Efficacy of Zolbetuximab Plus mFOLFOX6 Versus Placebo Plus mFOLFOX6 in Claudin 18.2-Positive, HER2-Negative Metastatic Gastric or GEJ Adenocarcinoma
- Trial ID
- 2024-511365-11-00
- Protocol
- 8951-CL-0301
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of zolbetuximab plus mFOLFOX6 compared with placebo plus mFOLFOX6 as a first-line treatment, as measured by **Progression-Free Survival (PFS)** in subjects with Claudin (CLDN)18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma. This is clinically relevant as it aims to determine the potential of zolbetuximab in improving PFS, which is a critical endpoint in assessing the effectiveness of cancer therapies.
Secondary objectives include: - Evaluating efficacy as measured by Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DOR), Time to Progression (TTP), and Disease Control Rate (DCR). - Assessing physical function (PF), OG25-Pain, and Global Health Status/Quality of Life (GHS/QoL) scores using EORTC questionnaires. - Evaluating safety and tolerability of zolbetuximab. - Assessing health-related quality of life (HRQoL) using additional parameters measured by EORTC QLQ-C30, QLQ-OG25, Global Pain (GP), and EuroQOL Five Dimensions Questionnaire 5L (EQ5D-5L). - Evaluating pharmacokinetics and immunogenicity profile of zolbetuximab. - Evaluating PFS following subsequent anti-cancer treatment (PFS2). - Evaluating potential genomic and/or other biomarkers that may correlate with treatment outcome to zolbetuximab and mFOLFOX6. - Evaluating Health Resource Utilization (HRU).
Participants
The clinical trial involves a total of **356 participants** diagnosed with **metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma**. The study population includes both male and female subjects, with an age range that encompasses adults as defined by local regulations, typically starting from 18 years of age. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of gastric or GEJ adenocarcinoma and radiologically confirmed locally advanced unresectable or metastatic disease. The trial population is characterized by a requirement for a known HER2-negative tumor and a tumor expression of CLDN18.2 in at least 75% of tumor cells. Subjects are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree not to participate in another interventional study while on study treatment. The trial includes vulnerable populations, and both male and female subjects must adhere to specific contraceptive guidelines to prevent pregnancy during and after the study period. The health status of participants is generally stable, with laboratory tests confirming adequate organ function and a predicted life expectancy of approximately 12 weeks as assessed by the investigator.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **zolbetuximab** in combination with mFOLFOX6 compared to a placebo with mFOLFOX6 in patients with **Claudin (CLDN)18.2-positive**, **HER2-negative**, locally advanced unresectable or metastatic **gastric or gastroesophageal junction (GEJ) adenocarcinoma**. The primary objective is to assess progression-free survival (PFS), with secondary endpoints including overall survival (OS), time to confirmed deterioration (TTCD), overall response rate (ORR), duration of response (DOR), safety, tolerability, health-related quality of life (HRQoL), pharmacokinetics, and immunogenicity of zolbetuximab. The trial is expected to conclude by March 31, 2025, with recruitment having commenced on September 24, 2018.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis, radiologically confirmed disease, and specific laboratory test results. Following randomization, participants will receive treatment and attend regular follow-up visits to monitor efficacy and safety outcomes. The end-of-study visit will occur after the completion of the treatment period or upon early termination. The expected duration of participant involvement is up to three months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.
Throughout the trial, participants will receive the investigational product, **ASP8951** (zolbetuximab), administered as a **powder for concentrate for solution for infusion**, alongside **Sodium Chloride 0.9% Intravenous Infusion BP**. The maximum daily dose is set at 800 mg/m², with the same limit for the total dose over the treatment period. The trial is conducted under the oversight of an Institutional Review Board (IRB) or Independent Ethics Committee (IEC), ensuring compliance with ethical standards and regulatory requirements. Participants are required to adhere to specific contraceptive measures and agree not to participate in other interventional studies during the trial period.
