A Randomized, Multicenter, Open-Label, Phase 2 Study of Givastomig (TJ033721) in Combination With Nivolumab and Chemotherapy Versus Nivolumab and Chemotherapy in Participants With Previously Untreated CLDN18.2 Positive and PD-1L Positive Locally Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Adenocarcinoma
Trial Snapshot
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- I-Mab Biopharma US Limited
- Enrollment
- 180
- Locations
- 6
- Primary Endpoint
- Progression-Free Survival (PFS), BICR-assessed
Study Overview
Brief Summary
The goal of this clinical trial is to learn if givastomig in combination with standard therapy works to treat adults with cancer in the stomach and/or esophagus (GEA adenocarcinoma). It will also help the researchers to learn more about the safety of givastomig. The main questions it aims to answer are:
- Does the addition of givastomig to standard therapy increase the amount of time that participants survive without progression of their cancer?
- What toxicities do participants experience when taking givastomig?
Participants may be able to take part in the study if they have unresectable or metastatic GEA and if their cancer cells express certain proteins called Claudin 18.2 (CLDN18.2) and PD-L1. Participants whose cancer cells express a protein called HER2 cannot take part.
Up to 180 participants will be randomly assigned to received givastomig at one of two doses in combination with an immunotherapy medicine called nivolumab and chemotherapy OR to receive nivolumab and chemotherapy alone. These therapies will be given primarily via intravenous (into a vein) infusion every 2 or 3 weeks.
Participants will:
- Visit the study treatment center for infusions and/or check-ups and tests every 1-3 weeks
- Report any changes in their symptoms to their study doctors
- Have scans to check for any changes in their cancer every 8-12 weeks
Detailed Description
This is a randomized, global, open-label, multicenter Phase 2 study evaluating the efficacy and safety of givastomig (TJ033721) in combination with nivolumab and chemotherapy compared with nivolumab and chemotherapy alone in participants with previously untreated, HER2-negative, CLDN18.2-positive, and PD-L1-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (GEA).
Approximately 180 participants will be randomized in a 1:1:1 ratio to one of three treatment arms. Two investigational arms will receive givastomig in combination with nivolumab and chemotherapy, and the control arm will receive nivolumab and chemotherapy alone. Chemotherapy will consist of either modified FOLFOX (mFOLFOX) or CAPOX, administered according to local standard of care. Participants enrolled in the United States, Japan, and South Korea will receive mFOLFOX only. Randomization will be stratified by chemotherapy regimen (mFOLFOX vs CAPOX) and by CLDN18.2 expression level (<75% vs ≥75% of tumor cells with membrane intensity score ≥2+).
Participants in the investigational arms will receive givastomig administered every 2 weeks or every 3 weeks, depending on the chemotherapy regimen. Tumor assessments will be performed at protocol-defined intervals and evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Enrollment of participants with high CLDN18.2 expression (defined as membrane intensity score ≥1+ in ≥75% of tumor cells) will be capped at approximately 50% of the total study population. Enrollment of participants receiving CAPOX will be capped at approximately 30% of the total study population.
Study treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, death, or completion of study treatment, whichever occurs first. The duration of chemotherapy treatment will follow the respective product labeling or local standards of care.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologically confirmed unresectable, locally advanced, or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma (EAC).
- •Treatment-naïve for advanced/metastatic disease (prior adjuvant/neoadjuvant therapy allowed if ≥6 months since last dose).
- •CLDN18.2 positive (membrane intensity score ≥1+ on ≥1% of tumor cells).
- •PD-L1 positive (CPS ≥1).
- •At least 1 measurable lesion per RECIST v1.
- •ECOG performance status 0 or
- •Adequate organ function, including:
- •Hematologic: WBC ≥2,000/μL; ANC ≥1,500/μL; platelets ≥100,000/μL; hemoglobin ≥9 g/dL
- •Hepatic: AST/ALT ≤3×ULN (≤5×ULN if liver metastases); bilirubin ≤1.5×ULN (≤3×ULN if Gilbert's)
- •Renal: Creatinine ≤1.5×ULN or eGFR ≥50 mL/min/1.73 m²
- •Life expectancy ≥90 days.
- •Women of childbearing potential (WOCBP) and men must use effective contraception during the study and for a defined period after treatment.
- •Willing and able to provide informed consent and comply with study procedures
Exclusion Criteria
- •HER2-positive tumors.
- •Second malignancy within 3 years, except certain skin or cervical cancers.
- •Active or unstable gastrointestinal ulcer or bleeding within 6 weeks.
- •Active autoimmune disease requiring systemic therapy within past 2 years or ongoing immunosuppressive therapy.
- •Active pneumonitis or history requiring steroids/immunosuppressive therapy within 3 years.
- •Participation in another therapeutic clinical trial.
- •Major surgery or significant injury within 4 weeks prior to first dose, or planned major surgery within 6 months.
- •Radiotherapy within protocol-specified timeframes without adequate recovery.
- •Active CNS metastases or carcinomatous meningitis (previously treated brain metastases allowed if stable).
