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

Phase 1TerminatedNCT03786926

Hutchmed53 enrolled

Overview

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

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Lymphoma

Interventions

HMPL-689DRUG

HMPL-689 is a PI3Kδ inhibitor

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. (ECOG) performance status of 0 or 1; 2. Histologically confirmed lymphoma (tumor types are restricted to CLL/SLL, FL (grade 1-3a), MCL, MZL, LPL/WM, PTCL or CBCL); 3. 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); 4. Expected survival of more than 24 weeks. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from study entry: 1. Primary central nervous system (CNS) lymphoma; 2. Any of the following laboratory abnormalities Absolute neutrophil count; \<1.0×10\^9/L, Hemoglobin \<80 g/L Platelets \<50 ×10\^9/L 3. 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; 4. International normalized ratio (INR) \> 1.5 × ULN, activated partial thromboplastin time (aPTT) \> 1.5 × ULN; 5. Serum amylase or lipase \> ULN at screening or known medical history of serum amylase or lipase \> ULN; 6. Patients with presence of second primary malignant tumors within the last 2 years; 7. Clinically significant history of liver disease; 8. Prior treatment with any PI3Kδ inhibitors; 9. 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; 10. Clinically significant active infection or interstitial lung diseases (including drug induced pneumonitis); 11. Major surgical procedure within 4 weeks prior to initiation of study treatment; 12. Adverse events from prior anti-neoplastic therapy that have not resolved to Grade less than or equal to 1, except for alopecia; 13. New York Heart Association (NYHA) Class II or greater congestive heart failure; 14. Congenital long QT syndrome or QTc \>470 msec; 15. Currently use medication known to cause QT prolongation or torsades de pointes; 16. History of myocardial infarction or unstable angina within 6 months prior to initiation of study treatment; 17. History of stroke or transient ischemic attack within 6 months prior to initiation of study treatment; 18. Inability to take oral medication, prior surgical procedures affecting absorption, or active peptic ulcer disease; 19. History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis); 20. Patients with ongoing chronic gastrointestinal diseases; 21. 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.

Locations (27)

Outcomes

Primary Outcomes

Dose Escalation Stage: Number of Patients With Dose-Limiting Toxicities (DLTs)

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.

Time frame: From the first dose of study drug (Day 1) up to Day 28 of Cycle 1 (each cycle is 28 days)

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)

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.

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

Data from ClinicalTrials.gov

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Secondary Outcomes

Dose Escalation and Dose Expansion Stages: Objective Response Rate (ORR)

ORR: percentage of patients with complete response (CR),CR with incomplete marrow recovery (CRi),nodular partial response (nPR),PR with lymphocytosis (PR-L) or PR for CLL patients; CR, very good PR (VGPR),PR or minor response (MR) for WM patients;CR or PR for patients with disease other than CLL and WM.CR: absence of serum (S) monoclonal immunoglobulin (Ig)M, normal S IgM, complete resolution of extramedullary disease,morphologically normal bone marrow aspirate and trephine biopsy. CRi:criteria fulfilled for CR but persistent cytopenia,anemia,thrombocytopenia or neutropenia. nPR:patients with residual CLL cells.PR-L:patients achieved PR with CLL-related signs/symptoms other than lymphocytosis and continued on therapy.PR, VGPR, MR: detectable monoclonal IgM,no new signs/symptoms of active disease and PR: ≥50% but \<90% reduction in S IgM,reduction in extramedullary disease,VGPR: \>=90% reduction in S IgM,complete resolution of extramedullary disease,MR: \>=25% but \<50% reduction in S IgM.

Time frame: 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)

TTR was defined as the time from the first dose of study drug to the first occurrence of CR, CRi, PR, nPR, VGPR, PR-L, or MR. CR: absence of serum monoclonal IgM, normal serum IgM, complete resolution of extramedullary disease, morphologically normal bone marrow aspirate and trephine biopsy. CRi: criteria fulfilled for CR but persistent cytopenia, anemia, thrombocytopenia or neutropenia. PR: detectable monoclonal IgM, no new signs/symptoms of active disease, 50% but \<90% reduction in serum IgM, reduction in extramedullary disease. nPR: patients with residual CLL cells. VGPR: detectable monoclonal IgM, no new signs/symptoms of active disease,\>=90% reduction in serum IgM, complete resolution of extramedullary disease. PR-L: patients achieved PR with CLL-related signs/symptoms other than lymphocytosis and continued on therapy. MR: detectable monoclonal IgM, no new signs/symptoms of active disease, \>=25% but \<50% reduction in serum IgM.

Time frame: 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)

DOR: time from when first response (CR, CRi, PR, nPR, VGPR, PR-L and MR) was achieved until earlier of first documentation of definitive PD or death from any cause, whichever was earlier. CR: absence of S monoclonal IgM, normal S IgM, complete resolution of extramedullary disease, morphologically normal bone marrow aspirate and trephine biopsy. CRi: criteria fulfilled for CR but persistent cytopenia, anemia, thrombocytopenia or neutropenia. nPR: patients with residual CLL cells. PR-L: patients achieved PR with CLL-related signs/symptoms other than lymphocytosis and continued on therapy. PR, VGPR, MR: detectable monoclonal IgM, no new signs/symptoms of active disease and PR: ≥50% but \<90% reduction in S IgM, reduction in extramedullary disease, VGPR: \>=90% reduction in S IgM, complete resolution of extramedullary disease, MR: \>=25% but \<50% reduction in S IgM. PD: \>=25% increase in S IgM level from lowest nadir and/or progression in clinical features attributable to the disease.

Time frame: 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)

CBR was defined as percentage of patients who had best overall response (BOR) with stable disease (SD) or better. BOR was defined as the best response recorded from the start of treatment until PD or new anti-cancer therapy, whichever came earlier. PD: \>=25% increase in serum IgM level from lowest nadir and/or progression in clinical features attributable to the disease. SD: detectable monoclonal IgM, \<25% reduction and \<25% increase in serum IgM level, no progression in extramedullary disease, no new signs/symptoms of active disease.

Time frame: 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)

PFS was defined as the time from the date of first study drug to the earliest date of PD or death of any cause, whichever occurred first. PD was defined as \>=25% increase in serum IgM level from lowest nadir and/or progression in clinical features attributable to the disease.

Time frame: 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

Blood samples were collected to determine plasma concentration of HMPL-689. The pharmacokinetic (PK) parameters were determined by non-compartmental analysis.

Time frame: 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

Blood samples were collected to determine Ctrough of HMPL-689. The PK parameters were determined by non-compartmental analysis.

Time frame: 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

Blood samples were collected to determine plasma concentration of HMPL-689. The PK parameters were determined by non-compartmental analysis.

Time frame: 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

Blood samples were collected to determine Ctrough of HMPL-689. The PK parameters were determined by non-compartmental analysis.

Time frame: Day 1 of Cycles 1, 2, 3, 5, 7, 9, 11, 13 and on Day 15 of Cycle 1 (each cycle is 28 days)

Dose Escalation and Dose Expansion Stages: Change From Baseline in Corrected QT Interval (QTc) Using Fridericia Formula (QTcF)

12-lead electrocardiogram was performed to evaluate the effect of HMPL-689 on cardiac repolarization by detecting the changes in QTcF intervals. Baseline was defined as the last assessment performed prior to or on first non-zero dose date with time point marked as "pre-dose".

Time frame: 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)