Phase 3 Randomized, Double-Blind Study of Bemarituzumab with mFOLFOX6 in FGFR2b-Overexpressing Advanced Gastric or Gastroesophageal Junction Cancer
- Trial ID
- 2023-505457-40-00
- Protocol
- 20210096
- Sponsor
- Amgen Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of bemarituzumab plus mFOLFOX6 to placebo plus mFOLFOX6, as assessed by overall survival (OS) in subjects with FGFR2b ≥ 10% 2+/3+ tumor cell staining. This is clinically relevant as it aims to determine the potential survival benefit of bemarituzumab in patients with previously untreated advanced gastric or gastroesophageal junction cancer with FGFR2b overexpression.
Secondary objectives include:
- Comparing efficacy between treatment arms as assessed by progression-free survival (PFS) and objective response (OR) in FGFR2b ≥ 10% 2+/3+ TC subjects.
- Evaluating the safety and tolerability of bemarituzumab plus mFOLFOX6 compared to placebo plus mFOLFOX6.
- Comparing efficacy of bemarituzumab plus mFOLFOX6 to placebo plus mFOLFOX6 in all randomized subjects as assessed by OS, PFS, and OR.
- Comparing efficacy between treatment arms in FGFR2b ≥ 10% 2+/3+ TC subjects as assessed by duration of response (DOR) and disease control.
- Assessing patient-reported outcomes and Quality of Life (QoL) outcomes in FGFR2b ≥ 10% 2+/3+ TC subjects.
- Characterizing the pharmacokinetics (PK) of bemarituzumab in combination with mFOLFOX6.
- Characterizing the immunogenicity of bemarituzumab.
Participants
The clinical trial involves a total of **173 participants** diagnosed with **previously untreated advanced gastric or gastroesophageal junction cancer** with FGFR2b overexpression. The study population includes both male and female subjects aged 18 years and older, with a focus on individuals who have histologically documented gastric or GEJ adenocarcinoma that is unresectable, locally advanced, or metastatic. Participants were selected based on specific criteria, including an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and adequate organ function. The trial includes a vulnerable population, and subjects must have no contraindications to mFOLFOX6 chemotherapy. Lifestyle factors such as diet and physical activity are not specified, but participants must have measurable or evaluable disease according to RECIST v1.1. The selection process ensures that all participants have provided informed consent and meet the necessary health requirements for trial inclusion.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** Phase 3 study designed to evaluate the efficacy of **bemarituzumab** in combination with chemotherapy compared to a placebo with chemotherapy in subjects with previously untreated advanced gastric or gastroesophageal junction cancer with FGFR2b overexpression. The primary objective is to assess overall survival, while secondary endpoints include objective response, treatment-emergent adverse events, and progression-free survival. The trial is expected to conclude by August 2025, with recruitment having commenced in November 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological documentation of the cancer type, and adequate organ function. Following randomization, participants will receive either bemarituzumab plus mFOLFOX6 or placebo plus mFOLFOX6, administered via **intravenous use**. The trial includes regular follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is determined by the maximum treatment period, which varies depending on the specific chemotherapy regimen, with bemarituzumab treatment lasting up to 97 days. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants will be closely monitored throughout the trial to ensure safety and adherence to the protocol.
Treatment
**Bemarituzumab** is the primary experimental medication used in this clinical trial. It is administered as a **solution for infusion** and is delivered via **intravenous use**. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 15 mg/kg and a total maximum dose of 743 mg/kg over the treatment period. The maximum treatment period for Bemarituzumab is 97 days. This investigational drug is a protein-based therapeutic agent developed by Amgen Inc., and it is also known by the sponsor product code AMG 552. The study aims to evaluate its efficacy in combination with chemotherapy in subjects with advanced gastric or gastroesophageal junction cancer exhibiting FGFR2b overexpression.
The trial also includes a **placebo** group, where participants receive a placebo solution in place of Bemarituzumab. The placebo is designed to match the experimental drug in appearance and administration method, ensuring the study remains double-blind. The placebo is administered intravenously, similar to the active treatment, to maintain consistency in the trial protocol.
**Fluorouracil** is used as part of the standard chemotherapy regimen in this study. It is provided as a **solution for infusion** and administered intravenously. The dosing is based on body surface area, with a maximum daily dose of 2800 mg/m² and a total maximum dose of 218,400 mg/m² over a treatment period of up to 155 days. Fluorouracil is classified as an antineoplastic agent and plays a critical role in the chemotherapy regimen.
