TIPIFARNIB IN RELAPSED OR REFRACTORY ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA (AITL) AND CXCL12+ PERIPHERAL T-CELL LYMPHOMA (PTCL): PRELIMINARY RESULTS FROM AN OPEN-LABEL, PHASE 2 STUDY
Author(s): ,
Thomas Witzig
Affiliations:
Mayo Clinic,Rochester,United States
,
Lubomir Sokol
Affiliations:
H. Lee Moffitt Cancer Center & Research Institute,Tampa,United States
,
Won Seog Kim
Affiliations:
Samsung Medical Center,Seoul,Korea, Democratic People's Republic Of
,
Francine Foss
Affiliations:
Yale University School of Medicine,New Haven,United States
,
Eric Jacobsen
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Fatima de la Cruz Vicente
Affiliations:
Hospital Universitario Virgen del Rocío,Sevilla,Spain
,
Dolores Caballero
Affiliations:
Hospital Universitario de Salamanca,Salamanca,Spain
,
Ranjana Advani
Affiliations:
Stanford University Medical Center,Stanford,United States
,
Maria Jose Roncero Vidal
Affiliations:
Institut Català d'Oncologia,Girona,Spain
,
Anna Marin Niebla
Affiliations:
Vall D’Hebron Institute of Oncology,Barcelona,Spain
,
Antonia Rodriguez Izquierdo
Affiliations:
Hospital Universitario 12 de Octubre,Madrid,Spain
,
Raquel de Ona Navarrete
Affiliations:
MD Anderson Cancer Center,Madrid,Spain
,
Maria Jose Terol
Affiliations:
Hospital Clinico Universitario de Valencia,Valencia,Spain
,
Eva Domingo-Domenech
Affiliations:
Institut Catala d'Oncologia,Barcelona,Spain
,
Marta Rodriguez
Affiliations:
Fundación Jiménez Díaz,Madrid,Spain
,
Miguel Piris
Affiliations:
Fundación Jiménez Díaz,Madrid,Spain
,
James Bolognese
Affiliations:
Cytel,Cambridge,United States
,
Matthew R Janes
Affiliations:
Wellspring Biosciences, Inc.,San Diego,United States
,
Francis Burrows
Affiliations:
Kura Oncology, Inc.,San Diego,United States
,
Linda Kessler
Affiliations:
Kura Oncology, Inc.,San Diego,United States
,
Vishnu Mishra
Affiliations:
Kura Oncology, Inc.,San Diego,United States
,
Robert Curry
Affiliations:
Kura Oncology, Inc.,Cambridge,United States
,
Michael Kurman
Affiliations:
Kura Oncology, Inc.,Cambridge,United States
,
Catherine Scholz
Affiliations:
Kura Oncology, Inc.,Cambridge,United States
Antonio Gualberto
Affiliations:
Kura Oncology, Inc.,Cambridge,United States
EHA Library. Witzig T. Jun 15, 2019; 267452; S869
Thomas Witzig
Thomas Witzig
Contributions
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Abstract

Abstract: S869

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 16:45 - 17:00

Location: Hall 5

Background
Tipifarnib 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. 

Aims
Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts).

Methods
This Phase 2 study (NCT02464228) is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age >/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in pts who received tipifarnib and 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 one treatment-emergent adverse event (TEAE); 39 (90%) had at least 1 study 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% or more 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 also 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 using the high CXCL12 subset using the cut-off point that predicted clinical benefit under tipifarnib therapy. Fifty percent of AITL and 35% of non-AITL samples overexpressed CXCL12. 

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.

Session topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical

Keyword(s): Clinical trial, Peripheral T-cell lymphoma, Tipifarnib

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