Iparomlimab and Tuvonralimab (QL1706) Plus Lenvatinib and Chemotherapy for Extrapulmonary Neuroendocrine Carcinoma

Official title

A Prospective, Randomized, Controlled Clinical Trial of Iparomlimab and Tuvonralimab Injection (QL1706) Plus Lenvatinib and Chemotherapy as First-Line Treatment for Extrapulmonary Neuroendocrine Carcinoma

Overview

The aim of this prospective, randomized, controlled clinical trial is to evaluate the efficacy and safety of iparomlimab and tuvonralimab injection (QL1706) plus lenvatinib and etoposide-based platinum chemotherapy, consisting of etoposide plus cisplatin or carboplatin, compared with etoposide-based platinum chemotherapy alone as first-line treatment for patients with extrapulmonary neuroendocrine carcinoma. Potential predictive biomarkers will also be explored through analyses of tumor tissue, peripheral blood, and relevant clinical and pathological data.

Detailed description

This is a prospective, randomized, controlled clinical trial evaluating iparomlimab and tuvonralimab (QL1706) plus lenvatinib and platinum-etoposide chemotherapy as first-line treatment for patients with unresectable or metastatic extrapulmonary neuroendocrine carcinoma.

The study includes a safety lead-in phase and a randomized phase. During the safety lead-in phase, six participants will receive QL1706 plus lenvatinib and platinum-etoposide chemotherapy. Dose-limiting toxicities will be evaluated. If two or more participants experience a dose-limiting toxicity, the starting dose of lenvatinib in the randomized phase will be reduced from 8 mg to 4 mg once daily.

In the randomized phase, eligible participants will be assigned to receive either QL1706 plus lenvatinib and platinum-etoposide chemotherapy or platinum-etoposide chemotherapy alone. After six cycles of combination treatment, participants in the experimental group will receive maintenance treatment with QL1706 plus lenvatinib until disease progression, unacceptable toxicity, or another protocol-defined reason for discontinuation. Participants in the control group will enter follow-up observation after completing six cycles of chemotherapy.

The study will evaluate treatment efficacy and safety, including the 6-month PFS rate, PFS, OS, tumor response, duration of response, and treatment-related adverse events. Potential predictive biomarkers will also be explored using tumor tissue, peripheral blood, and relevant clinical and pathological data.

Interventions

• Drug Iparomlimab and tuvonralimab injection (QL1706) + Lenvatinib + EP/EC
  Participants will receive iparomlimab and tuvonralimab injection (QL1706) at 5 mg/kg intravenously on Day 1, etoposide at 100 mg/m² intravenously on Days 1-3, and either cisplatin at 75 mg/m² intravenously per cycle or carboplatin at AUC 5 intravenously on Day 1 of each 21-day cycle. Lenvatinib will be administered orally once daily at 8 mg or 4 mg, as determined by the safety findings from the safety run-in phase. After six cycles of combination treatment, participants without disease progressi
• Drug EP/EC
  Patients will receive etoposide 100 mg/m² intravenously on Days 1-3, together with either cisplatin 75 mg/m² intravenously per cycle or carboplatin AUC 5 intravenously on Day 1 of each 21-day cycle.

Primary outcome measures

• 6-month PFS rate [Time frame: Up to 24 months]

Secondary outcome measures (5)

• PFS [Time frame: 2 years]
• OS [Time frame: 2 years]
• ORR [Time frame: 2 years]
• DCR [Time frame: 2 years]
• DoR [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

• Histologically and/or cytologically confirmed locally advanced unresectable or metastatic extrapulmonary neuroendocrine carcinoma. Eligible primary sites include the gastrointestinal tract, pancreas, biliary tract, and other extrapulmonary organs. Neuroendocrine carcinoma of the digestive system must be diagnosed according to the 2019 World Health Organization Classification of Tumours of the Digestive System.
• Age ≥18 years, with no restriction on sex.
• Life expectancy of at least 12 weeks.
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
• Patients must not have received prior first-line systemic anticancer therapy for advanced or metastatic disease. Patients who previously received adjuvant therapy following curative surgery are eligible, provided that disease recurrence occurred more than 6 months after completion of adjuvant therapy.
• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• No severe complications related to the primary tumor, including perforation, obstruction, or major bleeding that cannot be adequately controlled with medical treatment.
• Adequate organ function, as demonstrated by the following laboratory results obtained within 7 days before enrollment. Patients must not have received blood transfusion, granulocyte colony-stimulating factor (G-CSF), or other supportive treatment affecting the relevant laboratory parameters within 14 days before the first dose of study treatment: Hemoglobin ≥90 g/L; Platelet count ≥75 × 10⁹/L; White blood cell count ≥3.0 × 10⁹/L; Absolute neutrophil count ≥1.5 × 10⁹/L; Total bilirubin ≤1.5 × the upper limit of normal (ULN); Serum creatinine ≤1.5 × ULN; Alanine aminotransferase and aspartate aminotransferase ≤2.5 × ULN, or ≤5 × ULN in participants with liver metastases.
• Participants with active hepatitis B virus or hepatitis C virus infection must have received antiviral therapy for at least 14 days before the first dose of study treatment. Hepatitis B virus DNA must be ≤500 IU/mL or ≤2,500 copies/mL, and hepatitis C virus RNA must be below the lower limit of detection of the applicable assay. Such participants must be willing to continue effective antiviral treatment throughout the study.
• Voluntary participation in the study and provision of written informed consent.

