SD-101, a Novel Class C CpG-Oligodeoxynucleotide (ODN) Toll-like Receptor 9 (TLR9) Agonist, Given with Low Dose Radiation for Untreated Low Grade B-Cell Lymphoma: Interim Results of a Phase 1/2 Trial

Abstract

Introduction: Prior studies have shown preliminary clinical efficacy in combining CpG-ODN with radiation therapy (XRT) to patients with indolent B-cell lymphoma. We report interim Phase 1/2 data of combination XRT and SD-101, a synthetic class C CpG-ODN TLR9 agonist, selected for the strong induction of type I interferon.Methods: This dose-escalation Phase 1/2 trial enrolled patients with untreated indolent B-cell lymphoma having at least 2 measurable lesions (one palpable). The primary endpoints were safety and alpha-interferon-gene induction. Secondary endpoints included efficacy assessment using Cheson (1999) criteria and quantification of changes in tumor-infiltrating lymphocytes. A single lesion was treated with XRT (2 Gy daily X 2 days) followed by a single intratumoral dose of SD-101 (same lesion). 4 additional doses of intratumoral SD-101 were given weekly over next 4 weeks. The treated lesion and distal lesions were monitored during the study. Pharmacodynamic assessment included flow cytometry analysis of immune infiltrates in an FNA sample of the treated tumor and RT-PCR RNA assay of whole blood to assess induction of alpha-interferon genes. Efficacy assessment included imaging (CT at 3, 6, and every 6 months thereafter).Results: As of 01 Aug 2016, 13 patients were treated with escalating doses of SD-101 at 1, 2, 4 or 8 mg/dose. There were no dose limiting toxicities. The majority of related adverse events (AEs) were Grade 1 (mild). The most common were flu-like symptoms (chills, headache, malaise, myalgia), typically resolving within ≤ 48 hours without requiring intervention (e.g., acetaminophen). An induction of alpha-interferon genes occurred at all dose levels with a similar level of induction.For the dose expansion phase, 15 patients were enrolled at 1 mg (6) and 8 mg dose group (9). Similar to dose escalation phase, the most common related events were again flu-like symptoms, typically resolving within ≤ 48 hours mitigated with acetaminophen. There was one dose delay for Grade 3 neutropenia in one patient (1 mg) that resolved following drug interruption. Twenty-nine Grade 3 transient flu-like symptoms were reported for four patients (44%) who received the 8 mg dose (e.g., chills headache, malaise, myalgia, and fatigue). Only one of the four patients experienced all 5 Grade 3 flu-like symptoms after intratumoral injection. There were no grade 4 or serious events reported, and no patient discontinued due to an adverse event.A reduction in tumor sizes was observed in the study over time (see Figure 1). At Day 90 the median changes in the product of diameters from baseline were -46.1% and -10.2% for treated tumor and distal tumors, respectively. At Day 540, the median changes were -68.6% and -24.1%, respectively.In patients with follicular lymphoma (largest subgroup), preliminary data suggest a higher percentage of CD8+ T cells in the treated lesion (FNA at day 8) correlated with an increased abscopal response.Conclusions: Intratumoral SD-101 following radiation therapy has been well tolerated and preliminary efficacy, promising. Abscopal anti-tumor activity was observed with preliminary data suggesting that a higher percentage of CD8+ T cells in the treated lesion correlated with an increased abscopal response seen in follicular lymphoma. Enrollment is ongoing with an option for cycle 2 retreatment. [Display omitted] DisclosuresLevy:Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Reagan:Seattle Genetics: Research Funding. Friedberg:Bayer: Other: Data Safety Monitoring Committee. Bartlett:Gilead: Consultancy. Leung:Dynavax: Employment. Peterkin:Dynavax: Consultancy. Xing:Dynavax: Employment. Coffman:Dynavax: Employment. Janssen:Dynavax: Employment. Candia:Dynavax: Employment.