Gastric Cancer, Gastroesophageal Junction Adenocarcinoma, Esophageal Cancer
Conditions
Keywords
Advanced Gastroesophageal Junction (GEJ) Adenocarcinoma,, Advanced Gastric Adenocarcinoma,, Advanced Esophageal Adenocarcinoma,, Metastatic Gastric Adenocarcinoma,, Metastatic Gastroesophageal Junction (GEJ) Adenocarcinoma,, Metastatic Esophageal Adenocarcinoma,, Claudin 18.2,, PD-L1,, Human epidermal growth factor receptor 2 (HER2) Negative
Brief summary
The purpose of this study is to evaluate the efficacy and safety of sonesitatug vedotin in combination with capecitabine with or without rilvegostomig in first-line (1L) Claudin18.2 (CLDN18.2)-positive, human epidermal growth factor receptor 2 (HER2)-negative, gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma.
Detailed description
The purpose of this Phase III study is to evaluate the efficacy and safety of sonesitatug vedotin in combination with capecitabine with or without rilvegostomig in 1L CLDN18.2-positive, HER2-negative gastric, GEJ, and esophageal adenocarcinoma, and the clinical performance of the investigation in vitro diagnostics (IVDs). The study will include 2 cohorts to provide a treatment option for all participants that are HER2-negative and CLDN18.2-positive. Cohort 1 will evaluate sonesitatug vedotin in combination with rilvegostomig with capecitabine in participants who are CLDN18.2-positive and programmed death-ligand 1 (PD-L1) positive. Cohort 2 will evaluate sonesitatug vedotin in combination with capecitabine in participants who are CLDN18.2-positive and PD-L1 negative or immune checkpoint inhibitor (ICI) ineligible.
Interventions
DRUGSonesitatug vedotin
Intravenous
DRUGRilvegostomig
Intravenous
DRUGNivolumab
Intravenous
DRUGCapecitabine
Oral
DRUG5-Fluorouracil
Intravenous
DRUGOxaliplatin
Intravenous
DRUGZolbetuximab
Intravenous
DRUGLeucovorin
Intravenous
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
This is an open-label study; however, it will be conducted 'sponsor blind' and the specific treatment to be taken by a participant will be assigned using an IRT/RTSM. To maintain the integrity of the study, sponsor access to treatment records will be restricted, unless a positive result is observed at an interim analysis and access is required as per protocol-defined procedures
Intervention model description
Cohort 1 (3-arm design) will evaluate sonesitatug vedotin in combination with rilvegostomig and capecitabine (Arm A) or sonesitatug vedotin in combination with nivolumab and capecitabine (Arm B), versus SoC nivolumab plus capecitabine plus oxaliplatin (CAPOX) or folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) (Arm C) in PD-L1 positive participants. Participants will be randomized 1:1:1 to Arms A, B, or C. Cohort 2 (2-arm design) will evaluate sonesitatug vedotin in combination with capecitabine (Arm D) versus SoC (Arm E) in participants who are PD-L1 negative or ICI-ineligible. Participants will be randomised 1:1. SoC is CAPOX or FOLFOX alone or in combination with zolbetuximab.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Capable of giving signed informed consent * Participant must be 18 years or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent. * Previously untreated histologically documented unresectable, locally advanced, or metastatic gastric, GEJ, or distal esophagus (distal third of the esophagus) adenocarcinoma * Positive CLDN18.2 expression, as determined prospectively by central IHC testing * Confirmed PD-L1 CPS status by central IHC testing and ICI eligibility per investigator judgement is required to determine cohort eligibility as described below: 1. Cohort 1: PD-L1 positive as determined by central IHC testing and the participant is deemed ICI eligible per investigator judgement. 2. Cohort 2: PD-L1 negative as determined by central IHC testing OR the participant is ICI ineligible * ECOG performance status of 0 or 1 with no deterioration to \> 1 over the previous 2 weeks prior to baseline at screening and prior to randomisation. * Minimum life expectancy of ≥ 12 weeks. * At least one lesion (measurable and/or non-measurable) that can be accurately assessed by the investigator based on RECIST 1.1. * Adequate organ and bone marrow function as specified in the protocol * Body weight ≥ 35 kg. * Sex and contraceptive requirements
