Abstract OT1-01-04: A multicenter, phase 1b, first-in-human dose-escalation study of ADXS31-164, a Listeria monocytogenes-LLO immunotherapy, in patients with HER2-expressing solid tumors
Authors: Tan AR , Olszanski A , Golan T , Mauro D , Rugo H 
Published: May 2016

Abstract
Background: Wild type Listeria monocytogenes (Lm) is taken up by antigen-presenting cells (APCs) and has the capability to escape destruction in the phagolysosome and proliferate in the cytosol of the APC. ADXS31-164 is a live attenuated Lm-listeriolysin O (LLO) immunotherapy bioengineered to express the intracellular domain 1 and extracellular domains 1 and 2 of chimeric human epidermal growth factor receptor 2 (cHER2) as a fusion protein to a truncated form of the LLO (tLLO) in the cytoplasm of APCs. The resultant immunologic response generates tumor antigen-specific cytotoxic T lymphocytes while also inhibiting regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment. Preclinical studies have shown ADXS31-164 can delay the progression of tumors in both transplantable and autochthonous HER2-expressing mouse tumor models.
Trial Design: This is an open-label, multicenter Phase 1b trial (NCT02386501). Patients will receive ADXS31-164 every 3 weeks until progression of disease or unacceptable toxicity. Dose escalations will be performed according to a standard 3+3 design starting at 1 × 109 colony forming units (CFU) to a maximum dose level of 1 × 1010 CFU.
The maximum tolerated dose (MTD) will be identified as the dose level in which a dose-limiting toxicity is seen in 2 of 6 patients; the previous dose level will be selected as the recommended Phase 2 dose (RP2D). Once the MTD and RP2D have been identified, up to 4 HER2-overexpressing tumor-specific expansion cohorts will be evaluated. Treatment cycles can be repeated at the RP2D (or less) for each patient until a study discontinuation criterion is met or the subject completes 1 cycle of treatment post-observation of complete response. Blood samples will be evaluated for immunologic effects in cycle 1 only. Descriptive statistics will be used to evaluate the safety and tolerability of ADXS31-164.
Objectives: The primary aim of this trial is to evaluate safety and tolerability of ADXS31-164 in patients with solid tumors that express HER2, and to select the RP2D. Secondary objectives include tumor response rates and progression-free survival (measured by Response Evaluation Criteria In Solid Tumors [RECIST] 1.1 and immune-related RECIST criteria). Exploratory analyses will describe and evaluate data from correlative immunologic studies.
Key Eligibility Criteria: Patients aged ≥18 years with HER2-positive tumors determined by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC, at least 1 positive in 1% of the evaluable tumor cells) and an Eastern Cooperative Oncology Group performance status of 0–1 are eligible. Additional criteria include a diagnosis of locally advanced/metastatic solid tumor that has progressed or become intolerant to standard therapy or for which no standard therapy is available, measurable and/or evaluable disease per RECIST 1.1, and a left ventricular ejection fraction within normal limits.
Citation Format: Tan AR, Olszanski A, Golan T, Mauro D, Rugo H. A multicenter, phase 1b, first-in-human dose-escalation study of ADXS31-164, a Listeria monocytogenes-LLO immunotherapy, in patients with HER2-expressing solid tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-04.