Kura Oncology says primary endpoint achieved in Phase 2 trial of tipifarnib
Kura Oncology announced updated interim data from the ongoing Phase 2 clinical trial of its lead drug candidate, tipifarnib, in patients with relapsed or refractory peripheral T-cell lymphoma. The results, which will be presented during an oral session at 16:45 CET / 10:45 am ET tomorrow at the European Hematology Association Annual Congress in Amsterdam, demonstrate ongoing anti-tumor activity and a manageable safety profile in advanced patients with angioimmunoblastic T-cell lymphoma as well as non-AITL PTCL. The multi-center, single-arm, open-label Phase 2 trial was designed to determine the efficacy, safety and biomarkers of activity of tipifarnib in patients with relapsed or refractory PTCL. Initially, patients were enrolled without selection in the Phase 2 trial. Based upon molecular characterization of the initial patients, the Phase 2 trial was amended to include two expansion cohorts: 1) patients with AITL, an aggressive form of T-cell lymphoma often characterized by high levels of CXCL12 expression, and 2) patients with PTCL who lack a single nucleotide variation in the 3'-untranslated region of the CXCL12 gene. As of the May 24, 2019 data cutoff, a total of 50 relapsed/refractory PTCL patients with a median number of three prior regimens have been enrolled in all stages of the Phase 2 trial. Key preliminary findings include: The primary efficacy endpoint was achieved in each of the AITL and CXCL12+ expansion cohorts. Sixteen patients were treated in the AITL cohort and 15 in the CXCL12 SNP+ cohort. Among the 11 evaluable patients in the AITL extension cohort, three achieved a complete response and two achieved a partial response, for an objective response rate of 45%. Among the 12 evaluable patients in the CXCL12+ expansion cohort, three achieved a CR and two achieved a PR, for an ORR of 42%. Two of the five responders in the CXCL12+ expansion cohort were AITL patients. When all AITL patients and all PTCL not otherwise specified with available rs2839695 data and absence of this 3'UTR variant enrolled in all portions were taken into account, ORR were 53%/39% for AITL and 20%/18% for CXCL12 SNP+ PTCL-NOS. Thirty-four patients had available gene expression data. Patients with a high ratio of CXCL12 expression to its receptor CXCR4 experienced an ORR of 47% and a clinical benefit rate of 82% with tipifarnib. Next-generation sequencing of 16 AITL patients revealed a high rate of mutation/variation of the killer cell immunoglobulin-like receptors, including KIR3DL2. KIR3DL2 mutation at C336R was concurrent with Q386E and was associated with outcome from tipifarnib therapy. Four of the eight KIR3DL2 C336R/Q386E patients achieved a CR, two achieved a PR and two achieved stable disease for a CR rate of 50%, an ORR of 75% and a clinical benefit rate of 100%. Furthermore, high KIR3DL2 mutant variant allele frequency KIR3DL2 was predictive of complete response to tipifarnib in AITL. Tumors with KIR3DL2 mutations expressed low levels of CXCL5 and its receptor CXCR1 and CXCR2, a potential mechanism of resistance to tipifarnib. Tipifarnib was generally well-tolerated in this Phase 2 trial, with adverse events consistent with its known safety profile. The most frequently observed treatment-related adverse events were hematology-related, including thrombocytopenia, neutropenia, leukopenia, anemia, febrile neutropenia and lymphopenia. Separately, Kura has been evaluating the potential to use CXCL12 pathway biomarkers to enrich for clinical activity in other hematologic malignancies. In addition to AITL, high CXCL12 expression was observed in tumors from other lymphoma patients, including patients with PTCL-NOS, diffuse large B-cell lymphoma and mycosis fungoides, the most common form of cutaneous T-cell lymphoma. Lymphoma patients with CXCL12 reference sequences also appeared to have a higher chance of clinical benefit from tipifarnib treatment. The identification of these CXCL12 reference sequences in responders to tipifarnib across multiple hematologic malignancies will be presented in a poster presentation at 17:30 CET / 11:30 am ET tomorrow at the EHA Annual Congress in Amsterdam.