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First patient dosed in Phase 2 study of tipifarnib in advanced cancers with HRAS mutations

Posted: 18 May 2015 |

The first patient has been dosed in the Phase 2 clinical trial of tipifarnib in patients with locally advanced tumours that carry HRAS mutations…

The first patient has been dosed in the Phase 2 clinical trial of Kura Oncology’s tipifarnib in patients with locally advanced tumours that carry HRAS mutations.

tipifarnib

Tipifarnib is an inhibitor of farnesylation, a key cell signalling process implicated in cancer initiation and development.

“There are no approved treatments that target HRAS mutations specifically,” said Alan Ho, M.D., Ph.D., a medical oncologist at Memorial Sloan Kettering Cancer Centre and a lead investigator on the Phase 2 trial. “We look forward to investigating whether tipifarnib can inhibit HRAS-mediated activation of the MAPK pathway to produce therapeutic responses.”

“Tipifarnib has previously demonstrated durable responses in subsets of patients with cancer,” said Antonio Gualberto, M.D., Ph.D., Chief Medical Officer of Kura Oncology. “The selection of patients with tumours characterised by HRAS mutations represents a promising strategy to identify those patients most likely to benefit from tipifarnib.”

The HRAS protein is involved in regulating cell division in response to growth factor stimulation and other signals that instruct cells to grow or divide. HRAS is an early player in many signal transduction pathways and acts as a molecular on/off switch – once HRAS is turned on, it recruits and activates proteins necessary for the propagation of the signal. In certain tumours, mutations in the HRAS gene cause the HRAS protein to be permanently on, resulting in persistent activation of downstream growth and proliferation signals that drive tumour cell growth.

In preclinical studies, tipifarnib has been shown to block HRAS farnesylation and membrane localisation

Farnesyl transferase inhibitors, such as tipifarnib, prevent protein farnesylation, a key cell signalling process implicated in cancer initiation and development. In preclinical studies, tipifarnib has been shown to block HRAS farnesylation and membrane localisation, thereby inhibiting the growth and proliferation of HRAS mutant tumours. Collectively, cancers that have an HRAS mutation are estimated to have an annual incidence of approximately 8,000 patients in the US and, in general, patients with these cancers have poor prognosis and limited options for treatment.

The primary objective of the Phase 2 study will be to investigate the antitumour activity, in terms of objective response rate, of tipifarnib in patients with locally advanced, unresectable or metastatic, relapsed and/or refractory tumours that carry HRAS mutations. Secondary objectives include evaluation of progression-free survival, duration of response and safety. A total of 36 patients are planned to be enrolled into two non-randomized cohorts: malignant thyroid tumours with HRAS mutations; and non-hematological malignancies with HRAS mutations.

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