(ChemotherapyAdvisor) – A study of the gamma secretase inhibitor of notch signaling, RO4929097, has shown preliminary evidence of clinical antitumor activity in patients with refractory metastatic or locally advanced solid tumors, investigators reported in the Journal of Clinical Oncology online April 23.

In the multinational phase 1 study, patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days/week for 2 weeks every 3 weeks; and (B) 7 consecutive days every 3 weeks.

An expanded part of the study assessed reversible CYP3A4 autoinduction by testing three dosing schedules: B, as above; modified A, 3 consecutive days/week for 3 weeks; and C, continuous daily dosing. The investigators assessed tumor metabolic effects using FDG-PET scans.

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A total of 302 cycles of RO4929097 was administered to 58 patients on schedule A, 47 on schedule B, and 5 patients on schedule C, the expanded cohort. One patient with colorectal adenocarcinoma with neuroendocrine features had a partial response; 1 patient with sarcoma had a mixed response (stable disease); and 1 patient with melanoma had a nearly complete FDG-PET response. An effect on CYP3A4 induction was observed.

Fatigue, thrombocytopenia, fever, rash, chills, and anorexia were commonly observed grade 1 to 2 toxicities. Transient grade 3 hypophosphatemia (dose-limiting toxicity) was observed at 27mg in 1 patient and grade 3 pruritus in 2 patients at 60mg; on schedule A at 80mg, 1 patient had transient grade 3 asthenia. The investigators found RO4929097 270mg on schedule A and 135mg on schedule B to be well tolerated; safety of schedule C has not been fully evaluated.

“In conclusion, RO4929097 was well tolerated when administered by using both intermittent and continuous dosing schedules,” the investigators wrote. Several Cancer Therapy Evaluation Program-sponsored phase 1/2 studies are exploring the safety and efficacy of RO4929097, both alone and in combination. “Most of these studies use the three-on/four-off schedule at a starting dose of 20mg, which is a dose expected to not result in significant autoinduction and potential drug-drug interaction in this schedule. Recruitment on most of these studies is ongoing and results are awaited with interest,” they concluded.