A Phase 1 Dose-Escalation Study of LH031, a Kinesin Spindle Protein Inhibitor, in Patients with Refractory/Resistance Multiple Myeloma

PURPOSE: Kinesin spindle protein is an attractive target for cancer treatment since it plays an important role in mitosis without directly affecting microtubules. LH031 is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity.. This phase 1 study was conducted to evaluated dose limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for LH031 in Chinese patients with Refractory/Resistance Multiple Myeloma（RRMM）.The pharmacokinetics (PK) and preliminary efficacy of LH031 were also evaluated.

METHODS: A non-randomized, single-center, open-label, dose-escalation phase 1 trial was conducted to evaluate the safety, tolerability, pharmacokinetics and efficacy of single or multiple escalation dose（20 mg, 30 mg, 40 mg, 50 mg）of LH031 given as schedule of oral once a day. LH031 was administered on Day 1~5 of each week for 3 weeks (21 days) per cycle. A standard 3+3 dose escalation design was employed. An expansion cohort was conducted at the MTD. Pharmacokinetics was evaluated in plasma. A major efficacy evaluation was performed at the end of each treatment cycle.

RESULTS: The study is still on going, at present there are 6 patients received LH031 and completion of all visits, divided equally into 20mg and 30mg cohort. Patients in each cohort had received a median of 6 prior therapies. DLTs reported in two patients dosed at 30mg. Both of the DLTs were neutropenia. The most commonly reported treatment-related AEs were hematological toxicity（e.g. neutropenia，lymphocytopenia，leukocytopenia）that were similar to other Eg5 inhibitors. The main severe adverse events (CTCAE grade 3 or 4) in the 20mg and 30 mg dose groups were leukocytopenia and neutropenia, and they were all reversible. Neurotoxicity related to LH031 was not observed.

Efficacy data demonstrated that the best response was Stable Disease(SD) and Disease Control Rate (DCR, ≥SD[≥8 weeks]) was 50%. The longest treatment time was 177 days, even though PFS was determined according to the last tumor evaluation before the COVID period (D88).

The PK data shows that T_1/2 are approximately 20h in Chinese patients, which is longer than Caucasian (10h); Chinese AUC for 20mg is also higher than that of Caucasian (1996 h*ng/ml vs. 476 h*ng/ml) ; the exposure at 20mg dose group is close to that at 50 mg dose in Caucasian. These PK parameter indicates that the elimination of LH031 is slower in Chinese patients compared with Caucasian.

CONCLUSIONS: The current phase 1 study showed that LH031 was an accepted safety profile at 20mg. DLTs was expected and reversible. MTD is to be determined by recruiting 3 more subjects at 20mg dose. It demonstrated that the elimination rate of LH031 in Chinese patients was slower than Caucasian. The monotherapy showed some benefit to RRMM, Phase 2 clinical trials are being planned to include various combination therapies with existing treatments (e.g. lenalidomide, dexamethasone, bortezomib) for MM to benefit more potential refractory/resistance MM patients.