Gilbert, M. Jean

Abstract Genome-wide DNA methylation signatures correlate with and distinguish central nervous system (CNS) tumor types. Since the publication of the initial CNS tumor DNA methylation classifier in 2018, this platform has been increasingly used as a diagnostic tool for CNS tumors, with multiple studies showing the value and utility of DNA methylation-based classification of CNS tumors. A Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) Working Group was therefore convened to describe the current state of the field and to provide advice based on lessons learned to date. Here, we provide recommendations for the use of DNA methylation-based classification in CNS tumor diagnostics, emphasizing the attributes and limitations of the modality. We emphasize that the methylation classifier is one diagnostic tool to be used alongside previously established diagnostic tools in a fully integrated fashion. In addition, we provide examples of the inclusion of DNA methylation data within the layered diagnostic reporting format endorsed by the World Health Organization (WHO) and the International Collaboration on Cancer Reporting. We emphasize the need for backward compatibility of future platforms to enable accumulated data to be compatible with new versions of the array. Finally, we outline the specific connections between methylation classes and CNS WHO tumor types to aid in the interpretation of classifier results. It is hoped that this update will assist the neuro-oncology community in the interpretation of DNA methylation classifier results to facilitate the accurate diagnosis of CNS tumors and thereby help guide patient management.

TPS2621 Background: TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1, a serine/threonine kinase that regulates multiple critical aspects of cell cycle progression and mitosis. Anti-tumor activity, RNA interference and pharmacodynamic effects of PLK1 inhibition have been conclusively demonstrated in preclinical models. Demonstration of pharmacodynamic effects of PLK1 inhibition in patient biopsy samples is an exploratory objective of this first-in-human study. Methods: TKME080301 is being evaluated in an open-label, non-randomized, dose-escalation study in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKME080301 as a 30-minute intravenous infusion on Days 1, 8 and 15 of a 28-day cycle. Treatment can continue until disease progression, based on overall clinical benefit. Tumor response is determined according to RECIST criteria. Primary study objectives include determination of safety, maximum tolerated dose and dose limiting toxicities. Secondary objectives include characterization of pharmacokinetics and the preliminary assessment of anti-tumor activity. Five cohorts have been enrolled and a tentative Phase 2 dose has been identified. An expansion cohort of 10 patients began enrolling in February, 2013. The focus of the expansion cohort will be to collect additional safety and pharmacokinetic data at the tentative Phase 2 dose, as well as pharmacodynamic data from mandatory biopsy samples. Pre- and post-dose biopsy samples will be evaluated for potential evidence of PLK1 inhibition using 5’ RACE (rapid amplification of cDNA ends) polymerase chain reaction (to identify the predicted PLK1 mRNA cleavage product), histology (to assess for the presence of aberrant mitotic figures) and immunohistochemistry. An update on enrollment and pharmacodynamic evaluations will be presented. Clinical trial information: NCT01262235.

Abstract Background: Polo-like kinase 1 (PLK1) is a serine/threonine kinase that regulates multiple critical aspects of cell progression. PLK1 is over-expressed in many human tumor types and its over-expression is a negative prognostic indicator of patient outcome in a variety of cancers. TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1 that has been shown to effect highly selective reductions in PLK1 mRNA in vitro and in tumor xenograft models in mice. Methods: A phase I multi-center, open-label, non-randomized, dose-escalation study of TKM-080301 is ongoing in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKM-080301 as a 30-minute IV infusion on Days 1, 8, and 15 of a 28-day cycle. Primary objectives include determination of safety, maximum tolerated dose (MTD) and dose limiting toxicities (DLTs). Secondary objectives include characterization of pharmacokinetics (PK) and preliminary assessment of anti-tumor activity and pharmacodynamic effects. Pre-and post-dose biopsy samples are being collected from patients treated after DLT has been established. Results: Twenty-three (23) patients, receiving a cumulative total of 128 doses, have been treated with TKM-080301 at doses ranging from 0.15 to 0.9 mg/kg/week. The most common drug-related adverse events have been mild-to-moderate infusion related reactions with delayed onset, pyrexia, chills, nausea, vomiting, and fatigue. Mild, transient increases in certain cytokines (e.g., IL-6, IL-8, MCP-1) have been observed at dose levels ≤0.75 mg/kg/week and generally correlated with the timing of delayed infusion reactions. DLTs were observed at 0.9 mg/kg/week and included hypoxia/dyspnea in one patient (with a previous history of asthma) and thrombocytopenia in another patient. The dose level was subsequently reduced to 0.75 mg/kg/week. Pharmacokinetic parameters determined after the first dose in Cycles 1 and 2 demonstrated dose proportional Cmax and AUC and no obvious accumulation. Two patients have received TKM-080301 for at least 6 months (6 cycles) with no evidence of cumulative toxicity, including one patient with stable disease (colon) and one patient with a durable confirmed partial response (carcinoid tumor) who has received 8+ cycles of treatment. Conclusions: Preliminary results from this first-in-human trial indicate TKM-080301 was generally well-tolerated by the majority of patients. Preliminary antitumor efficacy has been observed, supporting PLK1 as a therapeutic target. As two DLTs were observed at the dose of 0.9 mg/kg/week, patient accrual is continuing at the 0.75 mg/kg/week dose level. Citation Format: Ramesh K. Ramanathan, Solomon I. Hamburg, Mitesh J. Borad, Mahesh Seetharam, Madappa N. Kundranda, Peter Lee, Paul Fredlund, Mark Gilbert, Cathy Mast, Sean C. Semple, Adam D. Judge, Brynne Crowell, Linda Vocila, Ian MacLachlan, Donald W. Northfelt. A phase I dose escalation study of TKM-080301, a RNAi therapeutic directed against PLK1, in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-289. doi:10.1158/1538-7445.AM2013-LB-289