CLL/SLL, NHL, MCL, MZL, Lymphoplasmacytic Lymphoma, Waldenstrom Macroglobulinemia, Follicular Lymphoma, DLBCL, Richter Syndrome
Conditions
Keywords
Lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia, Chronic lymphocytic leukemia, Non-Hodgkin lymphoma, Mantle cell lymphoma, Marginal zone lymphoma, Follicular lymphoma, Diffuse large B-cell lymphoma, BTK inhibitor
Brief summary
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
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
Interventions
DRUGHMPL-760
Administered orally QD for 28-day cycles
Sponsors
Hutchmed
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of DLTs | Up to 28 days after first dose of study drug | Adverse event (AE) that meets protocol defined DLT criteria during dose escalation |
| Incidence of AEs/SAEs | From 1st dose to within 30 days of last dose | Any untoward medical occurrence associated with the use of study drug |
| MTD | From 1st dose to within 30 days of last dose | To evaluate maximum tolerated dose of HMPL-760 in subjects, if reached |
| RP2D | From 1st dose to within 30 days of last dose | To determine recommended phase 2 dose of HMPL-760 in subjects |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration [Cmax] | From 1st dose to within 30 days of last dose | To determine the maximum observed plasma concentration of HMPL-760 |
| Objective Response Rate (ORR) | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | ORR is defined as the proportion of subjects achieving partial response and better response during the study |
| Phospho-BTK | From 1st dose to within 30 days of last dose | To observe the whole blood concentrations of phospho-BTK |
| Chemokines | From 1st dose to within 30 days of last dose | To observe blood plasma concentrations of chemokines such as CCL22 and CCL3 |
| Duration of Response (DoR) | From first dose of study drug to the time of progressive disease, assessed up to 36 months | DoR is defined as the time between the initial response to therapy and subsequent disease progression or relapse. |
| Clinical Benefit Rate (CBR) | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | CBR is defined as the proportion of subjects achieving objective response or stable disease |
| Progression-free Survival (PFS) | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | PFS is defined as survival without progression of the disease |
Countries
Australia, France, Israel, Italy, Poland, Spain, United States
Outcome results
None listed