HMPL-760 Safety and Tolerability Study in Patients With Previously Treated CLL/SLL or NHL

Study Overview
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Brief Summary
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An open label single-arm clinical trial to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of HMPL-760 in patients with previously treated CLL/SLL or NHL

Detailed Description
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HMPL-760 is a highly potent, selective, and reversible inhibitor against BTK, which would be studied in B-cell malignancy carrying either BTK(WT) or BTK(C481S). This is a phase 1, open-label, multicenter, single-arm study to evaluate safety, tolerability, PK, PD, and preliminary efficacy of HMPL-760 in patients with previously treated CLL/SLL or NHL The study consists of 2 parts: Part 1- Dose Escalation to determine MTD and/or RP2D of HMPL-760 Part 2- Dose Expansion to characterize the safety and tolerability of HMPL-760

Official Title
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A Multicenter, Open-label, Phase 1 Study Evaluating the Safety and Tolerability of HMPL-760 in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Other Non-Hodgkin Lymphoma (NHL)

Conditions
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NHL, CLL/SLL, MCL, MZL, Lymphoplasmacytic Lymphoma, Waldenstrom Macroglobulinemia, Follicular Lymphoma, DLBCL, Richter Syndrome

Intervention / Treatment
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* Drug: HMPL-760


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ECOG performance status of 0 or 1; Histologically confirmed NHL or CLL with disease progression or intolerance to either ≥2 prior regimens. Patients with CLL/SLL and indolent NHL must meet criteria for systemic therapy. Patients with gastric extranodal MZL who are H. pylori positive must have failed H. pylori eradication therapy. Availability of tumor sample: This may be an archival tissue sample obtained after most recent therapy or a fresh biopsy; if tumor sample is not available for patients in dose escalation, the Sponsor may waive the requirement after discussion. Dose expansion stage only: Patients must have been treated with 1 prior regimen containing a BTK inhibitor in cohorts 1 to 5; Expected survival of more than 24 weeks as determined by the Investigator. Exclusion Criteria: Patients with primary central nervous system lymphoma. Any of the following laboratory abnormalities: Absolute neutrophil count (ANC) <0.75×109/L Hemoglobin <8 mg/L Platelets <50×109/L Note: In the dose expansion stage, patients with cell counts below the thresholds listed above may be considered eligible if there is documented bone marrow infiltration and Sponsor approval Inadequate organ function International normalized ratio (INR) >1.5×ULN, activated partial thromboplastin time (aPTT) >1.5×ULN - Patients requiring anticoagulation therapy (except vitamin K antagonists [ie, warfarin]) but with a stable INR within the recommended range according to the local guideline are eligible. Patients with presence of second primary malignant tumors within the last 2 years, with the exception of the following: Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Clinically significant history of liver disease, including cirrhosis or current known active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV). Cancer therapy, including chemotherapy, hormonal therapy, biologic therapy, vaccine, or radiotherapy within 3 weeks prior to initiation of study treatment. For oral targeted therapies, a washout period of 5 half-lives of the agent (minimum 3 days) prior to the initiation of study treatment can be used. Any granulocyte colony-stimulating factor treatment/blood transfusion within 7 days before the screening hematology test. Prior use of any drug that is a strong inducer or inhibitor of CYP3A4 within 2 weeks prior to initiation of study treatment. Prior use of proton pump inhibitors (PPIs) within 5 days of study treatment Any transplant within 100 days prior to initiation of study treatment Clinically significant active infection or with an unexplained fever. Treatment within a clinical study of an investigational agent or using an investigational device within 3 weeks prior to initiation of the current study treatment. AEs from prior antineoplastic therapy that have not resolved to grade <1 Pregnant (positive urine or serum beta human chorionic gonadotropin test) or lactating women. New Your Heart Association (NYHA) class II or greater congestive heart failure. NOTE: Only key inclusion/exclusion criteria are listed. Full details are in the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>All patients to receive HMPL-760 daily. | Drug: HMPL-760<br>* Administered orally QD for 28-day cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DLTs | Adverse event (AE) that meets protocol defined DLT criteria during dose escalation | Up to 28 days after first dose of study drug | 
| Incidence of AEs/SAEs | Any untoward medical occurrence associated with the use of study drug | From 1st dose to within 30 days of last dose | 
| MTD | To evaluate maximum tolerated dose of HMPL-760 in subjects, if reached | From 1st dose to within 30 days of last dose | 
| RP2D | To determine recommended phase 2 dose of HMPL-760 in subjects | From 1st dose to within 30 days of last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the proportion of subjects achieving partial response and better response during the study | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Duration of Response (DoR) | DoR is defined as the time between the initial response to therapy and subsequent disease progression or relapse. | From first dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Clinical Benefit Rate (CBR) | CBR is defined as the proportion of subjects achieving objective response or stable disease | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Progression-free Survival (PFS) | PFS is defined as survival without progression of the disease | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Maximum Plasma Concentration [Cmax] | To determine the maximum observed plasma concentration of HMPL-760 | From 1st dose to within 30 days of last dose | 
| Chemokines | To observe blood plasma concentrations of chemokines such as CCL22 and CCL3 | From 1st dose to within 30 days of last dose | 
| Phospho-BTK | To observe the whole blood concentrations of phospho-BTK | From 1st dose to within 30 days of last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Follicular lymphoma, Lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia, Chronic lymphocytic leukemia, Non-Hodgkin lymphoma, Mantle cell lymphoma, Marginal zone lymphoma, Diffuse large B-cell lymphoma, BTK inhibitor