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

“Lurbinectedin was negative in the in vitro Ames assay but induced mutations in the mouse TK lymphoma assay, confirming that, as expected based on its mechanism of action, lurbinectedin is genotoxic.”

“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”

“Six pregnant rats received a single lurbinectedin dose of 0.1 mg/kg (0.6 mg/m2 ) or vehicle control on Day 10. There were no viable fetuses in lurbinectedin-treated dams.”

“There were no clear acute effects on cardiovascular, CNS, or respiratory parameters in any species.”

“Lurbinectedin was negative in the in vitro Ames assay but induced mutations in the mouse TK lymphoma assay, confirming that, as expected based on its mechanism of action, lurbinectedin is genotoxic.”

“Lurbinectedin was negative in the in vitro Ames assay but induced mutations in the mouse TK lymphoma assay, confirming that, as expected based on its mechanism of action, lurbinectedin is genotoxic.”

“In vivo testing was not conducted, but this is acceptable under ICH S2 for strongly cytotoxic compounds targeting rapidly dividing cells.”

“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”

“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”

“with estimated IC50 of 8.8 μM (~ 6900 ng/mL), which is far greater than the Cmax-values achieved in patients (~ 130 ng/mL) treated at the proposed clinical dosing (3.2 mg/m2, i.v., 1-h infusion).”