The CXCL12/CXCR4 Pathway As a Potential Target of Tipifarnib: Preliminary Results from an Open-Label, Phase II Study in Relapsed or Refractory Peripheral T-Cell Lymphoma

Abstract

BackgroundTipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. CXCL12 has been postulated to signal in part through HRAS, a signaling protein that is uniquely dependent on farnesylation for activity. We report herein the identification of CXCL12 as a marker of sensitivity to FT inhibition by tipifarnib in PTCL patients (pts).MethodsThis Phase 2 study is a multi-institutional, single-arm, open-label, two-stage (11+7) study designed to determine the efficacy, safety and biomarker correlates of tipifarnib in pts with relapsed/refractory (R/R) PTCL. Based on initial findings, the study has been extended to include a cohort of angioimmunoblastic T-cell lymphoma (AITL) pts (N=12). Pts with R/R PTCL after prior cytotoxic systemic therapy, aged ≥ 18 years old, and with a performance status of 0-2 were eligible. Pts enrolled in stages 1 and 2 of the study were treated with tipifarnib 600 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. Pts enrolled in the AITL cohort are treated with tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. The primary endpoint of the study was overall response rate. Biomarker studies included gene expression profiling of pre-treatment tumor biopsies by RNASeq and DNA next-generation sequencing (NGS). Clinical trial information: NCT02464228.ResultsAt data cut-off (July 2017), 19 pts (3 AITL, 1 ALK- ALCL, 15 PTCL-NOS) were treated with tipifarnib. The most common treatment-related AE (grade ≥ 3) was myelosuppression, including neutropenia (83%), thrombocytopenia (61%) and anemia (33%). Of 18 evaluable pts at data cut-off, 3 pts achieved a partial response (PR, 2 AITL; 1 PTCL-NOS) and 3 pts experienced stable disease (SD) with -38%, -45% and -47% tumor size reductions. One additional pt experienced a -63% tumor size reduction and splenomegaly. Median duration of response (PR/SD) was 4 months with treatment ongoing in 2 subjects at cycles 10 and 15. Tumor gene expression data were available for 12 pts. Five of those pts experienced tumor size reductions and prolonged (>6 mo) median time to progression that was associated with elevated CXCL12 expression (p<0.001). Two pts with AITL histology expressed high levels of CXCL12 and experienced PRs. One of the AITL pts overexpressed CXCL13 and moderate VCAM1 while the other one overexpressed VCAM1 and other vascular markers (PDGFRA, ANGPT1, TEK), pointing towards two known mechanisms of CXCL12 upregulation (Mir23A downregulation by CXCL13 in stroma cells and vascular endothelial cell production of CXCL12). In contrast, the 7 pts with tumors of low CXCL12 expression experienced a best response of disease progression (PD). Low CXCL12 expression and PD were significantly associated (p=0.04, P<0.001, respectively) with the presence of single nucleotide variations (SNV) in the 3'UTR of the CXCL12 gene, including rs2839695 and two novel SNVs identified by NGS. Studies investigating the interaction between plasma CXCL12 and the activity of tipifarnib as well as the prognostic value of CXCL12 expression and gene variation in tumor series of PTCL patients treated with standard therapy are ongoing. Enrollment continues in the AITL cohort.ConclusionEncouraging activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression. DisclosuresWitzig:Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Novartis: Research Funding. Advani:Sutro: Consultancy; Regeneron: Research Funding; Spectrum: Consultancy; Nanostring: Consultancy; Agensys: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy; Janssen: Research Funding; Kura: Research Funding; Infinity: Research Funding; Celgene: Research Funding; Gilead: Consultancy; Genentech: Research Funding; Seattle Genetics: Research Funding; Juno Therapeutics: Consultancy; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; FortySeven: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; Cell Medica: Research Funding. Foss:celgene: Honoraria; immune design: Research Funding; spectrum: Honoraria, Speakers Bureau; Eisai: Honoraria; seattle genetics: Speakers Bureau. Mondejar:Kura Oncology: Research Funding. Piris:Kura Oncology: Research Funding. Bolognese:Kura Oncology: Consultancy. Burrows:Kura Oncology: Employment, Equity Ownership. Kessler:Kura Oncology: Employment. Bracken:Kura Oncology: Employment. Mishra:Kura Oncology: Employment, Equity Ownership. Scholz:Kura Oncology: Employment, Equity Ownership, Patents & Royalties. Gualberto:Kura Oncology: Employment, Equity Ownership, Other: Chief Medical Officer, Patents & Royalties.