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
592 - Effects of novel targeted anticancer drugs on cytotoxicity, apoptosis, angiogenesis, EMT, drug resistance and autophagic mechanism
Presenter: Seyma Aydinlik
Session: Poster Display session 1
Resources:
Abstract
3235 - Delineating the mechanisms of alpha 1-3 fucosyltransferase FUT11 in ovarian cancer
Presenter: Qi Chen
Session: Poster Display session 1
Resources:
Abstract
3577 - The tyrosine kinase inhibitor Dasatinib blocks tumor growth, invasion and recurrence potential by interrupting the communication between cancer cells and their surrounding microenvironment in triple negative breast cancer
Presenter: Miriam Nuncia-Cantarero
Session: Poster Display session 1
Resources:
Abstract
4808 - NORE1A induces a feedback termination of TNF signaling by antagonizing TNFR1 through ITCH-mediated destruction complex
Presenter: Jieun Ahn
Session: Poster Display session 1
Resources:
Abstract
1294 - Hsp90 inhibitors enhance the antitumoral effect of osimertinib and overcome osimertinib resistance in non-small-cell cell lung cancer cell models
Presenter: Jordi Codony-Servat
Session: Poster Display session 1
Resources:
Abstract
1559 - Expression of IL-17RA promotes cancer stem-like properties of colorectal cancer cells by Stat3 activation
Presenter: Chih-Yung Yang
Session: Poster Display session 1
Resources:
Abstract
1615 - Adaption of Pancreatic Cancer Cells to AKT1 Inhibition Induces the Acquisition of Cancer Stem-Cell Like Phenotype Through Upregulation of Mitochondrial Functions
Presenter: Hugo Arasanz
Session: Poster Display session 1
Resources:
Abstract
4793 - Bub3 is phosphorylated by the Ataxia-Telangiectasia Mutated Kinase in mitosis and required for activation of the mitotic spindle checkpoint in Breast Cancer
Presenter: Mingming Xiao
Session: Poster Display session 1
Resources:
Abstract
1448 - The regulation of INK4 locus by long non-coding RNAs
Presenter: Yojiro Kotake
Session: Poster Display session 1
Resources:
Abstract
1858 - Vascular Endothelial Growth Factor in Colorectal Cancer Pathology, Survival and Treatment
Presenter: Liz Baker
Session: Poster Display session 1
Resources:
Abstract