Bemarituzumab in patients with FGFR2b-positive advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction, who failed at least one prior line of palliative chemotherapy - The IKF-AIO Phase IIa BEMARA trial

Prior treatment

• Patient received prior treatment any selective inhibitor of the FGF-FGFR pathway or participated in a study that randomized to FGFR-targeted therapy/placebo.
• Patient has a serious infection requiring oral or IV antibiotics within 14 days prior to trial enrollment.
• Patient experienced severe, life-threatening, or recurrent (Grade 2 or higher) immune-mediated adverse events (AEs) or infusion-related reactions including those that led to permanent discontinuation while on treatment with immune-oncology agents
• Patient received prior immunosuppressive therapy: immunosuppressive doses of systemic medications of > 10 mg/day of prednisone or equivalent must be discontinued ≥ 2 weeks before the first dose of study treatment. Short courses of high dose corticosteroids and/or continuous low dose of prednisone (< 10 mg/day) are permitted. In addition, inhaled, intranasal, intraocular, and/or joint injections of corticosteroids are allowed
• Patients has evidence of any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect
• Patient has known presence of tumors other than adenocarcinomas (e.g., leiomyosarcoma, lymphoma) or a secondary tumor other than squamous or basal cell carcinomas of the skin or in situ carcinomas of the cervix which have been effectively treated. The sponsor decides to include patients who have received curative treatment and have been disease-free for at least 5 years.
• Patient receives simultaneous, ongoing, systemic immunotherapy, chemotherapy, hormone therapy or investigational treatment not described in the study protocol.
• Patient received chemotherapy, radiotherapy (in which the field encompassed a planned injection site), biological cancer therapy, investigational treatment or major surgery within 28 days before enrollment, or if AEs resulting from cancer therapy administered more than 28 days prior to enrollment have not resolved to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1.
• Patient receives simultaneous treatment with a different anti-cancer therapy (including investigational treatment) other than that provided for in the trial (excluding palliative radiotherapy for symptom control).
• Patient has known untreated or symptomatic CNS or leptomeningeal metastases. Subjects with asymptomatic CNS metastases are eligible if clinically stable for ≥ 4 weeks and require no intervention (including use of corticosteroids). Subjects with treated brain metastases are eligible provided the following criteria are met: a. Definitive therapy was completed at least 2 weeks prior to the first planned dose of trial treatment (stereotactic radiosurgery at least 7 days prior to first planned dose of study treatment) b. At least 7 days prior to first dose of trial 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

Other illness

• Patient has evidence of or any ongoing ophthalmological disorders. a. History of systemic disease or ophthalmologic disorders requiring chronic use of ophthalmic steroids b. Evidence of any ongoing ophthalmologic abnormalities or symptoms that are acute (within 4 weeks) or are actively progressing c. Unwillingness to avoid use of contact lenses during study treatment and for ≥ 100 days after the end of treatment d. Recent (within 6 months) corneal surgery or ophthalmic laser treatment or recent (within 6 months) history of, or evidence of, corneal defects, corneal ulcerations, keratitis, or keratoconus, or other known abnormalities of the cornea that may pose an increased risk of developing a corneal ulcer
• Patient has an acute or chronic infection with human deficiency virus (HIV), or an acute infection with hepatitis B or C virus (HBV, HCV). Exception: Subjects with hepatitis B surface antigen or core antibodies who achieve a sustained virologic response with antiviral therapy directed against hepatitis B and subjects with hepatitis C, who achieve a sustained virologic response following antiviral therapy are permitted.
• Patient has known allergic / hypersensitive reactions to at least one of the treatment components

Lab values

• Patient has impaired cardiac function or clinically significant cardiac disease including unstable angina within 6 months before the first dose of study treatment, acute myocardial infarction < 6 months prior to the 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 mmHg despite optimal treatment, uncontrolled cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin, active coronary artery disease or corrected QT interval (QTc) ≥ 470

Other

• Female patient is pregnant or breast feeding or planning to become pregnant within and up to 4 months after end of treatment (if enrolled to Cohort 1) or up to 6 months after the end of treatment (if enrolled to Cohort 2 or 3).
• Contraindication for standard of care (SOC) treatment regimen chosen by investigator (irinotecan, paclitaxel plus ramucirumab or trifluridine/tipiracil) according to specific product information or clinical standards
• Patient has squamous/ adenosquamous cell carcinoma of the stomach or gastroesophageal junction.

• Patient* provide signed informed consent form.
• Patient has adequate hematological, hepatic and renal function a. Absolute number of neutrophils (ANC) ≥ 1.5 x 109/L b. Platelets ≥ 100 x 109/L c. Hemoglobin ≥ 9 g/dL (5.58 mmol/L), without transfusion support within 7 days before the first dose of study treatment d. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (or < 2 x ULN in case of liver involvement or Gilbert’s disease) e. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN without existing liver metastases, or ≤ 5 x ULN in the presence of liver metastases; AP ≤ 5 x ULN f. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (measured by 24 h urine) ≥ 50 mL/min (i.e., if serum creatinine level is > 1.5 x ULN, then a 24 h urine test must be performed to check the creatinine clearance to be determined).
• Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy).
• Female patients of childbearing potential, as defined in Section 5.1.7, or male patients with female partners of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year (see Section 5.1.7) during the treatment period and for at least 6 months after the last trial treatment. Male patients must agree not to donate sperm within the same period. Male patients with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy. Female patients of child-bearing potential must have a negative pregnancy test within the last 7 days prior to the start of trial therapy.
• Patient is willing and able to comply with the protocol (including contraceptive measures) for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Patient is ≥ 18 years at the time of given informed consent.
• Patient has been diagnosed with histologically proven advanced or metastatic adenocarcinoma of the stomach or of the gastroesophageal junction, which is not amenable to potentially curative resection. Primary tumor locations will be classified following AJCC/UICC 8thed.
• Patient has measurable disease or non-measurable, but evaluable disease, according to RECIST v1.1
• Patient received at least one previous line of treatment, which includes a fluoropyrimidine and a platinum in the advanced setting, or the patient has been intolerable or ineligible to fluoropyrimidine and/or platinum. Neoadjuvant/adjuvant treatment is not counted unless progression occurs <6 months after completion of the treatment. In these cases, neoadjuvant/adjuvant treatment is counted as one line of therapy. 5. Note: patient allocation to cohort 3 only if patient received at least two previous lines of treatment.
• Tumor material (archival and/or fresh) is available for centrally FGFR2b testing performed by IHC. • FGFR2b-selected population using 2+/3+ definition in ≥ 10% tumor cells.
• Patients with HER2/neu-positive tumors are eligible if they received prior HER2/neu-targeted therapy.
• Patient has an ECOG performance status ≤ 1
• Patient has a life expectancy > 12 weeks