Exclusion criteria
* Known HER2-positive status * Significant or unstable gastric bleeding and/or untreated gastric ulcers. * Active or history of autoimmune or inflammatory disorders requiring systemic treatment with steroids or other immunosuppressive treatment or assessed by investigator as not appropriate to participate due to undue risk are excluded. * CNS pathology * Clinically significant pleural effusions or ascites and/or pleural effusions or ascites that require drainage, peritoneal shunt, or indwelling catheter/drain. * Require parenteral nutrition support due to gastric or gastrointestinal obstruction. * Peripheral neuropathy, sensory or motor, ≥ CTCAE Grade 2 at screening. * Persistent toxicities caused by previous anticancer therapy excluding alopecia, not yet improved to Grade ≤ 1 or baseline. * Cardiac abnormalities as outlined in the protocol * Uncontrolled diabetes or diabetic neuropathy within 3 months prior to randomisation. * Infectious disease including active hepatitis A infection; uncontrolled hepatitis B and/or chronic or active hepatitis B with HBV DNA ≥ 100 IU/mL; Known chronic, active, or uncontrolled hepatitis C; HIV infection that is not well controlled * Known partial or total DPD enzyme deficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) (Cohort 1 and Cohort 2) | Up to approximately 5 years | PFS is defined as time from randomisation until progression per RECIST 1.1, or death due to any cause, whichever occurs first. |
| Overall Survival (OS) (Cohort 1) | Up to approximately 5 years | OS is defined as the time from randomisation until the date of death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) (Cohort 2) | Up to approximately 5 years | OS is defined as the time from randomisation until the date of death due to any cause. |
| Overall Survival (OS) (Cohort 1) | Up to approximately 5 years | OS is defined as time from randomisation until date of death due to any cause. Arm B versus C. |
| Progression Free Survival (PFS) (Cohort 1) | Up to approximately 5 years | PFS is defined as time from randomisation until progression per RECIST 1.1 or death due to any cause, whichever occurs first. Arms B versus C. |
| Objective Response Rate (ORR) (Cohort 1 and Cohort 2) | Up to approximately 5 years | ORR is defined as the proportion of participants who have a confirmed CR or confirmed PR, per RECIST 1.1. |
| Duration of Response (DoR) (Cohort 1 and Cohort 2) | Up to approximately 5 years | DoR (per RECIST 1.1) is derived for confirmed objective responses (CR or PR) only and is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of disease progression (ie, date of PFS event - date of first response + 1). |
| Pharmacokinetics of sonesitatug vedotin (Cohort 1 and Cohort 2) | Up to approximately 5 years | Pharmacokinetic parameters of sonesitatug vedotin (peak plasma concentration (Cmax)) |
| Immunogenicity of sonesitatug vedotin (Cohort 1 and Cohort 2) | Up to approximately 5 years | Presence of ADAs for sonesitatug vedotin in serum (confirmatory results: positive or negative, titres). |
| Pharmacokinetics of rilvegostomig (Cohort 1) | Up to approximately 5 years | Pharmacokinetic parameters of rilvegostomig (peak plasma concentration (Cmax)) |
| Immunogenicity of rilvegostomig (Cohort 1) | Up to approximately 5 years | Presence of ADAs for rilvegostomig in serum (confirmatory results: positive or negative, titres). |
| Safety and tolerability (Cohort 1 and Cohort 2) | Up to approximately 5 years | Safety and tolerability as evaluated in terms of incidence of AEs and SAEs |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, Germany, Hungary, India, Italy, Japan, Poland, Puerto Rico, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed