P539: A PHASE 1 STUDY OF HMPL-306, A DUAL INHIBITOR OF MUTANT ISOCITRATE DEHYDROGENASE (IDH) 1 AND 2, IN PTS WITH RELAPSED/REFRACTORY MYELOID HEMATOLOGICAL MALIGNANCIES HARBORING IDH1 AND/OR 2 MUTATIONS

Topic: 16. Myeloproliferative neoplasms - Clinical Background: HMPL-306 is a potent selective inhibitor of mutant IDH1/2. Aims: The phase 1 study aimed to evaluate safety, tolerability, recommended phase 2 study (RP2D), pharmacokinetics/pharmacodynamics (PK/PD) and preliminary efficacy of HMPL-306 in patients (pts) with relapsed/ refractory myeloid hematological malignancies (HMs) carrying mutant IDH1 and 2. Methods: The open-label, multicenter phase 1 study included dose escalation and dose expansion phases. Pts with relapsed/refractory myeloid HMs carrying mutant IDH1 and/or 2 were eligible. Dose escalation was from 25 mg QD to 250 mg QD in 6 cohorts with 28-day treatment cycles, using mTPI-2 design to determine the maximum tolerated dose (MTD). In dose expansion, pts received HMPL-306 at RP2D in 28-day cycles until disease progression or intolerability toxicity. Primary objectives were safety, tolerability and MTD/RP2D. Secondary objectives mainly included PK/PD and overall response rate (ORR, complete remission [CR]+CR with incomplete hematologic recovery [CRi]+marrow CR [mCR]/ morphologic leukemia-free state+partial remission [PR]). Results: Dose escalation was completed. As of 30 Nov 2022, 49 pts including non-hotspot mutations were enrolled (n=4, 3, 3, 25, 7, 7 in 25, 50, 100, 150, 200, 250 mg QD cohorts, respectively): aged (median) 63 years, 26 pts (53.1%) male, and 31 pts (63.3%) had received ≥2L of prior therapies. No dose-limiting toxicities (DLTs) were observed during DLT observation period. Based on safety, tolerability, PK/PD and preliminary efficacy in each cohort, 30 additional pts were enrolled in 150 (n=22), 200 (n=4) and 250 (n=4) mg QD cohorts. The best of response was 1 CR in 100 mg cohort; 9 CRs (CR+CRi, including 5 CRminimal residual disease negative [MRD-]) and 1 PR in 150 mg QD; 1 CR in 200 mg QD; and 3 CRs (CR+CRi, including 1 CRMRD-) in 250 mg QD; with an ORR of 33.3% (1/3), 40.0% (10/25), 14.3% (1/7) and 42.9% (3/7), respectively. Of pts with susceptible IDH1 and 2 mutations (IDH1-R132C, IDH2-R140Q or R172K) (n=37), the ORR was 50.0% (1/2), 45.0% (9/20), 25.0% (2/4) and 50.0% (3/6) in 100, 150, 200 and 250 mg QD cohorts, respectively. Drug exposures in plasma were increased with dose from 25 mg to 250 mg. Mean terminal t1/2 was 90-120 h, and the steady state was reached after 22 or 28 days with about 5-fold accumulation following multiple doses. Target inhibition indexed with plasma 2-HG level change was influenced by IDH mutation types and 2-HG baselines of subjects. After balancing baselines, 250 mg QD was predicted to achieve >90% target inhibition much earlier than 150 mg QD, and the maximum target inhibition after multiple doses of 250 mg QD was slightly higher than 150 mg. 34 (69.4%) pts reported TRAEs, and 13 (26.5%) pts reported grade ≥3 TRAEs. The safety profile was similar in 150 and 250 mg QD cohorts during all treatment cycles, and 250 mg QD showed a favorable non-hematological toxicities over 150 mg QD in Cycle 1. Summary/Conclusion: Combing with safety, tolerability, PK/PD and preliminary efficacy, the RP2D was set as 250 mg QD at Cycle 1, and then with 150 mg QD from Cycle 2. Dose expansion is ongoing. Clinical trial information: NCT04272957. Keywords: Myeloid malignancies, Hematological malignancy