Fotivda: genotox, carcinogenicity and repro: done or skipped?

“Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay.”

“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”

“In animal studies assessing mating and fertility parameters, oral doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m 2 basis) in rats were associated with increased epididymis and testis weights, and doses ≥ 0.3 mg/kg/day (2 times the maximum recommended clinical dose on a mg/m 2 basis) reduced mating and produced infertility.”

“A dose of 3 mg/kg resulted in increases in systolic, diastolic and mean arterial blood pressure 90 minutes post-dose. There were no test article-related effects on heart rates, RR, PR, QT, QTcF, QTcQ intervals and the QRS duration at any dose level.”

“Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay.”

“An in Vitro Chromosomal Aberration Assay in CHO Cells (Study RCK0002) was considered unreliable as the test material was very toxic to the cells in this treatment, and it appears that it may have caused cells to undergo abnormal cell division leading to diploid cells and hyperdiploid cells (cells with greater than the normal diploid count but not polyploidy).”

“Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay.”

“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”

“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”

“The lack of QT and QTc changes are consistent with findings in the in vitro study indicating that tivozanib hydrochloride does not inhibit the hERG channel.”