TIPIFARNIB IN RELAPSED OR REFRACTORY ANGIOIMMUNOBLASTIC T‐CELL LYMPHOMA (AITL) AND CXCL12+ PERIPHERAL T‐CELL LYMPHOMA (PTCL): PRELIMINARY RESULTS FROM A PHASE 2 STUDY

Abstract

Introduction: Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). 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. Tipifarnib has previously been shown to modulate the CXCL12 pathway and to drive clinical activity in CXCL12-expressing T cell lymphomas. Methods: This Phase 2 study (NCT02464228) is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) study to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg orally twice daily on days 1-21 of 28-day treatment cycles. The primary endpoint is overall response rate (ORR). Ancillary studies are ongoing to investigate the prognostic value of CXCL12 expression in pts who received standard of care treatment. Results: As of 20 February 2019, 43 PTCL pts (20 AITL, 21 PTCL-NOS, 1 ALK- ALCL, 1 gamma-delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 24 pts in the ongoing AITL histology and CXCL12 cohort. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts had at least 1 treatment-emergent adverse event (TEAE); 39 (90%) had at least 1 drug-related TEAE and 12 (28%) at least 1 drug related SAE. The most frequently observed drug-related TEAEs of Grade >3 occurring in >10% of pts were blood and lymphatic system disorders, including neutropenia (44%), thrombocytopenia (37%), leukopenia (28%), anemia (21%) and febrile neutropenia (21%). There have been 14 deaths on study; none were related to study drug. Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable pts), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the CXCL12+ cohort (n=3 evaluable pts), 1 PR and 2 SD have been observed, with 4 pts pending cycle 2 response evaluation. CXCL12 expression correlated with favorable outcome to tipifarnib treatment. Pre-treatment high CXCL12 expression had 90% sensitivity and 93% specificity to identify pts who experienced CR/PR/SD on study in a preliminary analysis of 24 pts. The prognosis of CXCL12 was retrospectively investigated in 73 pts who received standard of care therapy (AITL N=50, PTCL NOS=23). A trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR=1.8, p=0.09) was observed in the high CXCL12 subset using the cut-off point that predicted clinical benefit under tipifarnib therapy. Conclusion: Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment in the CXCL12+ cohort continues. Keywords: angioimmunoblastic T-cell lymphoma (AITL); peripheral T-cell lymphomas (PTCL). Disclosures: Witzig, T: Research Funding: Study Investigator for KO-TIP-002 (Kura Oncology). Sokol, L: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Kim, W: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Foss, F: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Jacobsen, E: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). de la Cruz Vincente, F: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Caballero, D: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Advani, R: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Roncero Vidal, J: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Marin-Niebla, A: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Rodriguez Izquierdo, A: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). de Ona Navarrete, R: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Terol, M: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Domingo-Domenech, E: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Rodriguez, M: Research Funding: Kura Oncology. Piris, M: Research Funding: Kura Oncology. Bolognese, J: Consultant Advisory Role: Kura Oncology. Janes, M: Consultant Advisory Role: Kura Oncology. Burrows, F: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Kessler, L: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Mishra, V: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Curry, R: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Kurman, M: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Scholz, C: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Gualberto, A: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology.