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
Overview
- Phase
- Phase 1
- Intervention
- HMPL-689
- Conditions
- Lymphoma
- Sponsor
- Hutchmed
- Enrollment
- 53
- Locations
- 27
- Primary Endpoint
- Dose Escalation Stage: Number of Patients With Dose-Limiting Toxicities (DLTs)
- Status
- Terminated
- Last Updated
- 10 months ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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;
Arms & Interventions
Treatment
All patients take HMPL-689 taken daily
Intervention: HMPL-689
Outcomes
Primary Outcomes
Dose Escalation Stage: Number of Patients With Dose-Limiting Toxicities (DLTs)
Time Frame: From the first dose of study drug (Day 1) up to Day 28 of Cycle 1 (each cycle is 28 days)
A DLT was defined as the occurrence of any of the following treatment-emergent adverse events (TEAEs) during the DLT assessment window, unless equivocally due to underlying malignancy or an extraneous cause. AEs were graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0: non-hematologic toxicity: all non-hematologic TEAEs of grade 3 or greater with the exception of grade 3 nausea or vomiting that could be controlled by supportive therapy; hematologic toxicity: grade 4 neutropenia \>5 days, grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding event or requiring platelet transfusion, grade \>=3 febrile neutropenia (defined as absolute neutrophil count \[ANC\] \<1000/cubic millimeter {mm\^3} with a single temperature \>38.3 degree Celsius \[°C\] or a sustained temperature of \>=38°C for more than 1 hour), grade 4 anemia not explained by underlying disease; any TEAE that required a dose delay of \>=15 days; any case of Hy's Law.
Dose Escalation Stage: Number of Patients With Treatment-Emergent Adverse Events (TEAEs), Treatment Related Treatment-Emergent Adverse Events (TRAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Treatment Related Serious Adverse Events (TRSAEs)
Time Frame: From the first dose of study drug (Day 1) up to 30 days after the last dose of study drug, approximately 34 months
An AE was any untoward medical occurrence in a clinical investigation patient administered a study drug, regardless of causal attribution. An SAE was an AE that resulted in any of the following: was fatal, was life threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect in a neonate/infant born to a female patient or female partner of a male patient exposed to the study drug, or was considered a significant medical event by the investigator. TEAEs were defined as AEs with onset date on or after the first dose of study drug and no later than 30 days after the date of last study drug administration or start of a new study drug of anti-neoplasm therapy, whichever was earlier. Treatment related AEs and SAEs were defined as AEs and SAEs collected later than 30 days after the last study drug date or start of a new study drug of anti-neoplasm therapy.
Dose Expansion Stage: Number of Patients With Treatment-Emergent Adverse Events and Treatment Related Treatment-Emergent Adverse Events
Time Frame: From the first dose of study drug (Day 1) up to 30 days after the last dose of study drug, approximately 27 months
An AE was any untoward medical occurrence in a clinical investigation patient administered a study drug, regardless of causal attribution. TEAEs were defined as AEs with onset date on or after the first dose of study drug and no later than 30 days after the date of last study drug administration or start of a new study drug of anti-neoplasm therapy, whichever was earlier. Treatment related AEs were defined as AEs collected later than 30 days after the last study drug date or start of a new study drug of anti-neoplasm therapy.
Secondary Outcomes
- Dose Escalation and Dose Expansion Stages: Change From Baseline in Corrected QT Interval (QTc) Using Fridericia Formula (QTcF)(2 and 4 hours on Baseline (Day 1) of Cycle 1; 0, 2 and 4 hours on Day 15 of Cycle 1 (dose escalation phase); 1, 2, 3 and 4 hours on Baseline (Day 1) of Cycle 1; 0, 1, 2, 3, and 4 hours on Day 15 of Cycle 1 (dose expansion phase) (each cycle is 28 days))
- Dose Escalation and Dose Expansion Stages: Objective Response Rate (ORR)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7days) thereafter, up to a maximum of 58 months)
- Dose Escalation and Dose Expansion Stages: Time to Response (TTR)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7days) thereafter, up to a maximum of 58 months)
- Dose Escalation and Dose Expansion Stages: Duration of Response (DOR)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7days) thereafter, up to a maximum of 58 months)
- Dose Escalation and Dose Expansion Stages: Clinical Benefit Rate (CBR)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7 days) thereafter, up to a maximum of 58 months)
- Dose Escalation and Dose Expansion Stages: Progression-Free Survival (PFS)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-7 days) thereafter, up to a maximum of 58 months)
- Dose Escalation Stage: Plasma Concentration of HMPL-689(Pre-dose on Days 1, 2, 15, 16, 28 of Cycle 1 and on Day 1 of Cycle 2; 0.5, 1, 2, 4 and 8 hours post-dose on Days 1, 15 and 28 of Cycle 1 (each cycle is 28 days))
- Dose Escalation Stage: Plasma Trough Concentration (Ctrough) of HMPL-689(Days 1, 2, 15, 16, 28 of Cycle 1 and Day 1 of Cycle 2 (each cycle is 28 days))
- Dose Expansion Stage: Plasma Concentration of HMPL-689(Pre-dose on Day 1 of Cycles 1, 2, 3, 5, 7, 9, 11, 13 and on Day 15 of Cycle 1; 0 hour on Day 1 of Cycle 1; 1, 2, 3, 4 hours post-dose on Days 1 and 15 of Cycle 1 (each cycle is 28 days))
- Dose Expansion Stage: Plasma Trough Concentration of HMPL-689(Day 1 of Cycles 1, 2, 3, 5, 7, 9, 11, 13 and on Day 15 of Cycle 1 (each cycle is 28 days))