Exclusion criteria

• Histologically confirmed neuroendocrine tumor, mixed adenoneuroendocrine carcinoma, or other non-neuroendocrine carcinoma pathological types.
• History of another malignancy with a disease-free interval of less than 5 years, except for adequately treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, or a gastrointestinal tumor confirmed to have been cured by endoscopic mucosal resection.
• Uncontrolled hypertension despite medical treatment, defined as systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg.
• Urine protein ≥2+ on routine urinalysis or 24-hour urinary protein ≥1 g.
• Major surgery within 4 weeks before enrollment, excluding diagnostic biopsy, or an incompletely healed surgical wound.
• Severe gastrointestinal disorders that may affect drug absorption, including but not limited to peptic ulcer, ulcerative colitis, active gastrointestinal bleeding, gastrointestinal obstruction, or severe diarrhea.
• A history of severe bleeding within the previous 3 months, defined as a single bleeding episode of >30 mL; hemoptysis within the previous 1 month, defined as a single episode of >5 mL; or a thromboembolic event within the previous 12 months, including pulmonary embolism or cerebral infarction.
• Severe cardiovascular disease, including but not limited to acute myocardial infarction, unstable angina, heart failure, ventricular arrhythmia requiring medical treatment, left ventricular ejection fraction <50%, or New York Heart Association cardiac functional class II or higher.
• Corrected QT interval (QTc) >480 ms on electrocardiography.
• Active autoimmune disease, a history of autoimmune disease with a risk of recurrence, or another condition requiring immunosuppressive treatment, such as prior organ transplantation. Participants with type 1 diabetes mellitus, hypothyroidism requiring only hormone replacement therapy, or skin disorders not requiring systemic treatment, such as vitiligo, psoriasis, or alopecia, may be enrolled.
• A history of interstitial lung disease or noninfectious pneumonitis that is symptomatic, or a previous pulmonary condition that may interfere with the evaluation or management of study treatment-related pulmonary toxicity.
• Active pulmonary tuberculosis within 1 year before the first dose of study treatment. Patients with a history of active pulmonary tuberculosis more than 1 year before the first dose must undergo careful evaluation, including sputum smear examination, T-SPOT.TB testing, erythrocyte sedimentation rate testing, and chest computed tomography. Such participants may be enrolled only if there is no evidence of active pulmonary tuberculosis.
• A history of chronic persistent diarrhea or the presence of complete intestinal obstruction.
• Requirement for systemic treatment with corticosteroids at a prednisone-equivalent dose of >10 mg/day or other immunosuppressive agents within 14 days before the first dose of study treatment. Inhaled or topical corticosteroids and adrenal replacement therapy at a prednisone-equivalent dose of ≤10 mg/day are permitted in the absence of active autoimmune disease. Short-term corticosteroid use for ≤7 days is permitted for prophylaxis, such as prevention of contrast-media allergy, or for the treatment of non-autoimmune conditions, such as delayed hypersensitivity caused by contact allergens.
• Prior treatment with any antibody or drug targeting a T-cell co-regulatory protein or immune checkpoint, including but not limited to anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-OX-40, anti-CD137, anti-TIM-3, or anti-LAG-3 therapies.
• Immunodeficiency disorder or human immunodeficiency virus infection.
• Severe medical or surgical comorbidities that impair organ function, or an acute infection associated with a body temperature >38°C, which, in the investigator's judgment, would make the patient unsuitable for the study.
• Leptomeningeal metastases or symptomatic brain metastases.
• Pregnant or breastfeeding women, or patients of reproductive potential, including male patients and women who have been postmenopausal for less than 1 year, who are unwilling to use effective contraception.
• A history of allergy or hypersensitivity to any component of the study treatments.
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for participation in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07738159 · 2026(1754)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