A Phase II a Study of Lenvatinib, a Multi-targeted Tyrosine Kinase Inhibitor, Combined With Pembrolizumab (PD-1 Inhibitor) for the Treatment of Metastatic Gastroesophageal Cancer Patients Who Have Progressed on First or Subsequent Line Therapies

Inclusion Criteria

• Be willing and able to provide written informed consent/assent for the trial.
• Be greater than 18 years of age on day of signing informed consent.
• Have histologically or cytologically confirmed metastatic or recurrent gastric or GEJ adenocarcinoma.
• Have measurable disease based on RECIST 1.1.
• Must have received and have progressed, or are intolerant to at least one systemic regimen (platinum- or fluoropyrimidine-based chemotherapy regimen for metastatic or recurrent disease.)
• If Her2 positive, must have received and have progressed or are intolerant to treatment with trastuzumab for metastatic or recurrent disease.
• Subjects must consent to provide archival tumor tissue (initial and subsequent tumor biopsy samples, if possible) for correlative biomarker studies.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.
• Adequately controlled blood pressure with or without antihypertensive medications defined as BP 1+ proteinuria on urine dipstick testing will undergo 24h urine collection for quantitative assessment of proteinuria. Subjects with urine protein >1g/24h will be ineligible.
• Gastrointestinal malabsorption or any other condition in the opinion of the investigator that might affect the absorption of lenvatinib.
• Prolongation of QTcF interval to >480ms
• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug.
• Bleeding disorders or active significant bleeding (i.e. hemoptysis, hematochezia, hematemesis) within 3 weeks.
• Thrombotic disorders or use of anticoagulants, such as warfarin, requiring therapeutic international normalized ratio (INR) monitoring. (treatment with low molecular weight heparin (LMWH) or direct acting oral anti-coagulants is allowed.)
• History of prior gastrointestinal fistula and/or perforation.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has a known history of Human Immunodeficie