The National Cancer Center of Japan and Daiichi Sankyo Company, Limited have announced a collaboration to develop an inhibitor for mutant isocitrate dehydrogenase IDH1 (DS-1001) as a new molecular targeting drug for malignant brain tumors (gliomas) and the commencement of a first-in-human phase 1 clinical trial.

Mutations in the IDH1 and IDH2 genes are frequently observed in patients with malignant tumors, such as gliomas, acute myeloid leukemia (AML), cholangiocarcinoma, and chondrosarcoma. The National Cancer Center Research Institute, Division of Hematological Malignancy research group led by Issay Kitabayashi discovered that inhibitions of mutant IDH1/2 were able to eliminate AML cancer stem cells. In addition, preclinical studies using patient-derived xenograft (PDX) models showed that DS-1001, which has high blood-brain barrier permeability, was effective in suppressing the proliferation of malignant gliomas, AML, and chondrosarcoma.

Most molecular targeted drugs developed to date target molecules that are active or highly expressed in tumors. However, these drugs may have problematic side effects because the targeted molecules are to some extent also active in normal, healthy cells. DS-1001 selectively inhibits the mutant form of IDH1, which is expressed only in cancer cells, and has minimum effect against wild-type IDH1, which is expressed in normal cells.

Mutations in the IDH1 genes are observed in more than 70% of patients who are diagnosed as grade 2 or 3 gliomas (astrocytomas or oligodendrogliomas). These types of glioma with IDH1 mutation are most frequently observed in 30 to 50 years old population, with multiple relapse and long term treatment course. DS-1001 may be effective in such a patient population.

This multicenter phase I clinical trial is planned to enroll patients with recurrent IDH1 mutant gliomas who have no standard treatment at the National Cancer Center Hospital (Chuo-ku, Tokyo) and other facilities in Japan.