Treatment
The clinical trial involves the administration of **zolbetuximab**, an investigational medication, under the product name ASP8951. Zolbetuximab is provided in the pharmaceutical form of a **powder for concentrate for solution for infusion**. The medication is administered via **intravenous use**. The dosing regimen specifies a maximum daily dose of 800 mg/m², with the same maximum total dose amount, over a treatment period of up to 3 weeks. Zolbetuximab is of biological/biotechnological origin and is classified as a protein of other origin. The product is developed by Astellas Pharma Global Development, Inc. and is designated as an orphan drug under the number EU/3/10/803.
In addition to the experimental treatment, the study utilizes **Sodium Chloride 0.9% Intravenous Infusion BP** as a non-experimental treatment. This solution for infusion serves as a placebo or comparator treatment. Sodium chloride is a chemical substance and is administered through infusion. The maximum daily and total dose amounts are aligned with those of the experimental medication, set at 800 mg/m², over a maximum treatment period of 3 weeks. The product is manufactured by Baxter Holding B.V. and is authorized for use in the trial.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, which is defined as the time from the date of randomization until the date of radiological progression of disease (PD) or death from any cause, whichever occurs first. This will be evaluated using the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 by an independent review committee (IRC). Secondary endpoints include Overall Survival (OS), which measures the time from randomization to death from any cause, and Time to Confirmed Deterioration (TTCD) using the PF, OG25-Pain, and GHS/QoL scores as measured by the EORTC QLQ-C30 and QLQ-OG25. TTCD is defined as the time from randomization to the first clinically meaningful deterioration confirmed at the next scheduled visit.
Additional secondary endpoints include Objective Response Rate (ORR), defined as the proportion of subjects achieving a best overall response of complete response (CR) or partial response (PR) as assessed by IRC per RECIST 1.1, and Duration of Response (DOR), which is the time from the first response (CR/PR) to PD or death. Safety and tolerability will be monitored through adverse events (AEs), laboratory test results, vital signs, ECGs, and Eastern Cooperative Oncology Group (ECOG) performance status. Health-related quality of life (HRQoL) will be assessed using EORTC QLQ-C30, QLQ-OG25 plus GP, and EQ5D-5L questionnaires. Pharmacokinetics of zolbetuximab will be evaluated by measuring Ctrough levels, and immunogenicity will be assessed by the frequency of antidrug antibody (ADA) positive subjects.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] Authorization for US sites) must be obtained from the subject or legally authorized representative (if applicable) prior to any study-related procedures
- Subject is considered an adult (e.g., ≥ 18 years of age in the US) according to local regulation at the time of signing the informed consent
- Subject agrees not to participate in another interventional study while on study treatment
- Female subject is eligible to participate if she is not pregnant (negative serum pregnancy test at Screening; female subjects with elevated serum beta human chorionic gonadotropin (βhCG) and a demonstrated non-pregnant status through additional testing are eligible) and at least 1 of the following conditions applies: a.Not a woman of childbearing potential (WOCBP) as defined in Appendix 12.3 Contraception Requirements OR b. WOCBP who agrees to follow the contraceptive guidance as defined in Appendix 12.3 Contraception Requirements throughout the treatment period and for 9 months after the final administration of oxaliplatin and 6 months after the final administration of all other study drugs
- Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 6 months after the final study treatment administration
- Female subject must not donate ova starting at Screening and throughout the study period, and 9 months after the final administration of oxaliplatin and for 6 months after the final administration of all other study drugs
- A sexually active male subject with female partner(s) who are of childbearing potential must agree to use contraception as detailed in Appendix 12.3 Contraception Requirements during the treatment period and for at least 6 months after the final study drug administration
- Male subject must not donate sperm starting at Screening and throughout the study period and for 6 months after the final study drug administration
- Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or for the time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration
- Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma
- Subject has radiologically confirmed locally advanced unresectable or metastatic disease within 28 days prior to randomization
- Subject has radiologically evaluable disease (measurable and/or nonmeasurable disease according to RECIST 1.1), per local assessment, ≤ 28 days prior to randomization. For subjects with only 1 evaluable lesion and prior radiotherapy ≤3 months before randomization, the lesion must either be outside the field of prior radiotherapy or have documented progression following radiation therapy
