A Phase 1 Study of HMPL-523, Highly Selective and Potent a Small Molecule Inhibitor of Spleen Tyrosine Kinase in Patients with Relapsed or Refractory Lymphoma

Background:

The B-cell receptor (BCR) signaling pathway plays a critical role in the pathogenesis of lymphomas, particularly in non-Hodgkin lymphomas (NHL). Despite availability of therapeutic agents targeting BCR pathway, there continue to be unmet medical need for more effective and less toxic therapeutic agents for patients with advanced relapsed, refractory or resistant lymphoma.

HMPL-523 is a novel, orally available, highly selective, and potent small molecule inhibitor of spleen tyrosine kinase (SYK), a crucial component of BCR signaling pathway. A clinical study is currently ongoing in the USA and in EU countries of France, Italy, Poland, and Spain. Preliminary results from dose escalation and expansion stages of these trials are expected soon. Herein is the description of an ongoing phase 1 open-label, multi-center, single-arm study of HMPL-523 in patients with advanced relapsed, refractory or resistant (R/R) NHL (NCT03779113).

Study Population:

Targeted patient population is adult patients with histologically confirmed advanced relapsed, R/R NHL. To be eligible for enrollment, patients must have exhausted all approved therapeutic options available.

Objectives and Endpoints:

The primary objective is to assess safety and tolerability of HMPL-523 and to determine the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoints are the incidence of dose-limiting toxicity (DLT) and safety parameters, including treatment-emergent adverse events and laboratory abnormalities

The secondary objectives are to characterize the pharmacokinetic (PK) parameters and to evaluate the safety and preliminary efficacy of HMPL-523. The secondary endpoints are the incidence of treatment-emergent adverse events (TEAE), PK parameters, and efficacy parameters, including objective response rate, duration of response, time to response, and progression-free survival.

Study Design:

Study consists of a dose escalation stage and an expansion stage. The dose-escalation utilizes a modified 3+3 design, with anticipated enrollment of approximately 24 patients until MTD is reached, and RP2D is determined. The proposed doses of escalation cohorts are 100, 200, 400, 600 and 800 mg, QD, PO in a 28-day cycle. Patients will be treated until disease progression, intolerable toxicity, no further benefit, withdrawal, end of study, or death.

The expansion stage will be dosed at the MTD to further evaluate safety, tolerability, PK, drug exposure, target engagement, PD and their correlation with clinical benefit of HMPL-523. Approximately 10 patients will be enrolled in each of the following cohorts:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),

• Mantle cell lymphoma (MCL),

• Follicular lymphoma (FL)

• Marginal zone lymphoma (MZL)

• Peripheral T-cell lymphoma (PTCL)

• Cutaneous B-cell lymphoma

• Waldenström's macroglobulinemia / lymphoplasmacytic lymphoma (WM)

Statistical Methods:

For the escalation stage, the sample size is based on the dose-escalation rules of the 3+3 design. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in a given cohort of 6 patients is 46.9%, 26.5%, and 5.8%, respectively.

For the dose expansion stage, a total of 70 patients (10 patients per expansion cohort) will provide robust safety data in the study patient populations. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in 70 patients is 99.9%, 97.2%, and 50.5%, respectively. For preliminary assessment of anti-tumor activity based on ORR, if at least 8 patients in a specific lymphoma subtype are evaluable for tumor response, the chance of observing at least one response is 94.2%, if the true ORR is 30%.

Safety parameters, including DLTs, recorded TEAEs, clinical laboratory parameters, vital signs, 12-lead ECG parameters and physical examination findings, will be summarized by dose level across both dose escalation and dose expansion stages.

Efficacy endpoints will be summarized by dose level for each type of malignancy.

Significance:

This study is the first global clinical study of HMPL-523, a novel inhibitor of the BCR signaling pathway currently enrolling patients with advanced relapsed, refractory or resistant NHL who have exhausted all approved therapeutics options available.