Final Results from a Phase 2 Study of Tipifarnib in Subjects with Relapsed or Refractory Peripheral T-Cell Lymphoma
The T-cell non-Hodgkin lymphomas continue to be an area of unmet need for new therapies that offer novel mechanisms of action. Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). Tipifarnib inhibits farnesylation of key regulatory proteins involved in CXCL12 produc...
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Veröffentlicht in: | Blood 2021-11, Vol.138 (Supplement 1), p.621-621 |
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Sprache: | eng |
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Zusammenfassung: | The T-cell non-Hodgkin lymphomas continue to be an area of unmet need for new therapies that offer novel mechanisms of action. Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). Tipifarnib inhibits farnesylation of key regulatory proteins involved in CXCL12 production (Gualberto et al, EHA 2019). CXCL12 is a chemokine that is essential for T-cell homing to lymphoid organs and bone marrow, and for the maintenance of immune cell progenitors via its receptor CXCR4 (Susek et al, Front Immunology, 2018). Angioimmunoblastic T-cell lymphoma (AITL) is associated with high levels of CXCL12 expression, which is also a negative prognostic factor (Witzig et al, Blood, 2019). Additionally, Peripheral T-Cell lymphoma Not Otherwise Specified (PTCL-NOS) patients with the CXCL12 rs2839695 A/A wildtype genotype (PTCL-CXCL12+) have also been found to have elevated levels of CXCL12. Therefore, there is strong rationale for targeting these subsets of PTCL with tipifarnib.
This Phase 2 study (NCT02464228) was a multi-institutional, single-arm, open-label trial determining the efficacy, safety, and potential predictive biomarkers for tipifarnib in adult patients with relapsed or refractory (R/R) PTCL. Patients received tipifarnib 300 mg orally twice daily on Days 1-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. The primary objective of the study was to determine the antitumor activity by overall response rate (ORR) per Lugano Classification. Secondary objectives included safety, duration of response (DoR) and progression-free survival (PFS), and exploratory analyses included overall survival (OS) and identification of potential biomarkers associated with tipifarnib activity.
Sixty-five R/R PTCL patients (38 AITL, 14 PTCL-NOS, 11 PTCL-CXCL12+, 2 other (1 ALCL-ALK negative, 1 PTCL-subtype not specified) were treated with tipifarnib. The population was heavily pretreated with a median of 3 prior regimens (range 1-8). All patients had at least one treatment-emergent adverse event (TEAE); most patients (87.7%) had at least one treatment-related TEAE, and 18 (27.7%) patients had at least one treatment-related serious TEAE. The most frequently observed (≥20%) treatment-related TEAEs (all grades) were hematological (neutropenia, thrombocytopenia, anemia,) and gastrointestinal (nausea, diarrhea), as well as fatigue, which is consistent with the known safety profile of tipifarnib. Fifty-eight patients were efficacy |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2021-147279 |