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

“Trilaciclib was negative for mutagenic potential in the Ames assays and negative for clastogenic potential in primary human fibroblasts. Trilaciclib increased micronucleus formation in human peripheral blood lymphocytes in vitro, suggesting clastogenic activity.”

“Carcinogenic potential of trilaciclib has not been assessed in animals.”

“No fertility, developmental, or reproductive toxicity studies were conducted in animals.”

“There were signals for potential cardiovascular effects of trilaciclib based on a low potency in vitro signal for hERG inhibition (IC50 ≈ 20 μM) and increased heart rate in dogs. In vitro hERG inhibition is a biological marker of QT prolongation but no QT prolongation was observed in animal studies.”

“Trilaciclib was negative for mutagenic potential in the Ames assays and negative for clastogenic potential in primary human fibroblasts.”

“Trilaciclib increased micronucleus formation in human peripheral blood lymphocytes in vitro, suggesting clastogenic activity. However, lymphocytes were shown to be very sensitive to the intended pharmacologic effect of G1 cell cycle by trilaciclib, so the increase in micronuclei seen in HPBL cells was confounded by direct drug-related effects on lymphocyte proliferation.”

“Genetic toxicity was not assessed in any in vivo assay (e.g., rat liver micronucleus formation in vivo to assess clastogenic potential).”

“Importantly, trilaciclib clinical dosing is in patients who are receiving chemotherapy to target existing small cell lung cancer so there was little to be gained”

“Importantly, trilaciclib clinical dosing is in patients who are receiving chemotherapy to target existing small cell lung cancer so there was little to be gained”

“There were signals for potential cardiovascular effects of trilaciclib based on a low potency in vitro signal for hERG inhibition (IC50 ≈ 20 μM) and increased heart rate in dogs. In vitro hERG inhibition is a biological marker of QT prolongation but no QT prolongation was observed in animal studies.”