Results of the PK/PD analysis of the ClarIDHy study showed that the study dose of the IDH1 inhibitor ivosidenib resulted in good exposure and inhibition of oncometabolite D-2-HG.
Mutations in isocitrate dehydrogenase 1 (IDH1) occur in up to 20% of intrahepatic CCA, leading to excessive production and accumulation of the oncometabolite D-2-hydroxyglutarate (D-2-HG), which is implicated in pathogenesis of CCA. Ivosidenib (Tibsovo) is an oral, targeted inhibitor of the mutant IDH1 enzyme that was evaluated in the global, phase 3, multicenter, double-blind ClarIDHy study (NCT02989857), which demonstrated prolongation of PFS with ivosidenib treatment compared with placebo in patients with advanced CCA harboring IDH1 mutations. At the ASCO 2020 Gastrointestinal Cancers Symposium, results were presented of the PK/PD analysis of the ClarIDHy study as well as assessment of plasma D-2-HG levels with clinical outcomes.
In the ClarIDHy study, eligibility criteria included unresectable or metastatic CCA, centrally confirmed IHD1 mutations by NGS, and 2 previous therapies. Eligible patients were randomized 2:1 to receive ivosidenib 500 mg once daily in continuous 28-day cycles or placebo, stratification was by number of previous systemic therapies (1 or 2). The study design allowed crossover from placebo to ivosidenib on radiographic progressive disease. PK/PD analyses was a secondary end point of the study, with samples collected at the following time point: predose, and 0.5, 2, and 4 hours postdose on day 1 of cycles 1-2; predose and 2 hours postdose on day 15 of cycle 1-2; predose on day 1 from cycle 3 onwards. Plasma levels of ivosidenib and D-2-HG were measured using validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methods.
At data cutoff (January 31, 2019), 185 patients had received ivosidenib (N = 124) or placebo (N = 61), and 35 placebo patients crossed over to ivosidenib. Of these, 156 patients treated with ivosidenib were evaluable for the PK/PD analysis, including the 35 crossover patients. Ivosidenib was found to be absorbed rapidly following single (tmax, 2.63 hours) and multiple oral doses (tmax, 2.07 hours); exposure, as measured by Cmax and area under the curve, was higher at cycle 2 day 1 than after a single dose, with low accumulation. Steady-state levels of plasma ivosidenib were reached within cycle 1 of daily dosing. In the ivosidenib-treated cohort, D-2-HG inhibition was robust and durable over the course of the treatment, with mean plasma D-2-HG concentration reducing from 1108 ng/mL at baseline to 97.7 ng/mL at cycle 2 day 1, nearly reaching levels in healthy subjects (72.6 ± 621.8 ng/mL); the observed inhibition was persistent up to cycle 19. Even after multiple ivosidenib administrations, an average D-2-HG inhibition of 75% (up to 97.3%) was achieved at steady state. In contrast, no plasma D-2-HG decreases were observed in the placebo cohort. Responders to ivosidenib treatment achieved lower steady-state D-2-HG levels that persisted over longer time periods and were associated with prolonged PFS.
Results of the PK/PD analysis of the ClarIDHy study indicated that oral ivosidenib 500 mg once daily demonstrated good exposure and maintained the inhibition of D-2-HG to levels observed in healthy subjects, which is in contrast to patients in the placebo subgroup, who showed elevated levels of D-2-HG.
Source: Fan B, et al. J Clin Oncol. 2020;38(4_suppl). Abstract 539.
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