Conversion Therapy of Sintilimab in Combination With Fruquintinib and Chemotherapy Versus Sintilimab and Chemotherpay in Stage IV Gastric Cancer

Official title

Sintilimab Combined With Fruquintinib and Chemotherapy Versus Sintilimab and Chemotherapy for Conversion Therapy in Unresectable Stage IV Gastric Cancer: a National Multicenter Randomized Controlled Study

Overview

This is a multicenter, randomized, open-label, phase 2 clinical study aiming to evaluate the feasibility and efficacy of sintilimab (PD-1 inhibitor) in combination of fruquintinib and chemotherapy (S-1 plus nab-paclitaxel) versus sintilimab and chemotherapy as conversion therapy in patients with stage IV gastric cancer in China.

Interventions

• Drug Sintilimab + Fruquinitinib + S-1 plus nab-paclitaxel
  Drug: Sintilimab Sintilimab 200mg, D1, IV, Q3W 4-8 cycles Drug: Fruquintinib Fruquinitinib 4mg/d, QD, PO, D1-D14, Q3W 4-8 cycles Drug: S-1 BSA\<1.25 m2, 40mg twice/day; BSA 1.25-1.5m2, 50mg twice/day; BSA≥1.5 m2, 60mg twice/day, po, D1-D14, Q3W 4-8 cycles Drug: Nab-paclitaxel * without peritoneal metastases: 260 mg/m2, IV, D1 for 3h, Q3W 4-8 cycles; * with peritoneal metastases: 80mg/m2 IP, plus 180mg/m2, IV, D1, Q3W 4-8 cycles.
• Drug Sintilimab + S-1 plus nab-paclitaxel
  Drug: Sintilimab Sintilimab 200mg, D1, IV, Q3W 4-8 cycles Drug: S-1 BSA\<1.25 m2, 40mg twice/day; BSA 1.25-1.5m2, 50mg twice/day; BSA≥1.5 m2, 60mg twice/day, po, D1-D14, Q3W 4-8 cycles Drug: Nab-paclitaxel * without peritoneal metastases: 260 mg/m2, IV, D1 for 3h, Q3W 4-8 cycles; * with peritoneal metastases: 80mg/m2 IP, plus 180mg/m2, IV, D1, Q3W 4-8 cycles.

Primary outcome measures

• R0-surgery conversion rate [Time frame: about 3 years]

Secondary outcome measures (8)

• Pathological complete response (pCR) [Time frame: about 3 years]
• Major pathological response rate (MPR) [Time frame: about 3 years]
• Rate of downstaging [Time frame: about 3 years]
• Objective response rate (ORR) [Time frame: about 3 years]
• Disease control rate (DCR) [Time frame: about 3 years]
• Overall survival (OS) [Time frame: about 3 years]
• Progression-free survival (PFS) [Time frame: about 3 years]
• Adverse event (AEs) [Time frame: about 3 years]

Eligibility criteria

Inclusion criteria

• Histologically confirmed gastric/gastroesophageal junction adenocarcinoma through gastroscopy.
• Ages: 18-70 Years (concluding 18 and 70 Years)
• Life expectancy ≥3 months.
• Treatment-naive Stage IV (clinical staging, AJCC 8th) unresectable patients, no prior antitumor therapy (including radiation, chemotherapy, targeted therapy or immunotherapy, etc.).
• The Eastern Cooperative Oncology Group Performance status (ECOG PS) of 0-1.
• Preoperative examinations using CT, MRI, PET-CT, etc., indicating only one unresectable factor OR peritoneal metastasis with another unresectable factor, such as:

• N3 lymph node metastasis, mainly referring to group 16 lymph node metastasis.
• Extensive or bulky lymph nodes (D2)
• Locally advanced T4b.
• Hepatic metastases (H1): ≤5 lesions with a total diameter ≤8cm.
• Peritoneal metastasis (CY1, P1).
• Ovarian metastasis (Krukenberg tumor).
• Physically fit for major abdominal surgery.
• Adequate organ and marrow function, defined as:

• Hematological status: Absolute neutrophil count (ANC) ≥1.5×10\^9/L; Platelet count (PLT) ≥100×10\^9/L; Hemoglobin (HGB) ≥9.0 g/dL.
• Liver function: For patients without liver metastasis, serum total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); ALT and AST ≤2.5×ULN. For patients with liver metastasis: TBIL ≤1.5×ULN; ALT and AST ≤5×ULN.
• Renal function: Creatinine clearance (Ccr) ≥50 mL/min (calculated using the Cockcroft/Gault formula).
• Adequate coagulation function, defined as International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times ULN.
• Voluntary participation and signed informed consent with expected good compliance and follow-up.
• Not involved in other clinical trials.
• Willing to provide blood and histological samples.
• No serious conditions affecting anesthesia, or surgery.
• No hematologic disorders affecting postoperative hemoglobin levels.

Exclusion criteria

• Has distal metastases other than oligometastases as defined in the inclusion criteria, such as pulmonary metastases, brain metastases, bone metastases, etc.
• HER-2 positive patients or willing to receive Trastuzumab.
• Endoscopic signs of active bleeding from the lesion.
• Patients with moderate/large volume of ascites.
• Near-obstruction at the cardia or pylorus affecting feeding and gastric emptying or difficulty swallowing tablets.
• Concurrently suffering from other serious illnesses that are difficult to control (Severe uncontrolled recurrent infections, atrial fibrillation, angina pectoris, cardiac insufficiency, ejection fraction measurement under 50%, uncontrolled hypertension, renal insufficiency, symptomatic peripheral neuropathy, and NCI classification >II)
• Has already on other medications prior to enrollment or could not be assured of compliance after enrollment.
• Allergy to any drugs in the regimen.
• Women who are pregnant or breastfeeding and have childbearing potential but are not taking adequate contraceptive measures.
• Organ transplant recipients requiring immunosuppression.
• Patients without decision-making capacity or with psychiatric disorders.
• Systemic treatment with Chinese herbal anti-tumor or immunomodulatory drugs (including thymosin, interferons, interleukins) within 2 weeks before the first dose.
• Use of immunosuppressive drugs within 4 weeks before the first study treatment, excluding local steroids or physiological doses of systemic steroids.
• Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study treatment.
• Has a diagnosis of autoimmune disease within the previous 2 years (Patients with vitiligo, psoriasis, alopecia areata, or Graves' disease who do not require systemic therapy within the last 2 years, hypothyroidism requiring only thyroid hormone replacement therapy, and type I diabetes mellitus requiring only insulin replacement therapy are eligible for enrollment).
• Known history of primary immunodeficiency.
• Known to have active tuberculosis.
• Has history of human immunodeficiency virus (HIV) infection (i.e., HIV antibody . positive); untreated acute or chronic active hepatitis B or hepatitis C infection. Patients receiving antiretroviral therapy are eligible for enrollment on an individual basis as determined by the physician with monitoring of viral copy number.
• Urinalysis indicating urine protein ≥2+ and 24-hour urine protein quantification >1.0g.

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

China · 1 center

• Tianjin Medical University Cancer Institute and Hospital — Tianjin

Identifiers

NCT: NCT06454435 · E20231573

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