Intra-tumoral (IT) Injection of vvDD-hIL2-2-RG-1 for Metastatic Gastrointestinal and Peritoneal Tumors

This is a Phase I, open-label, single dose, dose-escalation trial in subjects with metastatic gastrointestinal tumors who have failed standard systemic chemotherapy or immunotherapy. Gastrointestinal tumors include esophageal cancer (EC), gastric cancer (GC), colon cancer (CC), rectal cancer (RC), liver cancer (LC), and pancreatic cancer (PC)

The vvDD-IL-2 virus was designed to activate T-cells with a goal to reduce systemic toxicity while optimizing immune clearance of tumors following intraperitoneal delivery. Utilizing a platform of a thymidine kinase (tk) and vaccinia growth factor (vgf) deleted oncolytic Western Reserve (WR) strain vaccinia virus (vvDD), vvDD-IL-2 variants have been designed to deliver membrane bound IL-2 into the tumor microenvironment.

All subjects who have refractory tumors will receive the virus at one of the three dose levels in a single dose sequential dose modified toxicity probability interval (mTPI) design. Eligible subjects will receive one needle injection (per tumor) of vvDD-hIL-2-RG-1. A minimum of 28 days observation period must pass after injection of the first subject in each level without experiencing a dose-limiting toxicity (DLT) before administering/injecting the second patient at that dose level. A new dose level will not be initiated until the completion of the 28-day observation period from the administration of the previous dose level.

Inclusion criteria

• Males or females age, 18 to < 70 years at the time of consent
• Histologically confirmed metastases from gastrointestinal tumors with molecular determinants for MSI and KRAS.
• For microsatellite stable (MSS) tumors, subjects must have failed (or be ineligible for) standard 1st and 2nd line chemotherapy. For microsatellite instability-high (MSI-H) tumors, subjects must also have failed (or be ineligible for) systemic immunotherapy.
• Karnofsky Performance Status (KPS) of > 70
• Anticipated survival of at least 12 weeks.
• Written informed consent in accordance with national, local, and institutional guidelines obtained prior to any study procedures (subject or subject's legally authorized representative (LAR) must have the ability to understand and willingness to sign a written informed consent).
• Adequate bone marrow function: WBC > 2,000 and <50,000 cells/mm3, ANC > 1,000 cells/mm3, hemoglobin >8 g/dL, and platelet count >100,000 cells/mm3.
• Adequate renal function: serum creatinine level ≤ 2xULN
• Adequate liver function: Serum bilirubin < 1.5 x ULN
• Acceptable coagulation status: INR < ULN +15%. All patients must be able to suspend anticoagulant therapy for study specific biopsies and intra-tumoral injection.
• Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have negative serum or urine pregnancy test.
• If sexually active, to prevent pregnancy and to prevent the spread of virus, subject must use an acceptable method of contraception as well as barrier contraception from screening through 6 weeks following study treatment with vvDD-hIL-2-RG-1.
• Subjects must be willing to comply with all study procedures, requirements, adhere to post-treatment care instructions and follow-up examinations.
• Have measurable disease based on RECIST 1.1 criteria.
• Have at least one tumor at least 1 cm in diameter amenable to safe intra-tumoral injection.

Exclusion criteria

• Pregnant or nursing an infant.
• Systemic corticosteroid or other immunosuppressive medication use within 2 weeks of the study treatment.
• Significant immunodeficiency (e.g. due to underlying illness and/or medication) in subject or household contacts (must be able to avoid household contact with immunodeficient person for 3 weeks).
• Clinically significant active infection or uncontrolled medical condition (e.g., pulmonary, neurological, cardiovascular, gastrointestinal, genitourinary) considered high risk for investigational new drug treatment, per investigator discretion.
• Active eczema or psoriasis or other inflammatory skin conditions
• Unstable cardiac disease which includes but is not limited to any of the following within 6 months prior to study entry: myocardial infarction (MI), unstable angina, congestive heart failure, myocarditis, ventricular arrhythmias diagnosed and requiring medication.

• New York Heart Association functional class III-IV heart failure on active treatment
• Pulse oximetry of < 90% in room air at rest
• Subjects who have received radiation, chemotherapy or other potentially immunosuppressive therapy within 2 weeks prior to study screening and within 4 weeks prior to anticipated vvDD-hIL-2-RG-1 treatment.
• Experienced a severe systemic reaction or side-effect as a result of a previous smallpox vaccination.
• Subjects who, in the opinion of the Investigator, have a medical condition that would subject the subject to prohibitive risk by participation in this study, or who may be unable to safely complete the required tumor biopsies.
• Subjects with household contacts who are children < 5 years old, have active eczema, psoriasis or other inflammatory skin conditions or have a significant immunodeficiency due to underlying illness (e.g. human immunodeficiency virus) and/or medication (e.g. systemic corticosteroids) will be excluded unless alternate living arrangements can be made during the subject's active dosing period and for three weeks following the study medication.
• Vaccination with a live virus in the previous 60 days prior to Day 0.
• Inability or unwillingness to give informed consent.
• Is unable or unwilling to comply with protocol follow-up requirements. -