Genetic, gender and age related differences in pharmacodynamic response Not applicable. Pharmacodynamic interactions Not applicable. Evaluator’s overall conclusions on pharmacodynamics No pharmacodynamic data derived from healthy volunteers or subjects with RCC have been submitted. The PD of cabozantinib was derived form in vitro and murine models and is described in the nonclinical evaluation. Given the mechanism of action and what is already know about TKIs this is acceptable. Dosage selection for the pivotal studies Pharmacokinetics and pharmacodynamics: dose finding studies None submitted. Phase II dose finding studies No formal dose finding studies have submitted. Study XL184-001 investigated the maximum tolerated dose of cabozantinib and was determined to be 140 mg once per day. Phase III pivotal studies investigating more than one dose regimen Study SL184-308 was the pivotal study for this application. The initial starting dose was 60 mg once per day. Dose adjustments were allowed for tolerability and are summarised in 7. Table 8: Cabozantinib dose reductions in Study XL184-308 Dose reductions occurred for 70% of subjects and equal proportions of patients were taking the 60 mg dose and 40 mg dose at the data cut-off. Evaluator’s conclusions on dose finding for the pivotal studies No formal dose finding has been undertaken. The 60 mg dose was carried forward into the pivotal At the data cut-off point an equal proportion of patients were receiving the 40 mg and 60 mg doses. This would indicate that the lowest effective dose may not have been established. The prescribing information contains sufficient information about dose adjustment based on tolerability. Clinical efficacy Studies providing evaluable efficacy data Studies to support the indication Treatment of RCC:
Genetic, gender and age related differences in pharmacodynamic response Not applicable. Pharmacodynamic interactions Not applicable. Evaluator’s overall conclusions on pharmacodynamics No pharmacodynamic data derived from healthy volunteers or subjects with RCC have been submitted. The PD of cabozantinib was derived form in vitro and murine models and is described in the nonclinical evaluation. Given the mechanism of action and what is already know about TKIs this is acceptable. Dosage selection for the pivotal studies Pharmacokinetics and pharmacodynamics: dose finding studies None submitted. Phase II dose finding studies No formal dose finding studies have submitted. Study XL184-001 investigated the maximum tolerated dose of cabozantinib and was determined to be 140 mg once per day. Phase III pivotal studies investigating more than one dose regimen Study SL184-308 was the pivotal study for this application. The initial starting dose was 60 mg once per day. Dose adjustments were allowed for tolerability and are summarised in 7. Table 8: Cabozantinib dose reductions in Study XL184-308 Dose reductions occurred for 70% of subjects and equal proportions of patients were taking the 60 mg dose and 40 mg dose at the data cut-off. Evaluator’s conclusions on dose finding for the pivotal studies No formal dose finding has been undertaken. The 60 mg dose was carried forward into the pivotal At the data cut-off point an equal proportion of patients were receiving the 40 mg and 60 mg doses. This would indicate that the lowest effective dose may not have been established. The prescribing information contains sufficient information about dose adjustment based on tolerability. Clinical efficacy Studies providing evaluable efficacy data Studies to support the indication Treatment of RCC:
auspar-cabozantinib-181018-cer.docx