- Subject's tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing
- Subject has a known HER2-negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen. (Unique to China: Subject has a known HER2-negative gastric or GEJ tumor)
- Subject has ECOG performance status 0 to 1
- Subject has predicted life expectancy ~12 weeks in the opinion of the investigator
- Subject must meet all of the following criteria based on the centrally or locally analyzed laboratory tests collected within 14 days prior to randomization. In the case of multiple sample collections within this period, the most recent sample collection with available results should be used to determine eligibility. a.Hemoglobin (Hgb) ≥ 9 g/dL. Subjects requiring transfusions are eligible if they have a post-transfusion Hgb ≥ 9 g/dL. b.Absolute neutrophil count ≥ 1.5 x 109/L c.Platelets ≥ 100 x 109/L d.Albumin ≥ 2.5 g/dL e.Total bilirubin ≤ 1.5 x upper limit of normal (ULN) without liver metastases (or < 3.0 x ULN if liver metastases are present) f.Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN without liver metastases (or ≤ 5 x ULN if liver metastases are present) g.Estimated creatinine clearance ≥ 30 mL/min h.Prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
Exclusion Criteria
- Subject has received prior systemic chemotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. However, subject may have received either neo-adjuvant or adjuvant chemotherapy, immunotherapy or other systemic anticancer therapies, as long as it was completed at least 6 months prior to randomization. Subject may have received treatment with herbal medications that have known antitumor activity > 28 days prior randomization
- Per investigator judgment, subject has significant gastric bleeding and/or untreated gastric ulcers that exclude the subject from participation
- Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive HBs Ag) or C infection. NOTE: Screening for these infections should be conducted per local requirements. a.For subjects who are negative for HBs Ag, but HBc Ab positive, an HB DNA test will be performed and if positive, the subject will be excluded. b.Subjects with positive hepatitis C (HCV) serology, but negative HCV RNA test are eligible. c.Subjects treated with HCV with undetectable viral load results are eligible
- Subject has an active autoimmune disease that has required systemic treatment within the past 3 months prior to randomization
- Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization
- Subject has significant cardiovascular disease, including any of the following: a.Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to randomization. b.History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointesc. QTc interval > 450 msec for male subjects: QTc interval > 470 msec for female subjects d.History or family history of congenital long QT syndrome e.Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate controlled atrial fibrillation for > 1 month prior to randomization are eligible)
- Subject has a history of central nervous system metastases and/or carcinomatous meningitis from gastric/GEJ cancer
- Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma ≤ 14 days prior to randomization and recovered from any related toxicit
- Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subjects using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of systemic corticosteroids, or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed
- Subject has received other investigational agents or devices within 28 days prior to randomization
- Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibodies, including humanized or chimeric antibodies
- Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment
- Subject has prior severe allergic reaction or intolerance to any component of mFOLFOX6
- Subject has known dihydropyrimidine dehydrogenase deficiency (DPD). (NOTE: Screening for DPD deficiency should be conducted per local requirements)
- Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting
- Subject has known peripheral sensory neuropathy > grade 1 unless the absence of deep tendon reflexes is the sole neurological abnormality
- Subject has had a major surgical procedure 28 days prior to randomization. a.Subject is without complete recovery from a major surgical procedure 14 days prior to randomization
- Subject has psychiatric illness or social situations that would preclude study compliance, per investigator judgment
- Subject has another malignancy for which treatment is required per investigator's clinical judgment
- Subject has any concurrent disease, infection or comorbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data in the opinion of the investigator
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 24 Sept 2018 | 17 |
 France | Not Recruiting | 24 Sept 2018 | 29 |
 Germany | Not Recruiting | 24 Sept 2018 | 14 |
 Italy | Not Recruiting | 24 Sept 2018 | 64 |
 Poland | Not Recruiting | 24 Sept 2018 | 15 |
 Spain | Not Recruiting | 24 Sept 2018 | 71 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ASP8951 | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 800 | 3 | PRD11142563 |
Sodium Chloride 0.9% Intravenous Infusion BP | Test | INTRAVENOUS INFUSION BP | INFUSION | 800 | 3 | PRD7372533 |