Trial to Evaluate the Safety and Pharmacokinetics of HMPL-689 in Patients With Lymphomas

Study Overview
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Brief Summary
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An open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability and PK of HMPL-689 in patients with relapsed or refractory lymphomas

Detailed Description
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This is a Phase 1, open-label, multicenter study of HMPL-689 administered orally to patients with relapsed or refractory lymphoma. HMPL-689 is a selective and potent small molecule inhibitor targeting the isoform phosphoinositide 3'-kinase delta (PI3Kδ), a key component in the B-cell receptor signaling pathway This study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2). Dose Escalation Stage (Stage 1): This stage will end when any of the following criteria is met: The dose level 1 demonstrates an excessive toxicity, ie, 3 dose limiting toxicities (DLTs) are observed out of the first 3 patients at dose level 1. The maximum sample size is reached. The MTD and/or RP2D is confirmed. Dose Expansion Stage (Stage 2): To further characterize the safety and explore the preliminary anti-tumor activity of HMPL-689 at RP2D, patients with B cell lymphoma will be enrolled in the dose expansion stage.

Official Title
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A Phase 1, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of HMPL-689 in Patients With Relapsed or Refractory Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: HMPL-689


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (ECOG) performance status of 0 or 1; Histologically confirmed lymphoma (tumor types are restricted to CLL/SLL, FL (grade 1-3a), MCL, MZL, LPL/WM, PTCL or CBCL); Patients with relapsed or refractory NHL for whom: Standard of care treatment options no longer exist (Stage 1 only); Standard of care treatment options no longer exist with the exception of PI3K-delta inhibitors (Stage 2 only); Expected survival of more than 24 weeks. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from study entry: Primary central nervous system (CNS) lymphoma; Any of the following laboratory abnormalities Absolute neutrophil count; <1.0×10^9/L, Hemoglobin <80 g/L Platelets <50 ×10^9/L Inadequate organ function, defined by the following: Total bilirubin ≥1.5 times the upper limit of normal (× ULN); AST or ALT > 2.5 × ULN; Estimated creatinine clearance (CrCl) per Cockcroft-Gault; Dose Escalation stage of trial (Stage 1) - CrCl < 40 mL/min; Dose Expansion stage of trial (Stage 2) - CrCl <30 mL/min; International normalized ratio (INR) > 1.5 × ULN, activated partial thromboplastin time (aPTT) > 1.5 × ULN; Serum amylase or lipase > ULN at screening or known medical history of serum amylase or lipase > ULN; Patients with presence of second primary malignant tumors within the last 2 years; Clinically significant history of liver disease; Prior treatment with any PI3Kδ inhibitors; Any prior use of the following: cancer therapy within 3 weeks of study treatment, GCSF within 7 days of screening, steroid therapy or targeted anti-neoplastic intent within 7 days of treatment, any use of strong CYP3A4 inducers within 2 weeks prior to initiation of study treatment, prior autologous transplant within 6 months of study treatment, prior allogenic stem cell transplant within 6 months of study treatment; Clinically significant active infection or interstitial lung diseases (including drug induced pneumonitis); Major surgical procedure within 4 weeks prior to initiation of study treatment; Adverse events from prior anti-neoplastic therapy that have not resolved to Grade less than or equal to 1, except for alopecia; New York Heart Association (NYHA) Class II or greater congestive heart failure; Congenital long QT syndrome or QTc >470 msec; Currently use medication known to cause QT prolongation or torsades de pointes; History of myocardial infarction or unstable angina within 6 months prior to initiation of study treatment; History of stroke or transient ischemic attack within 6 months prior to initiation of study treatment; Inability to take oral medication, prior surgical procedures affecting absorption, or active peptic ulcer disease; History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis); Patients with ongoing chronic gastrointestinal diseases; Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications.

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 take HMPL-689 taken daily | Drug: HMPL-689<br>* HMPL-689 is a PI3Kδ inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events as evaluated by the NCI CTCAE v5.0 grade | The safety and tolerability of HMPL-689 dose will be evaluated based on adverse events data | From first dose to within 30 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum plasma concentration (Cmax) | To characterize the pharmacokinetic (PK) properties of HMPL-689 in patients with relapsed or refractory lymphoma | from cycle 1 day 1 30 min pre-dose until cycle 2 day 1 30 min pre dose (escalation) from cycle 1 day 1 30 min pre-dose to Cycle 5 day 1 pre-dose 30 min (expansion) (cycle is 28 days) | 
| Area under the concentration-time curve in a selected time interval (AUC0-t) | To characterize the pharmacokinetic (PK) properties of HMPL-689 in patients with relapsed or refractory lymphoma | from cycle 1 day 1 30 min pre-dose until cycle 2 day 1 30 min pre dose (escalation) from cycle 1 day 1 30 min pre-dose to Cycle 5 day 1 pre-dose 30 min (expansion) (cycle is 28 days) | 
| Objective response rate (ORR) defined as the proportion of patients who have a CR or PR | To evaluate the anti-tumor activity of HMPL-689 in patients with relapsed or refractory lymphoma according to: (1) Chronic Lymphocytic Leukemia (CLL) - modified International Workshop on CLL guidelines, (2) Waldenstrom's Macroglobulinemia (WM) - consensus of international workshops on WM, (3) Lymphomas other than CLL or WM: Lugano Response Criteria for Hodgkin and Non-Hodgkin's Lymphoma | from first 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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CLL, SLL, FL, MZL, LPL, WM, MCL, PTCL, CBCL