- •Significant cardiovascular disease (NYHA Class 3-4 CHF, recent MI, unstable angina, TIA/stroke, or major cardiac procedures within 6 months).
- •Active or uncontrolled HIV, hepatitis B, or hepatitis C infection, or immunodeficiency (controlled infection allowed).
- •Receipt of live vaccine within 30 days or other vaccines within 7 days of first dose.
- •Active infection requiring parenteral therapy.
- •Known hypersensitivity to study drug components (e.g., DPD deficiency).
- •Any other condition or laboratory abnormality that, in the investigator's judgment, increases risk or interferes with study participation.
Arms & Interventions
Experimental: Givastomig Arm 1 Combination
Givastomig (IV) 8 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 12 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Leucovorin (Drug)
Experimental: Givastomig Arm 2 Combination
Givastomig (IV) 12 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 18 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Nivolumab (Drug)
Experimental: Givastomig Arm 1 Combination
Givastomig (IV) 8 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 12 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Givastomig (Drug)
Experimental: Givastomig Arm 1 Combination
Givastomig (IV) 8 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 12 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Nivolumab (Drug)
Experimental: Givastomig Arm 2 Combination
Givastomig (IV) 12 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 18 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Leucovorin (Drug)
Control: Nivolumab Plus Chemotherapy
Nivolumab in combination with modified FOLFOX (mFOLFOX) or CAPOX
Intervention: Oxaliplatin (Drug)
Control: Nivolumab Plus Chemotherapy
Nivolumab in combination with modified FOLFOX (mFOLFOX) or CAPOX
Intervention: Capecitabine (Drug)
Control: Nivolumab Plus Chemotherapy
Nivolumab in combination with modified FOLFOX (mFOLFOX) or CAPOX
Intervention: 5Fluorouracil (Drug)
Control: Nivolumab Plus Chemotherapy
Nivolumab in combination with modified FOLFOX (mFOLFOX) or CAPOX
Intervention: Leucovorin (Drug)
Experimental: Givastomig Arm 1 Combination
Givastomig (IV) 8 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 12 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: 5Fluorouracil (Drug)
Experimental: Givastomig Arm 1 Combination
Givastomig (IV) 8 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 12 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Oxaliplatin (Drug)
Experimental: Givastomig Arm 1 Combination
Givastomig (IV) 8 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 12 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Capecitabine (Drug)
Experimental: Givastomig Arm 2 Combination
Givastomig (IV) 12 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 18 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Givastomig (Drug)
Experimental: Givastomig Arm 2 Combination
Givastomig (IV) 12 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 18 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: 5Fluorouracil (Drug)
Experimental: Givastomig Arm 2 Combination
Givastomig (IV) 12 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 18 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Oxaliplatin (Drug)
Experimental: Givastomig Arm 2 Combination
Givastomig (IV) 12 mg/kg every 2 weeks (Q2W) in combination with nivolumab and modified FOLFOX (mFOLFOX) or Givastomig 18 mg/kg every 3 weeks (Q3W) in combination with nivolumab and CAPOX
Intervention: Capecitabine (Drug)
Control: Nivolumab Plus Chemotherapy
Nivolumab in combination with modified FOLFOX (mFOLFOX) or CAPOX
Intervention: Nivolumab (Drug)
Outcomes
Primary Outcomes
Progression-Free Survival (PFS), BICR-assessed
Time Frame: Up to 5 years
Compare PFS between participants receiving givastomig plus nivolumab and chemotherapy versus control (nivolumab plus chemotherapy)
Safety and Tolerability
Time Frame: Throughout treatment and up to 30 days after last dose
Incidence, severity, and type of adverse events, including treatment-emergent and immune-related adverse events, graded by NCI CTCAE v5.0
Secondary Outcomes
- Duration of Response (DOR), BICR-assessed(Up to 108 weeks)
- Objective Response Rate (ORR), BICR-assessed(Up to 108 weeks)
- Best Overall Response (BOR), BICR-assessed(Up to 108 weeks)
- Overall Survival (OS)(Up to 5 years)
- Optimized Dose of Givastomig(Up to 2 years)
- Peak Plasma Concentration (Cmax) of Givastomig(Up to 2 years)
- Correlation of baseline CLDN18.2 expression with response and safety measures(Baseline and up to 2 years)
- Change in serum levels of soluble 4-1BB (s4-1BB) from baseline(Baseline and up to 2 years)
- Health Related Quality of Life (HRQoL) measured by the Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30)(Baseline and up to 2 years)
- Trough Plasma Concentration (Ctrough) of Givastomig(Up to 2 years)
- Number of participants positive for anti-drug antibody (ADA) to Givastomig(Up to 2 years)
- Correlation of baseline PDL1 expression with response and safety measures(Baseline and up to 2 years)
- HRQoL measured by the Oesophago-Gastric Module (EORTC QLQ-OG25) questionnaire(Baseline and up to 2 years)
- HRQoL measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L)(Baseline and up to 2 years)