A Phase 1 Study of HMPL-689, a Small Molecule, Highly Selective, and Potent Inhibitor of Phosphoinositide 3 Kinase-Delta, 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 is an unmet medical need for more effective and well-tolerated therapeutic agents for patients with advanced relapsed, refractory, or resistant NHL.

HMPL-689 is a novel, orally available, highly selective, and potent small molecule inhibitor of phosphosinositide 3 kinase-delta (PI3Kδ), a crucial signaling transduction molecule in the BCR signaling pathway. A global clinical study of HMPL-689 is currently ongoing in the USA and the EU countries of France, Italy, Poland, and Spain. Preliminary results from dose escalation and expansion stages of this study are expected soon. Herein is the description of an ongoing phase 1, open-label, multi-center, single-arm study of HMPL-689 in patients with advanced relapsed, refractory, or resistant (R/R) NHL (NCT03786926).

Study Population:

Target patient population is adult patients with histologically confirmed advanced relapsed, refractory, or resistant NHL. To be eligible for enrollment, patients must have exhausted all approved therapeutic options available. Patients are ineligible for the study if they have primary central nervous system lymphoma.

Objectives and Endpoints:

The primary objective is to determine the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) of HMPL-689. The primary endpoints are the incidence of dose-limiting toxicity (DLT) and safety parameters, including treatment-emergent adverse events and laboratory abnormalities

The secondary objective is to evaluate the pharmacokinetic (PK) parameters and preliminary efficacy. The secondary endpoints include concentration-time profiles, PK parameters, and efficacy parameters, including objective response rate, time to response, duration of response, and progression-free survival.

Study Design:

Study consists of a dose escalation and dose expansion stages. The dose-escalation stage utilizes a mTPI-2 design, with anticipated enrollment of approximately 24 patients until MTD is reached, and RP2D is determined. The proposed doses for escalation cohorts are 10, 15, 20, 25, 30, 35, 40, 45, and 50 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. 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:

The maximum sample size in the dose-escalation stage will be determined based on the accumulated safety data and the mTPI-2 design. The maximum sample size under the mTPI-2 method is k × (d + 1), where k denotes the cohort size and d denotes the number of doses. The minimum cohort size in this study is 3 patients per cohort. To ensure that the highest dose (if needed) is reached, it is estimated that approximately 33-39 patients will be needed in this study.

For dose expansion, approximately 70 patients (10 in each cohort) will provide robust safety data in the patient populations studied. 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%.

Data will be summarized by dose level, subtype of malignancy, and overall as appropriate. Continuous assessments will be summarized by number of patients (n), mean, standard deviation, median, minimum and maximum.

Significance:

This study is the first global clinical study of HMPL-689, a novel inhibitor of the BCR signaling pathway, which is currently enrolling patients with advanced relapsed, refractory, or resistant NHL who have exhausted all approved therapeutics options available.