior anti-cancer therapy for cervical cancer; C. FIGO 2018 stage IB3 or IIA2; D. Stage IIICr without involvement of the lower third of the vagina and without parametrial infiltration.

  (4) At least one measurable lesion by CT or MRI per RECIST 1.1. Note: Lesions situated in a prior radiation field or previously treated by local-regional therapy must be classified as non-target lesions unless clear progression is documented or tumor viability is confirmed by biopsy, and no other measurable lesion exists; in that case the lesion may serve as a target lesion.

  (5) Archival tumor tissue obtained within 5 years before enrollment OR a freshly obtained biopsy (≈ 7 unstained FFPE slides, minimum 5; preference for recent sample).

The biopsied lesion must not be selected as a RECIST 1.1 target lesion unless no other site is suitable and the biopsy was performed outside the screening period. If a subject cannot provide the required slides and the investigator judges re-biopsy to be unsafe, the number of slides may be reduced at the investigator's discretion.

(6) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. (7) Life expectancy ≥ 12 weeks. (8) Adequate function of major organs documented within 14 days before randomisation (no transfusion, albumin, recombinant human thrombopoietin or colony-stimulating factors allowed during this period): Haematology Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L Platelets ≥100 × 10⁹/L Haemoglobin ≥90 g/L Hepatic Total bilirubin ≤1.5 × upper limit of normal (ULN) ALT and AST ≤2.5 × ULN (≤5 × ULN if liver metastases present) Serum albumin ≥30 g/L Renal Serum creatinine ≤1.5 × ULN; OR if >1.5 × ULN, calculated creatinine clearance ≥60 mL/min (Cockcroft-Gault) Coagulation APTT ≤1.5 × ULN PT/INR ≤1.5 × ULN Cardiac Left-ventricular ejection fraction (LVEF) ≥50% Urinalysis Dipstick proteinuria <2+ If ≥2+, 24-hour urine protein must be <1.0 g to permit entry (9) Women of child-bearing potential must use a highly effective contraceptive method from informed-consent signature until 180 days after the last study-dose administration and must not be pregnant or lactating.

Exclusion Criteria:

• (1) Prior exposure to any immunotherapy, including immune-checkpoint inhibitory antibodies (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4), immune-checkpoint agonistic antibodies (e.g., anti-ICOS, CD40, CD137, GITR, OX40), or cellular immunotherapy.

  (2) Systemic or severe infection requiring intravenous antibiotics for >7 days within 2 weeks before enrolment, or unexplained fever >38.5 °C detected during screening or within 2 weeks prior to enrolment (fever judged by the investigator to be tumour-related is permitted).

  (3) Systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive agents (e.g., cyclophosphamide, azathioprine, methotrexate, thalidomide, TNF-α inhibitors) for any indication within 2 weeks before enrolment. Topical, nasal or inhaled corticosteroids are allowed; systemic steroids given solely for prophylaxis of contrast allergy are also permitted.

  (4) Treatment with immunomodulatory agents such as thymosin, lentinan, interferon or interleukins within 2 weeks before enrolment.

  (5) Use within 2 weeks before enrolment of aspirin (>325 mg/day), clopidogrel (>75 mg/day), dipyridamole, ticlopidine, cilostazol, or any therapeutic-dose anticoagulant other than low-molecular-weight heparin.

  (6) Use of modern Chinese herbal preparations approved by NMPA for anti-cancer therapy within 2 weeks before enrolment.

  (7) Major surgery, open biopsy or significant traumatic injury within 4 weeks before enrolment; or planned elective major surgery during the study. Local invasive procedures (e.g., core biopsy) within 1 week before enrolment are excluded, except for vascular-access device placement.

  (8) Anti-cancer therapy (chemotherapy, endocrine therapy, targeted therapy, biological therapy, trans-arterial chemo-embolisation, etc.) within 4 weeks before enrolment.

  (9) Symptomatic CNS metastases, leptomeningeal disease or spinal-cord compression at baseline. Asymptomatic subjects with stable CNS disease who have completed any prior CNS-directed therapy ≥2 weeks earlier and have been off corticosteroids and anti-convulsants for ≥2 weeks may be enrolled.

  (10) Clinically significant hydronephrosis that cannot be relieved by nephrostomy or ureteral stenting.

  (11) Recurrent third-space fluid (e.g., pleural effusion or ascites) requiring repeated drainage and judged poorly controlled.

  (12) Active or potentially relapsing autoimmune disease, except: vitiligo, alopecia, psoriasis or eczema not requiring systemic therapy; hypothyroidism due to autoimmune thyroiditis on stable hormone replacement; or type 1 diabetes on stable-dose insulin.

  (13) History of gastrointestinal or genitourinary perforation/fistula, or intra-abdominal abscess within 6 months before enrolment (subjects are eligible if the underlying defect has been surgically corrected).

  (14) Bowel obstruction within 6 months before enrolment (subjects with incomplete obstruction that has resolved after treatment may be enrolled at the investigator's discretion), active intra-abdominal inflammation (including but not limited to peptic ulcer, diverticulitis or colitis).

  (15) Clinically significant cardiovascular disorders:

  1. Myocardial infarction, unstable angina, pulmonary embolism or other arterial/venous thrombo-embolic or cerebrovascular event requiring medical intervention within 6 months before enrolment;
  2. NYHA class III-IV congestive heart failure;
  3. Serious arrhythmia requiring medication;
  4. Mean QTcF >470 ms on 12-lead ECG (Fridericia formula) at screening. (16) Co-existing conditions that would increase the risk of adverse events during the study:

  1. Poorly controlled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) despite optimal therapy;

  2. Prior hypertensive crisis or hypertensive encephalopathy;

  3. History of intracranial or spinal haemorrhage;

  4. Bleeding diathesis, severe coagulopathy (off anticoagulation) or tumour encasing major vessels;

  5. Haemoptysis ≥½ teaspoon bright-red blood per episode, radiation enteritis/colitis or radiation cystitis with bleeding within 3 months before enrolment;

  6. Evidence of free intra-abdominal air;

  7. Serious non-healing or dehiscent wound or untreated fracture;

  8. Any other condition judged by the investigator to confer unacceptable risk. (17) Interstitial lung disease, pneumoconiosis, drug-related pneumonitis or severely impaired pulmonary function that might interfere with detection or management of suspected drug-related pulmonary toxicity.

     (18) HIV-positive; active hepatitis B (HBsAg-positive and HBV-DNA >500 IU/mL, or above local lower limit of detection if >500 IU/mL); active hepatitis C (subjects with positive HCV antibody but HCV-RNA below local lower limit of detection are eligible).

     (19) Known active tuberculosis; known active syphilis. (20) Other active malignancy within 5 years before informed consent, except adequately treated localised cancers (e.g., basal- or squamous-cell skin cancer, superficial bladder cancer, ductal carcinoma in situ of the breast).

     (21) Prior allogeneic haematopoietic stem-cell or organ transplantation (corneal transplant allowed).

     (22) Live-vaccine administration within 4 weeks before enrolment. (23) Participation in another clinical trial and receipt of an investigational product within 4 weeks before enrolment.

     (24) History of substance abuse (drugs or alcohol) or psychiatric/neurological disorder (epilepsy, dementia, hepatic encephalopathy, etc.) that could compromise compliance.

     (25) Known hypersensitivity to macromolecular protein preparations, or contraindication/allergy to any component of QL1706, cisplatin/carboplatin or paclitaxel.

     (26) Any condition that, in the opinion of the investigator, could increase study-related risk or interfere with interpretation of results.