LAUSR

Abstract Background The B-cell receptor (BCR) signaling pathway plays a central role in non-Hodgkin lymphoma (NHL). Despite available agents targeting the BCR pathway, there continues to be a need for alternative therapies in the relapsed/refractory (R/R) setting due to agent-specific toxicities and differences in efficacy among agents and lymphoma subtypes. HMPL-689 is a highly selective small molecule inhibitor of phosphoinositide 3-kinase-delta (PI3Kδ), one of the key signaling molecules in BCR function. HMPL-689 has shown strong dose- and time-dependent inhibition of B-cell activation in rats. There is one ongoing clinical study in China, as well as the current study, which is being conducted in the United States (US) and European Union (EU). We present here a trial-in-progress description of this US/EU study, a phase 1 trial with a dose-escalation stage (ESC) and a dose expansion stage (EXP). Trial design Study Population: The target population is patients (pts) with histologically confirmed R/R NHL, including chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Waldenstrom’s macroglobulinemia/ lymphoplasmacytic lymphoma. In the ESC, patients must have exhausted all available approved therapy options. In the EXP, patients must be naive to PI3K inhibitors. Objectives: The primary objective is to assess the safety and tolerability of HMPL-689 in pts with R/R NHL and to determine the maximum-tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Preliminary efficacy will be evaluated in the dose expansion stage. Study Design: Dose-escalation will follow a modified toxicity probability interval scheme-2 and enroll 6 to 30 pts, until the MTD or the maximum sample size is reached. The proposed doses are 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg oral, once daily in 28-day cycles. HMPL-689 will be administered until disease progression, intolerable toxicity, no further benefit from study treatment, withdrawal, end of study, or death. The EXP will further evaluate the MTD/RP2D in ∼50 pts, with ∼10 pts each, in subtype-specific cohorts. Clinical trial identification NCT03786926. Editorial acknowledgement Hoang-Lan Nguyen, PhD, Hutchison MediPharma (US), Inc. Legal entity responsible for the study Hutchison MediPharma, Limited. Funding Hutchison MediPharma, Limited. Disclosure J. Cohen: Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Janssen; Advisory / Consultancy: Kite/Gilead; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): LAM Therapeutics; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): LRF; Research grant / Funding (institution): ASH; Research grant / Funding (institution): UNUM; Research grant / Funding (institution): BioInvent; Research grant / Funding (institution): AstraZeneca. R. Cordoba Mascunano: Advisory / Consultancy, Travel / Accommodation / Expenses: AbbVie; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Gilead; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Speaker Bureau / Expert testimony: Bristol-Myers Squibb. A.J.M. Ferreri: Advisory / Consultancy, Travel / Accommodation / Expenses: Gilead; Advisory / Consultancy, Speaker Bureau / Expert testimony: Kite; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche Pharma AG. C. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. M. Kania: Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. J. Kauh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Hutchison MediPharma Ltd. N. Ghosh: Advisory / Consultancy, Speaker Bureau / Expert testimony: Seattle Genetics; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pharmacyclics; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Gilead/Kite; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: TG Therapeutics; Advisory / Consultancy: Celgene/Juno.