Local and Systemic Immune Modulation by Rilvegostomig (AZD2936) in the Treatment of Advanced Gastric Cancer (RILVE Project)

Inclusion criteria

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (eg, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Age > 18 years at time of study entry.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Body weight >30 kg.
• Histologically confirmed gastric or gastroesophageal junction adenocarcinoma.
• Unresectable or metastatic gastric cancer or gastroesophageal junction with no previous systemic therapy for advanced disease.
• IHC of PD-L1 CPS>=1 and HER2-negative.
• Prior curative intent treatment (surgery and, if given in the adjuvant setting, chemotherapy and/or radiation) is permitted, regardless of time to recurrence, provided that no prior immunotherapy was administered in the curative or perioperative setting.
• At least one lesion that qualifies as a RECIST 1.1 measurable target lesion at baseline. However, patients without measurable lesions, but with evaluable disease, would be accepted (e.g.; those patients with advanced disease with peritoneal metastasis).
• At least one lesion amenable to biopsy must be present.
• Adequate normal organ and marrow function as defined below:

• Haemoglobin ≥9.0 g/dL(5.59 mmol/L) with no blood transfusions (packed red blood cells) within 14 days prior to first dose.
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1,500 per mm3), with no growth factor support within 14 days prior to first dose.
• Platelet count ≥ 100 × 109/L (100,000 per mm3) with no platelet transfusions within 14 days prior to first dose.
• Serum bilirubin ≤ 1.5 × ULN in the absence of Gilbert's syndrome, ≤ 3 × ULN if the patient has Gilbert's syndrome.
• AST (SGOT)/ALT (SGPT) ≤ 3 × ULN, ≤ 5 × ULN in the case of liver metastasis.
• Measured creatinine clearance (CL) ≥ 45 mL/minute or Calculated creatinine CL>45 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
• Left ventricle ejection fraction (LVEF) ≥ 50% by echocardiogram or multi-gated acquisition (MUGA) scan (performed at screening; historical assessment within 3 months prior to first dose is acceptable if available).
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
• Patient is willing to comply with the following Reproduction and Contraception guidance:

Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Refer to Contraception Guidance for definitions of women of childbearing potential and highly effective methods of contraception.

Female patients of childbearing potential:

• Must have negative pregnancy test at screening and prior to each administration of investigational product.
• If sexually active with a non-sterilized male partner, must use at least 1 highly effective method of birth control from screening until the required contraception period after the last dose of study treatment received, i.e., 60 days after the last dose of rilvegostomig, 4 months after the last dose of pembrolizumab, or 6 months after the last dose of chemotherapy, as applicable and in accordance with local labeling.
• Non-sterilized male partners of female patients of childbearing potential must use a male condom plus spermicide (if not available, a male condom without spermicide is acceptable) from screening until the applicable contraception period after the last fose of study treatment received (i.e., 60 days after the last fose of rilvegostomig, 4 months after the last dose of pembrolizu,ab, or 6 months after the last dose of chemotherapy). Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
• Must not breastfeed and must not donate, or retrieve for their own use, ova from screening to 60 days after the last dose of investigational product.

Non-sterilized male patients who are sexually active with a female partner of childbearing potential:

• Non-sterilized male patients who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide (if not available, a male condom without spermicide is acceptable) from screening until the applicable contraception period after the last dose of stdy treatment received (60 days after livegostomig, 4 monhts after pembroliumab, or 6 months after chemotherapy). Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
• Female partners (of childbearing potential) of a male patient also must use at least 1 highly effective method of contraception (see Contraception Guidance) throughout this period.
• Male patients must refrain from fathering a child or donating sperm during the study and for the applicable contraception period after the last dose of study treatment received.
• As judged by investigator, no contradictions for FOLFOX or CAPOX.

Exclusion criteria

• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Non-adenocarcinoma histological subtypes.
• Active or ongoing interstitial lung disease/pneumonitis (of any grade), serious chronic gastrointestinal conditions associated with diarrhoea, primary immunodeficiency, or active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment.
• Any severe or uncontrolled systemic diseases which, in the investigator's opinion, makes it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol, including psychiatric illness/social situations and substance abuse.
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Rilvegostomig may be included only after consultation with the Study Physician.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Palliative radiotherapy with a limited field of radiation within 3 weeks of the first dose of study intervention.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of treatment. Intranasal, inhaled, or topical steroids and doses below 10mg/24h or prednisone are allowed.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• History of organ transplant or allogenic stem cell transplant.
• Active or prior documented autoimmune disorders or inflammatory disorders requiring chronic systemic treatment with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs. Patients receiving replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) can be enrolled at the discretion of the investigator. t
• History of another primary malignancy, except for malignancy treated with curative intent and with no known active disease ≥ 3 years before the first dose of study intervention and of low potential risk for recurrence, basal cell carcinoma of the skin, squamous cell carcinoma of the skin or lentigo maligna that has undergone potentially curative therapy or adequately treated carcinoma in situ without evidence of disease.
• History of leptomeningeal carcinomatosis or central nervous metastases.
• Known to have tested positive for HIV or active tuberculosis infection.
• Evidence of any of the following infections:

• Hepatitis B infection with anti-HBc IgM positive and/or HBV DNA ≥ 2000 IU/ml. Patients with hepatitis B infection who are anti-HBc total positive and HBV DNA < 2000 IU/mL can be included provided they receive antiviral prophylaxis and are managed for their HBV status.
• Active hepatitis C infection defined as: anti-HCV positive with HCV RNA detectable, or anti-HCV positive with HCV RNA undetectable less than 12 weeks following treatment for HCV.

Patients who are anti-HCV positive with HCV RNA undetectable for least 12 weeks, either due to successful treatment, or spontaneous clearance of HCV infection, are eligible. These patients do not need periodic testing of HCV RNA on study, unless clinically indicated.

• Any other active or uncontrolled infection requiring systemic treatment that has not resolved by the time of study assignment.
• Any of the following cardiac conditions as determined by the investigator:

• Complex ventricular arrhythmia (such as multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3).
• Symptomatic heart failure (as defined by New York Heart Association class ≥ 3).
• Cardiomyopathy of any etiology or history of myocarditis.
• Myocardial infarction or unstable angina within the past 6 months.
• Uncontrolled hypertension.
• Mean resting corrected QT interval > 470 ms, obtained from triplicate ECGs performed at screening.
• History of QT prolongation associated with other medications that required discontinuation of that medication.
• Congenital long QT syndrome], family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
• History of symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on investigator's judgement with cardiologist consultation recommended.
• Left ventricular ejection fraction (LVEF) < 50% by echocardiogram or MUGA at screening
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Pregnant or breastfeeding or intend to become pregnant during the study.