Tipifarnib Granted FDA Fast Track Designation for T-cell Lymphomas

Tipifarnib Granted FDA Fast Track Designation for T-cell Lymphomas
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Kura Oncology‘s investigational lead therapy candidate tipifarnib was given fast track status by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with different subtypes of peripheral T-cell lymphoma (PTCL).

A fast track designation is meant to accelerate the development and review of a treatment, facilitating discussions with the FDA and enabling the therapy to qualify for priority review and accelerated approval, provided that certain criteria are met.

Specifically, the designation was given for the indications of relapsed or refractory angioimmunoblastic T-cell lymphoma (AITL), follicular T-cell lymphoma (FTCL) and nodal peripheral T-cell lymphoma with T follicular helper (TFH) phenotype.

“This important designation from the FDA comes just two months after tipifarnib was awarded fast track for the treatment of patients with HRAS mutant head and neck squamous cell carcinomas,” Bridget Martell, MD, acting chief medical officer of Kura Oncology, said in a press release.

“We believe that this designation reflects tipifarnib’s significant potential in these devastating disease settings, and we are now actively preparing to initiate a second registration-directed trial of tipifarnib in advanced nodal lymphomas of TFH phenotype, including AITL,” Martell said.

Tipifarnib blocks the activity of farnesyl transferase, an enzyme essential for protein farnesylation, a process implicated in tumor cell growth, survival and proliferation. However, the mechanism of action of tipifarnib, as that of other farnesyl transferase inhibitors, is still not fully understood.

In lymphoma, researchers believe the treatment works to prevent the CXCL12 signaling molecule from reaching the cell surface, a process that is required for T-cell migration and proliferation. Data presented at the American Society of Hematology (ASH) 2018 Annual Meeting validated CXCL12 as a therapeutic target of tipifarnib.

At the ASH 2019 meeting, the company presented preliminary results from a Phase 2 clinical trial (NCT02464228) testing tipifarnib for the treatment of PTCL patients positive for CXCL12, including those with relapsed or refractory AITL.

The trial is ongoing and recruiting participants at multiple sites in the U.S., Korea, and Spain. Its main goal is to determine the proportion of patients who responded to oral, twice-daily tipifarnib. Secondary goals include duration of response, time to disease progression or death, and safety.

At the time of the analysis, the study had included 50 participants, who had received a median of three prior treatment regimens. Nineteen had undergone stem cell transplants.

A strong clinical benefit was observed for AITL patients, with 45% achieving a response to treatment —including three complete responses, or clearance of all cancer signs, and two partial responses — and an additional 28% attaining stable disease.

Mutations in the KIR gene – a biomarker of CXCL12 signaling – also predicted better responses, with 75% of patients with such mutations responding to tipifarnib, including 50% who had no signs of disease after treatment.

Likewise, the 12 patients with a normal CXCL12 gene showed a response rate of 42%, including three complete responses and two partial responses.

“AITL histology, KIR3DL2 [patients carrying KIR3DL2 gene variants] and CXCL12 genotype provided robust tools for the selection/stratification of PTCL subjects treated with tipifarnib,” the researchers wrote.

All 48 patients who were evaluated for safety experienced at least one treatment-emergent adverse event (TEAE). The most common serious TEAEs related to tipifarnib were low levels of certain blood cells, such as neutrophils, platelets, and red blood cells. One patient died due to a lung infection that was related to tipifarnib.

Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
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