Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 1 Abbreviated Title: Ad5-based combination vaccine s CC Protocol #: 18C0032 A Version Date : May 16, 2018 IBC#: RD-17-VIII-13 OSP#: 1712 -1703 NCT #: NCT03384316 Title: Phase I Trial Using a Multi -Targeted Recombinant Ad5 (CEA/MUC1/Brachyury ) Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer NCI Principal Investigator: Julius Strauss, MD Laboratory of Tumor Immunology & Biology (LTIB ), CCR, NCI 10 Center Drive Building 10, Room 13N240A Bethesda, MD 20892 Phone: 301 -480-0202 Email: julius.strauss@nih.gov Investigational Agents: Drug Name: ETBX -011; adenoviral CEA vaccine ETBX -061; adenoviral MUC1 vaccine ETBX -051; adenoviral brachyury vaccine IND Number: 17676 17676 17676 Sponsor: Center for Cancer Research Center for Cancer Research Center for Cancer Research Manufacturer: Etubics Etubics Etubics Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 2 PRÉCIS Background: • The overall goal of the current project is to expand our immunotherapeutic approach for the treatment of advanced cancer employing a multi -targeted approach. • Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to activate T cells against tumors. • A novel adenovirus based vaccine targeting three (3) human tumor associated antigens (TAA), CEA, MUC1, and brachyury, respectively h as demonstrated anti -tumor cytolytic T cell responses in pre -clinical animal models of cancer. Objectives: • To determine the overall safety and recommended phase 2 dose of a combination of three immunotherapeutic vaccines (ETBX -011/ETBX -061/ETBX -051), when administered subcutaneously (SC) to subjects with advanced solid tumors Eligibility: • Subjects age 18 and older with cytologically or histologically confirmed locally advanced or metastatic solid tumor malignancy who have completed or had disease progress ion on at least one prior line of disease -appropriate therapy or who are not candidates for therapy of proven efficacy for their disease. • Subjects may have measurable or non -measurable but evaluable disease. Subjects with surgically resected metastatic dis ease at high risk of relapse are also eligible. • ECOG performance status < 1 • Adequate organ and bone marrow function • Subjects with active autoimmune diseases requiring systemic treatment and subjects requiring system ic steroids (except for physiologic doses for steroid replacement) are not allowed Design: • This is a Phase I trial in subjects with advanced cancer. A combination of three therapeutic vaccine s (ETBX -011, ETBX -51, EBX -61) using the same modified Adenovirus vector backbone, separately encoding three well -studied tumor -associated antigens will be assessed. The vaccine will be tested at a single dose level, and a dose de -escalation design (if required). The dose level of each vaccine tested will be 5 x1011 VP. This dose has been found in prior phase 1 testing of Ad5 [E1 -, E2b -]-CEA(6D) (ETBX -011) to be well tolerated (with no dose -limiting toxicities (DLTs) or related Serious adverse events (SAEs), and optimal for in duction of immune responses. Each of the three vaccines will be administered subcutaneously (SC) at separate injection sites (proximal limb, preferably the thigh), every 3 weeks for 3 doses, then bi -monthly (every 8 week) boosts for up to a year. • Up to six patients will be enrolled at Dose Level 1 . If ≤1 of 6 patients experience a DLT, initiation of the dose expansion phase will occur. If ≥2 of 6 experience DLT at Dose Level 1, then dose de -escalation will occur. Up to six patients will be enrolled at the lower dose level Dose Level -1 (1x 1011 VP). If ≤1 of 6 patients experience a DLT, then the maximum tolerated (MTD) will be declared at this dose, and initiation of the dose expansion phase Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 3 will occur. If ≥2 of 6 experience DLT at Dose Level -1, then a protocol amendment may be written to evaluate a further dose de -escalation. • A dose expansion phase of study will be enrolled after the MTD of the combination vaccine has been determined. An additional 4 subjects will be enrolled in the dose expansion component of the trial, for a total of 10 subjects at the MTD. • The ETBX -011, ETBX -51 and ETBX -61 vaccines will be administered SC every 3 weeks for 3 doses, and then bi monthly boosts for up to a year. Evaluations including immunological assessments will be carried out at baseline, on days of va ccination, and after the last vaccination. Abbreviated Title: Ad5 -based combination vaccines Version Date: 05.16.2018 4 TABLE OF CONTENTS PRÉCIS 2 TABLE OF CONTENTS ................................ ................................