CTNI-27. PHASE I/II STUDY OF ZOTIRACICLIB FOR RECURRENT MALIGNANT GLIOMAS WITH IDH MUTATIONS: RESULTS OF THE PHASE I STUDY

Abstract BACKGROUND Selective sensitivity to zotiraciclib (ZTR) in isocitrate dehydrogenase (IDH)-mutant gliomas was demonstrated in preclinical studies. A phase I/II clinical trial of ZTR was designed for recurrent IDH-mutant gliomas to exploit their therapeutic vulnerability to ZTR, a CDK9 inhibitor that regulates transcription and metabolism of glioma cells. Phase I results are reported here. METHODS Participants with recurrent IDH-mutant glioma, WHO grade 3-4, age ≥ 18, KPS ≥70, adequate organ function, and previously having received standard of care were enrolled. The primary objective was to determine the Recommended Phase II Dose (RP2D). Bayesian optimal interval design was utilized to determine maximum tolerated dose (MTD). The toxicity profile of ZTR at 3 dose levels was planned (150mg, 200mg and 250mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle with starting dose level at 200mg). RP2D was established based on MTD, pharmacokinetics (PK), and anti-tumor activities. PK samples were collected before and 2-, 4-, 24-, 48- and 72-hours after initial dosing on C1D1. RESULTS Of 16 enrolled patients, 12 were evaluable for DLT; median age 42.9, KPS 90. Of 6 evaluable patients treated at the 200 mg dose level, 0/6 had DLT; at the 250mg dose level, 3/6 had DLTs: 2 instances of Gr3 elevated ALT, and one instance of dose reduction in cycle 1 due to treatment-related Gr3 fatigue and diarrhea. There were no significant differences in T₁/₂, Tmax, Cmax, AUCinf, Vz/F, or CL/F between the 250mg and 200mg dose levels by unpaired t-test. Two participants treated at 200mg achieved partial responses. Dose level of 200mg was declared as RP2D. CONCLUSION ZTR at the RP2D of 200mg, q3D, 3wks on/1wk off in a 28-day cycle is well tolerated. Objective responses suggest activity of this regimen in IDH-mutant gliomas, supporting continued investigation.