Abstract 4403
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 Waldenström’s macroglobulinemia/ lymphoplasmacytic lymphoma. In the ESC, patients must have exhausted all available approved therapy options. In the EXP, patients must be naïve 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.
Resources from the same session
2728 - MicroRNA expression and DNA methylation profiles do not distinguish between primary and recurrent well-differentiated liposarcoma
Presenter: Melissa Vos
Session: Poster Display session 1
Resources:
Abstract
3197 - Genomic Alterations, Tumor Mutation Burden and Prognosis of Chinese Cardiac Sarcoma Patients
Presenter: Na Zhu
Session: Poster Display session 1
Resources:
Abstract
4214 - Evaluation of a peptide-conjugated alkylator melflufen in osteosarcoma preclinical models
Presenter: Konstantin Byrgazov
Session: Poster Display session 1
Resources:
Abstract
2654 - Expression analysis of NHEJ and HR genes in Ewing sarcomas: indications of DSB repair dysfunction
Presenter: Anastasios Kyriazoglou
Session: Poster Display session 1
Resources:
Abstract
4383 - Epidemiology of Synovial Sarcoma in EU28 countries
Presenter: Nedra Joseph
Session: Poster Display session 1
Resources:
Abstract
1937 - Resection Of High-Grade Large Soft Tissue Sarcoma With Adequate Wide Margin Can Lead To Good Local Control Without Adjuvant Radiotherapy
Presenter: Toshiyuki Kunisada
Session: Poster Display session 1
Resources:
Abstract
3757 - Influence of eribulin on proliferation, migration and invasion properties of leiomyosarcoma cell line models
Presenter: Marta Mendiola
Session: Poster Display session 1
Resources:
Abstract
1040 - EREMISS: Efficacy of regorafenib (REG) as maintenance therapy in non-adipocytic soft tissue sarcomas (STS) having received 1st-line doxorubicin-based chemotherapy (Doxo-CT)
Presenter: Nicolas Penel
Session: Poster Display session 1
Resources:
Abstract
1048 - A Phase 2 biomarker-driven study evaluating the clinical efficacy of an MDM2 inhibitor, milademetan, in patients with intimal sarcoma, a disease with a high unmet need
Presenter: Kan Yonemori
Session: Poster Display session 1
Resources:
Abstract
1511 - A pilot study of oral paclitaxel (ORAXOL) in subjects with cutaneous angiosarcomas (KX-ORAX-010)
Presenter: Herbert Loong
Session: Poster Display session 1
Resources:
Abstract