**Oxaliplatin** is another component of the chemotherapy regimen, also administered as a **solution for infusion** via intravenous use. The dosing is calculated based on body surface area, with a maximum daily dose of 85 mg/m² and a total maximum dose of 2465 mg/m². The maximum treatment period for Oxaliplatin is 58 days. It is an antineoplastic agent used to enhance the efficacy of the chemotherapy protocol.
**Folinic Acid** is included in the treatment regimen to mitigate the cytotoxic effects of chemotherapy. It is administered as a **solution for infusion** through intravenous use. The dosing is based on body surface area, with a maximum daily dose of 400 mg/m² and a total maximum dose of 28,800 mg/m² over a treatment period of up to 143 days. Folinic Acid is used to support patients undergoing chemotherapy by reducing potential side effects.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the endpoint of **overall survival (OS)**, defined as the time from randomization until death from any cause. Subjects who are still alive at the time of analysis will be censored at the date they were last known to be alive. Secondary endpoints include objective response, treatment-emergent adverse events, progression-free survival, and disease control, among others. Objective response is defined as the best overall response of complete response or partial response as determined by the investigator per RECIST v1.1 criteria.
Additional assessments will include changes in quality of life and symptom scores using validated instruments such as the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the Stomach Cancer-specific module (EORTC-QLQ-STO22). The trial will also evaluate pharmacokinetic parameters for bemarituzumab, including maximum observed concentration and observed concentration at the end of a dose interval, as well as anti-bemarituzumab antibody formation.
Data collection will occur at specified timepoints throughout the trial, with analyses conducted to determine the efficacy of bemarituzumab plus mFOLFOX6 compared to placebo plus mFOLFOX6 in subjects with advanced gastric or gastroesophageal junction cancer exhibiting FGFR2b overexpression. The trial is designed to provide comprehensive insights into the therapeutic potential and safety profile of the investigational treatment regimen.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject has provided informed consent prior to initiation of any study specific activities/procedures.
- Age ≥18 years (or legal adult age within country, whichever is older)
- Histologically documented gastric or GEJ adenocarcinoma (not amenable to curative therapy). Primary tumor location will be classified following the American Joint Committee on Cancer/Union for International Cancer Control [AJCC/UICC] 8th edition.
- Disease that is unresectable, locally advanced, or metastatic (not amenable to curative therapy)
- FGFR2b ≥ 10% 2+/3+ TC as determined by centrally performed IHC testing, based on tumor sample
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- Adequate organ function as follows: absolute neutrophil count ≥ 1.5 x 109/L platelet count ≥ 100 x 109/L hemoglobin ≥ 9 g/dL without red blood cell (RBC) transfusion within 7 days prior to the first dose of study treatment aspartate aminotransferase and ALT < 3x upper limit of normal (ULN) (or < 5 x ULN if liver involvement). Total bilirubin < 1.5 x ULN (or < 2 x ULN if liver involvement; with the exception of subjects with Gilbert's disease) calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute calculated using the formula of Cockcroft and Gault ([140 - Age]) x Mass [kg]/[72 x Creatinine mg/dL]) (x 0.85 if female) international normalized ratio or prothrombin time (PT) < 1.5 x ULN except for subjects receiving anticoagulation, who must be on a stable dose of anticoagulant therapy for 6 weeks prior to enrollment
- Measurable disease or non-measurable, but evaluable disease, according to RECIST v1.1.
