Tremelimumab with Durvalumab to Increase Immune Cells in Patients with Resectable or Locally Advanced Unresectable MSI-Stable or pMMR Esophageal, Gastroesophageal Junction and Gastric Adenocarcinoma with ARID1A Mutations

Inclusion Criteria

• Histologically proven adenocarcinoma of the esophagus, GEJ, or the stomach with ARID1a mutation either by liquid biopsy (ctDNA) or tissue next generation sequencing (NGS)/whole-exome sequencing (WES)
• Resectable or locally advanced unresectable disease
• Patients must be willing to undergo repeat esophagogastroduodenoscopy (EGD) biopsy
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• MSI stable or pMMR
• Age ≥ 18 years at time of study entry, female or male
• Body weight > 66 pounds
• 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 (e.g., Health Insurance Portability and Accountability Act in the United States [US], 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 * Both men and women and members of all races and ethnic groups are eligible for this trial. Non English speaking, deaf, hard of hearing and illiterate individuals are eligible for this trial
• 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
• Must have a life expectancy of at least 12 weeks
• Leukocytes ≥ 3,000/mcL
• Hemoglobin ≥ 8.0 g/dL
• Absolute neutrophil count ≥ 1,000/mcL
• Platelets ≥ 75,000/mcl
• Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional upper limit of normal
• Creatinine clearance (CL) > 40 mL/min or calculated creatinine clearance CL> 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance

Exclusion Criteria

• Patients with known metastatic disease
• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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 durvalumab or tremelimumab may be included only after consultation with the study physician
• Prior systemic treatment for esophagus, GEJ, or the stomach adenocarcinoma
• Patients with uncontrolled autoimmune disease per investigator discretion
• Inability or refusal to undergo biopsy procedures to obtain tissue samples
• Uncontrolled ongoing illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements substantially increase risk of incurring adverse events (AEs) or compromise the ability of the patient to give written informed consent
• History of another primary cancer within the last 3 years with the exception of * Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of investigational product (IP) and of low potential risk for recurrence * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Early-stage prostate cancer * Adequately treated carcinoma in-situ without evidence of disease * Other malignancies which do not require active treatment and will not interfere with study procedures based on investigator assessment are allowed
• History of leptomeningeal carcinomatosis
• Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements
• Patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab and tremelimumab combination therapy
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
• 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
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
• 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 allogeneic organ transplantation
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients without active disease in the last 5 years may be included but only after consultation with the study physician * Patients with celiac disease controlled by diet alone
• Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an magnetic resonance imaging (MRI) (preferred) or CT each preferably with IV contrast of the brain prior to study entry. Brain metastases will not be recorded as Response Evaluation Criteria in Solid Tumors (RECIST) target lesions at baseline if study allows patients with brain mets. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging (RECIST for details on the imaging modality) obtained during the screening period or identified prior to signing the ICF. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of ≤ 10mg/day of prednisone or its equivalent and anti-convulsants for at least 14 days prior to the start of treatment. Brain metastases will not be recorded as RECIST target lesions at baseline
• Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). Adjust wording as necessary and consider evaluating at screening for studies with known hepatotoxicity or other relevant requirements. * Participants co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus (HDV), namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBV deoxyribonucleic acid [DNA]); AND * HCV positive (presence of anti-HCV antibodies); OR * HDV positive (presence of anti-HDV antibodies)
• Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice)
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) * Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP * Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment
• Patients who have received prior anti–PD-1, anti–PD-L1 or anti–CTLA-4: * Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy * All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study * Must not have experienced a ≥ grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤ grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic * Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day
• Known allergy or hypersensitivity to IP or any excipient
• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms calculated from 3 electrocardiograms (ECGs) (within 15 minutes at 5 minutes apart) <<for durvalumab monotherapy and durvalumab and tremelimumab combination studies this criterion can be removed. For durvalumab +- tremelimumab in combination with an agent with pro-arrhythmic potential or where effect of the combination on QT is not known if this criterion should be retained. Patient safety and the cardiac statokinesigram (SKG) should be consulted as needed>>