NCI 9922: Phase 2 study of ibrutinib in treatment-refractory distant metastatic cutaneous melanoma (DMCM).

Abstract

TPS9592 Background: We have previously shown that the IL-2 inducible kinase (ITK) is highly expressed in primary melanomas compared with nevi due to promoter hypomethylation (Conway PCMR 2011). We have also shown using 2-color immunofluorescence (2CIF) that ITK protein expression is increased even more in metastatic compared to primary melanomas (S100+) and that molecular targeting (shRNA) or pharmacologic inhibition of ITK (BI 10N) in various melanoma cell lines, various melanoma xenografts and an immunocompetent melanoma mouse model suppresses cell proliferation and retards tumor growth without inducing cell death (Carson CCR 2015). We have also shown by intracellular stain of peripheral blood mononuclear cells (PBMC) that ITK is expressed in PBMC obtained from patients (pts) treated with MAPK or CTLA-4 inhibitors. Other groups have shown that ITK and BTK are expressed in Th2 cells, myeloid-derived suppressor cells, and tumor-associated macrophages. We have also shown that ibrutinib suppresses proliferation of various melanoma cell lines in low nM concentrations depending on tumoral expression of ITK. We hypothesize that targeting DMCM with ibrutinib alone will induce antitumor responses and/or prolong survival if DMCM expresses high levels of melanoma-associated ITK by 2CIF (S100/ITK). Methods: This is an open-label, single-arm, multicenter, phase II study of DMCM refractory to or ineligible for PD-1 and MAPK inhibitors. Ibrutinib will be dosed at 840 mg p.o. qd. The null hypothesis is that an ineffective drug will confer a 5% response rate (RR) and 18% 6-month PFS (6m PFS), whereas ibrutinib will confer > = 20% RR and > = 35% 6m PFS (KEYNOTE-002). This trial accrues in two stages; if either the RR and/or 6m PFS endpoint are met after 18 patients, then 14 additional pts will be accrued for a total of 32. The Simon’s design will reject the null hypothesis if > = 4 responses are observed or > = 9 pts have PFS better than 6 months out of 32 patients. All pts are required to have baseline tumor tissue available for analysis of ITK expression by 2CIF. Immune monitoring will be performed on PBMC collected at baseline and various time points during treatment. Trial is currently recruiting pts (NCT02581930). Clinical trial information: NCT02581930.