- Subject has no contraindications to mFOLFOX6 chemotherapy
Exclusion Criteria
- Untreated or symptomatic central nervous system (CNS) metastases and leptomeningeal disease Subjects with asymptomatic CNS metastases are eligible if clinically stable for at least 4 weeks and do not require intervention (including use of corticosteroids). Subjects with treated brain metastases are eligible provided the following criteria are met: Definitive therapy was completed at least 2 weeks prior to the first planned dose of study treatment (stereotactic radiosurgery at least 7 days prior to first planned dose of study treatment) At least 7 days prior to first dose of study treatment: any CNS disease is clinically stable, subject is off steroids for CNS disease (unless steroids are indicated for a reason unrelated to CNS disease), and subject is off or on stable doses of anti-epileptic drugs
- Unwillingness to avoid use of contact lenses during study treatment
- Major surgical procedure within 28 days prior to first dose of study treatment
- Impaired cardiac function or clinically significant cardiac disease including: unstable angina within 6 months prior to first dose of study treatment, acute myocardial infarction < 6 months prior to first dose of study treatment, New York Heart Association (NYHA) class II-IV congestive heart failure, uncontrolled hypertension (defined as an average systolic blood pressure > 160 mmHg or diastolic > 100 mm Hg despite optimal treatment (measured following European Society for Hypertension/European Society of Cardiology [ESH/ESC] 2018 guidelines); uncontrolled cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, active coronary artery disease, QTc ≥ 470 msec
- Peripheral sensory neuropathy G2 or higher
- Active infection requiring systemic treatment or any uncontrolled infection ≤14 days prior to first dose of study treatment
- Known positive HER2 status (as defined by positive IHC test of 3+ or IHC 2+ with positive in situ hybridization [ISH])
- Known human immunodeficiency virus (HIV) infection with CD4+ T-cell (CD4+) counts < 350 cells/µL, hepatitis C infection (subjects with hepatitis C that achieve a sustained virologic response following antiviral therapy are allowed), or hepatitis B infection (subjects with hepatitis B surface antigen [SAg] or core antibody that achieve sustained virologic response with antiviral therapy directed at hepatitis B are allowed)
- History of interstitial lung disease
- History or evidence of systemic disease or ophthalmological disorders requiring chronic use of ophthalmic corticosteroids
- Evidence of any ongoing ophthalmologic abnormalities or symptoms that are acute (within 4 weeks) or actively progressing
- History of other malignancy within the past 2 years, except: curatively treated non-melanoma skin malignancy cervical cancer in situ curatively treated uterine cancer stage I curatively treated ductal or lobular breast carcinoma in situ and not currently receiving any systemic therapy localized prostate cancer that has been treated surgically with curative intent and presumed cured
- Evidence of, or recent (within 6 months) history of, corneal defects, corneal ulcerations, keratitis, or keratoconus, history of corneal transplant, or other known abnormalities of the cornea that may pose an increased risk of developing a corneal ulcer. Recent (within 6 months) corneal surgery or ophthalmic laser treatment
- Prior treatment for metastatic or unresectable disease except for a maximum of 1 dose of mFOLFOX6 Prior adjuvant, neo-adjuvant, and peri-operative therapy is allowed, if completed more than 6 months prior to the first dose of study treatment Palliative radiotherapy is allowed, provided it has been completed more than 14 days prior to the first dose of study treatment All treatment-related toxicity needs to be resolved to grade ≤ 1 prior to the first dose of study treatment, with the exception of alopecia or toxicities considered irreversible (defined as having been present and stable for > 21 days) which are not otherwise described in the exclusion criteria
- Prior treatment with any selective inhibitor of the FGF-FGFR pathway
- Currently receiving treatment in another investigational device or drug study, or within 28 days of first dose of study treatment or during this clinical study. Other investigational procedures while participating in this study are excluded
- Female subjects of childbearing potential unwilling to use protocol specified method of contraception during treatment and for an additional 9 months after the last dose of protocol-mandated therapy
- Female subjects who are breastfeeding or plan to breastfeed while on study through 3 months after the last dose of protocol-mandated therapy
- Female subjects planning to become pregnant while on study through 9 months after the last dose of protocol-mandated therapy
- Female subjects of childbearing potential with a positive pregnancy test assessed at screening and within 72 hours prior to first dose of study treatment
- Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 6 months after the last dose of protocol-mandated therapy.
- Male subjects unwilling to abstain from donating sperm during treatment and for an additional 6 months after the last dose of protocol-mandated therapy
- Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures within the subject's capacity to the best of the subject and investigator’s knowledge
- History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
- Known allergy, hypersensitivity, or contraindication to components of the bemarituzumab formulation including polysorbate
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 03 Nov 2021 | 6 |
 Bulgaria | Not Recruiting | 03 Nov 2021 | 14 |
 Czechia | Not Recruiting | 03 Nov 2021 | 15 |
 Denmark | Not Recruiting | 03 Nov 2021 | 7 |
 Estonia | Not Recruiting | 03 Nov 2021 | 10 |
 France | Not Recruiting | 03 Nov 2021 | 30 |
 Greece | Not Recruiting | 03 Nov 2021 | 47 |
 Hungary | Not Recruiting | 03 Nov 2021 | 14 |
 Ireland | Not Recruiting | 03 Nov 2021 | 6 |
 Italy | Not Recruiting | 03 Nov 2021 | 45 |
Sites & Investigators
Research 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 |
|---|---|---|---|---|---|---|
OXALIPLATIN | Other | — | INTRAVENOUS USE | 85 | 58 | SUB09490MIG |
Bemarituzumab | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 15 | 97 | PRD10433724 |
Placebo for AMG 552 | Placebo | N/A | — | — | — | N/A |
FLUOROURACIL | Other | — | INTRAVENOUS USE | 2800 | 155 | SUB07721MIG |
FOLINIC ACID | Other | — | INTRAVENOUS USE | 400 | 143 | SUB13910MIG |