EVITA: PHASE I/II STUDY OF EVEROLIMUS PLUS ITACITINIB IN RELAPSED/REFRACTORY CLASSICAL HODGKIN LYMPHOMA

Abstract

Introduction: There is an unmet need for patients (pts) with relapsed/refractory classical Hodgkin lymphoma (cHL) who failed or cannot tolerate immune check point inhibitors and brentuximab vedotin (BV). Biology of cHL is characterized by scant Hodgkin Reed Sternberg cells (HRS) within a pro-inflammatory tumor microenvironment (TME). Both HRS and TME are rich with therapeutic targets. One of those is Akt which is constitutively activated in cHL-derived cell lines and its downstream effectors include mTOR substrates. Other promising targets in cHL are components of JAK/STAT pathway as genetic alterations in multiple genes (including STAT3, STAT5B, JAK1, JAK2, PTPN1) have been demonstrated in cHL. In pre-clinical studies, co-treatment of mTOR and JAK inhibitors resulted in synergistic activity against the proliferation of JAK mutated cell lines. Everolimus (oral inhibitor of mTOR) is clinically active in cHL with overall response rate (ORR) 40%, but low complete response rate (CR) of 5%. Ruxolitinib (oral JAK1/2 inhibitor) monotherapy produced only modest responses in cHL. Itacitinib adipate is another oral JAK inhibitor with potent selectivity for JAK1, but limited data in cHL. Itacitinib also inhibits STAT protein phosphorylation and pro-inflammatory cytokines including IL-6 which is expressed on HRS/TME and its expression has been associated with B symptoms. To our knowledge, no clinical studies have been done with concurrent mTOR/JAK inhibition in cHL. We hypothesize that targeting multiple pathways in HRS/TME using combination of everolimus and itacitinib will result in deeper disease control compared to everolimus monotherapy. Methods: An open-label, single-group study of everolimus in combination with itacitinib is currently opened at the University of Pennsylvania. Eligible pts must have relapsed/refractory cHL after at least 2 prior systemic therapies and must have relapsed after or be ineligible for autologous stem cell transplant. They also must have progressed after treatment with, be intolerant to, or are not a candidate for BV and pembrolizumab/nivolumab. Phase I will evaluate the safety and tolerability of the combination using a standard 3 + 3 design with dose-escalation or de-escalation. The starting dose of everolimus is 5 mg daily and of itacitinib is 300 mg daily with treatment planned for 2 years or until progression/intolerance. Phase II will evaluate the efficacy of the combination in cHL as demonstrated by CR (the null hypothesis is set at CR rate of 5%). Secondary objectives include progression free/overall survival, ORR, duration of response. Exploratory analyses include impact on quality of life/B symptoms. Ancillary studies exploring tumor biology/biomarkers are planned. Since opening in January 2019, 2 pts have been enrolled. The goal is to enroll 23 pts over a period of 3 years. Keywords: Hodgkin lymphoma (HL); JAK/STAT; mTor inhibitors. Disclosures: Nasta, S: Research Funding: Incyte.