Comprehensive statistical analysis of the pharmacokinetics, safety and clinical benefit rate of MitoTam in a single-center phase I/Ib trial in patients with metastatic solid tumors

Background MitoTam, the first mitochondrial inhibitor to disrupt complex I (CI)-dependent respiration, previously showed antitumor activity against renal cell carcinoma (RCC) with a good safety profile. We investigated the relationships of pharmacokinetic (PK) parameters, biodistribution, and patient baseline diagnosis with the clinical outcome and toxicity of MitoTam. Methods In the phase I/Ib MitoTam-01 trial, patients with metastatic solid tumors were treated with MitoTam monotherapy. PK parameters were calculated separately for the doses used in both trial phases. Data were analyzed descriptive analyses and using the generalized linear model framework as stochastic test. Results The non-compartmental analysis of PK parameters showed that the extent of exposure was positively correlated with the dose. Most of the PK profiles suggested that MitoTam was redistributed from the tissues or from protein binding back into the blood circulation, with very low accumulation. The exposure‒efficacy relationship did not show significant differences between responders and non-responders in phase Ib. However, the AUC _0-t and C _max values were greater in RCC patients than in responders with other diagnoses. These data are consistent with the preclinical findings showing preferential MitoTam accumulation in kidneys and the high clinical benefit rate in RCC patients in the phase Ib part. Conclusion These comprehensive analyses demonstrate the impact of MitoTam on the clinical benefit rate that is related to the dose and corresponding PK parameters, as well the underlying diagnosis. The PK data supported the previously recommended dose of 3.0 mg/kg weekly for future trials. Registration: EudraCT 2017-004441-25 (November 1, 2017)