Advanced Cancer, Esophageal Adenocarcinoma, Gastric Cancer, Gastroesophageal Junction Carcinoma, Metastatic Cancer, Solid Tumor
Conditions
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.
Interventions
DRUGGivastomig
Givastomig 8mg/kg Q2W IV or 12mg/kg Q3W IV
DRUGNivolumab
Q2 or Q3W IV
DRUG5Fluorouracil
Q2W IV
DRUGLeucovorin
Q2W IV
DRUGOxaliplatin
Q2W or Q3W IV
DRUGCapecitabine
Twice daily x 14 days every 3 weeks PO
Sponsors
I-Mab Biopharma US Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 v1.1. * ECOG performance status 0 or 1. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS), BICR-assessed | Up to 5 years | Compare PFS between participants receiving givastomig plus nivolumab and chemotherapy versus control (nivolumab plus chemotherapy) |
| Safety and Tolerability | 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
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR), BICR-assessed | Up to 108 weeks | Proportion of participants with complete or partial response by RECIST v1.1 |
| Duration of Response (DOR), BICR-assessed | Up to 108 weeks | Time participants maintain complete or partial response |
| Best Overall Response (BOR), BICR-assessed | Up to 108 weeks | Best response achieved during treatment according to RECIST v1.1 |
| Overall Survival (OS) | Up to 5 years | Comparison of overall survival between arms |
| Optimized Dose of Givastomig | Up to 2 years | Determine the recommended dose of givastomig in combination with nivolumab and chemotherapy |
| Peak Plasma Concentration (Cmax) of Givastomig | Up to 2 years | Cmax will be derived from the PK plasma samples collected |
| Correlation of baseline CLDN18.2 expression with response and safety measures | Baseline and up to 2 years | Tumor expression of CLDN18.2 will be assessed at baseline and will be correlated with measures of response (including ORR, PFS, OS) and safety (incidence of AEs) |
| Change in serum levels of soluble 4-1BB (s4-1BB) from baseline | Baseline and up to 2 years | Serum s4-1BB levels will be assessed at baseline and while on treatment. Changes will be correlated with efficacy measures including ORR. |
| Health Related Quality of Life (HRQoL) measured by the Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30) | Baseline and up to 2 years | The EORTC QLQ-C30 is a cancer specific instrument consisting of 5 functional domain scales: physical, role, emotional, social, and cognitive |
| Trough Plasma Concentration (Ctrough) of Givastomig | Up to 2 years | Ctrough will be derived from the PK plasma samples collected |
| Number of participants positive for anti-drug antibody (ADA) to Givastomig | Up to 2 years | Immunogenicity will be measured by the number of participants that are ADA positive |
| Correlation of baseline PDL1 expression with response and safety measures | Baseline and up to 2 years | Tumor expression of PDL1 will be assessed at baseline and will be correlated with measures of response (including ORR, PFS, OS) and safety (incidence of AEs) |
| HRQoL measured by the Oesophago-Gastric Module (EORTC QLQ-OG25) questionnaire | Baseline and up to 2 years | The EORTC-QLQ-OG25 questionnaire evaluates gastric cancer and gastroesophageal cancer specific symptoms |
| HRQoL measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) | Baseline and up to 2 years | he EQ-5D-5L questionnaire is a validated measure of generic health outcomes including mobility, self-care, usual activities, pain/depression, and anxiety/depression |
Countries
China, Japan, United States
Contacts
CONTACTI-MAB US Clinical Trials
Outcome results
None listed