030: Effects of Itraconazole & Rifampin on Tazemetostat Pharmacokinetics in Patients With Advanced Malignancies

Statement of Purpose, Innovation or Hypothesis: Tazemetostat is an EZH2 inhibitor approved in the US for patients with follicular lymphoma and epithelioid sarcoma. Tazemetostat is primarily metabolized in vitro by CYP3A to form inactive metabolites, but the in vivo drug-drug interaction potential with modifiers of CYP3A activity remains unknown. This two-part study (NCT04537715) was conducted to investigate the effects of itraconazole (CYP3A inhibitor) and rifampin (CYP3A inducer) on tazemetostat pharmacokinetics in patients with advanced malignancies.

Description of Methods & Materials: In Part 1, patients received a single dose of tazemetostat 400 mg orally (PO) on the mornings of Day (D) 1, D15, and D36, and 400 mg twice daily (BID) on D3–D14 and D21–D35. Itraconazole 200 mg once daily (QD) PO was administered on D18–D38. Plasma concentrations of tazemetostat following tazemetostat dosing on D1, D15, D21, and D36 were quantified for pharmacokinetic analyses. In Part 2, patients received tazemetostat 800 mg QD PO on the mornings of D1, D15, and D24, and 800 mg BID on D3–D14 and D17–D23. Rifampin 600 mg QD PO was administered on D17–D25. Plasma concentrations of tazemetostat following tazemetostat dosing on D1, D15, and D24 were quantified for pharmacokinetic analyses. Patients were continually assessed for safety and permitted to continue tazemetostat 800 mg BID PO in 28-day cycles starting from D40 and D27, in Parts 1 and 2 respectively.

Data & Results: Forty-two patients were enrolled and treated in the study and 21 patients in each part completed the PK assessments. Nineteen patients (90.5%) in Part 1 and all patients in Part 2 had solid tumors with medians of four and three prior lines of therapy, respectively. In Part 1, co-administration of itraconazole resulted in higher exposures of tazemetostat after single doses (D21 vs D1) and at steady state (D36 vs D15). Compared with tazemetostat alone, itraconazole increased the mean C_max and AUC_0–12 by 2.00-fold (90% confidence interval [CI] 1.60–2.48) and 3.12-fold (90% CI 2.44–3.99), respectively, after single doses. Following BID dosing, itraconazole increased the mean steady-state C_max­ and AUC_0–12 by 1.86-fold (90% CI 1.49–2.31) and 2.47-fold (90% CI 2.02–3.02), respectively. However, the magnitude of tazemetostat exposure increases in the presence of itraconazole was significantly lower than expected from a strong CYP3A inhibitor. In Part 2, tazemetostat steady-state C_max and AUC_0–12 decreased by approximately 84% when co-administered with rifampin (D24 vs D15). Treatment-related treatment-emergent adverse events (TEAEs) were reported in 13 patients (61.9%) in Part 1 and 18 patients (85.7%) in Part 2. Tazemetostat-related TEAEs were reported by 12 patients (57.1%) and 16 patients (76.2%) in Parts 1 and 2, respectively; itraconazole- and rifampin-related TEAEs were reported by 8 patients (38.1%) each.

Interpretation, Conclusion or Significance: Co-administration of itraconazole (a strong CYP3A inhibitor) with tazemetostat 400 mg BID increased tazemetostat exposure by 2-3-fold indicating that concomitant administration of strong CYP3A inhibitors with tazemetostat should be discouraged. Coadministration of rifampin (a strong CYP3A inducer) with tazemetostat 800 mg BID in patients decreased tazemetostat exposure by 84%, and coadministration of strong CYP3A inducers with tazemetostat should be avoided.

Disclosures: YC, RB, AS, AK, and JO are employees of, and may own stock/stock options in Ipsen. DM has received research funding from Amgen, Merck, Oncolytics and Rafael; scientific advisory board for Actuate, Qurient, and an advisory/speaker bureau for Amgen, BMS, Eisai, and Exelixis; has received funding paid to their institution from Acepodia, Actuate Therapeutics, ADC Therapeutics, Amgen, AVEO, Bayer, Blueprint Medicines, BMS, BioNTech, Dialectic Therapeutics, Epizyme, Fujifilm, ImmuneSensor, Immune-Onc Therapeutics, Leap Therapeutics, Lycera Corp, Merck, Millennium, MiNA Alpha, NGM Biopharmaceuticals, Novartis, Oncolytics, Orano Med, Puma, Qurient, Rafael, Repare Therapeutics, Triumvira Immunologics, Vigeo Therapeutics, Warewolf Therapeutics.

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Additional Information/Authors: This study was sponsored by Epizyme, an Ipsen company. The authors thank all patients involved in the study, as well as their caregivers, care team, investigators and research staff in participating institutions. The authors thank Joshua Quartey, BSc, of Nucleus Global, London, UK for providing medical writing support, which was sponsored by Epizyme, an Ipsen company, in accordance with Good Publication Practice guidelines.