Trial Outcomes & Findings for An Open-label, Dose Escalation Trial to Evaluate the Safety and Pharmacokinetics of HMPL-523 in Patients With Lymphoma (NCT NCT03779113)

This Phase 1 open-label study was conducted in patients with relapsed or refractory lymphoma who had exhausted approved therapy options. Study recruitment was terminated based on a strategic decision made by the Sponsor to discontinue development of HMPL-523 for lymphoma in the United States, Europe, and Australia with no safety concerns.

A total of 87 patients were screened for this study (24 in dose escalation stage \[Stage 1\] and 63 in dose expansion stage \[Stage 2\]), out of which 18 patients were screen failures (3 in dose escalation and 15 in dose expansion stages). A total of 21 patients in dose escalation stage and 48 patients in dose expansion stage were enrolled in this study and received at least one dose of HMPL-523.

An Open-label, Dose Escalation Trial to Evaluate the Safety and Pharmacokinetics of HMPL-523 in Patients With Lymphoma

A DLT was defined as the occurrence of any of the following treatment-emergent adverse events (TEAEs) during the DLT assessment window, unless clearly unrelated to the study treatment. AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0: non-hematologic toxicity: all non-hematologic TEAEs of Grade 3 or greater with the exception of Grade 3 nausea or vomiting controlled by supportive therapy; hematologic toxicity: Grade 4 neutropenia \>5 days, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or which required platelets transfusion, Grade \>=3 febrile neutropenia (defined as absolute neutrophil count \<1000/cubic millimeter 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.

An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment, whether or not considered related to the treatment. TEAEs were defined as AEs with an onset date on or after the first dose of study treatment and no later than 30 days after the date of last study treatment administration or start of a new treatment of anti-neoplasm therapy, whichever was earlier. Treatment related AEs were the TEAEs that were reported as related to study treatment by the Investigator.

RP2D was based on the pharmacokinetics (PK), safety, and tolerability assessments in dose escalation stage patients.

ORR:percentage of patients who had best overall response (BOR) with complete response (CR),CR with incomplete marrow recovery (CRi),nodular partial response (nPR) 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 type other than CLL and WM. BOR:best response from start of treatment until progression or any further anticancer therapy.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, 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.

CR rate was defined as the percentage of patients who had BOR with CR or CRi for CLL patients, and CR only for other patients. BOR was defined as the best response from start of treatment until progression or any further anticancer therapy. CR was defined as the absence of serum monoclonal IgM, normal serum IgM, complete resolution of extramedullary disease, morphologically normal bone marrow aspirate and trephine biopsy. CRi was defined as the criteria fulfilled for CR but persistent cytopenia, anemia, thrombocytopenia or neutropenia.

CBR was defined as the percentage of patients who had BOR of stable disease (SD) or better. BOR was defined as the best response from start of treatment until progression or any further anticancer therapy. SD was defined as detectable monoclonal IgM, \<25% reduction and \<25% increase in serum IgM level, no progression in extramedullary disease, no new signs/symptoms of active disease.

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. 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 disease.

TTR was defined as the time from the first dose of study treatment 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. 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 serum IgM, reduction in extramedullary disease, VGPR: \>=90% reduction in serum IgM, complete resolution of extramedullary disease, MR: \>=25% but \<50% reduction in serum IgM. Kaplan Meier analysis included only the responders.

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

Blood samples were collected to determine Cmax of HMPL-523. The PK parameters were determined by non-compartmental analysis. Eventually, the patients discontinued as they progressed in the study. Hence, fewer patients at each cycle and no patients returned on Cycle 1 Day 28 in dose expansion stage: MZL arm.

Blood samples were collected to determine tmax of HMPL-523. The PK parameters were determined by non-compartmental analysis. Eventually, the patients discontinued as they progressed in the study. Hence, fewer patients at each cycle and no patients returned on Cycle 1 Day 28 in dose expansion stage: MZL arm.

Blood samples were collected to determine AUC0-t of HMPL-523. The PK parameters were determined by non-compartmental analysis.

Blood samples were collected to determine AUCtau of HMPL-523. The PK parameters were determined by non-compartmental analysis. Eventually, the patients discontinued as they progressed in the study. Hence, fewer patients at each cycle and no patients returned on Cycle 1 Day 28 in dose escalation stage: HMPL-523 800 mg QD and dose expansion stage: MZL arms.

Blood samples were collected to determine CL/F of HMPL-523. The PK parameters were determined by non-compartmental analysis. Eventually, the patients discontinued as they progressed in the study. Hence, fewer patients at each cycle and no patients returned on Cycle 1 Day 28 in dose escalation stage: HMPL-523 800 mg QD and dose expansion stage: MZL arms.

Blood samples were collected to determine Cmin of HMPL-523. The PK parameters were determined by non-compartmental analysis. Eventually, the patients discontinued as they progressed in the study. Hence, fewer patients at each cycle and no patients returned on Cycle 1 Day 28 in dose escalation stage: HMPL-523 800 mg QD and dose expansion stage: MZL arms.

Blood samples were collected to determine MRCmax. The metabolites of HMPL-523 were M1 (HM5023222) and M44 (HM5025866) only. The PK parameters were determined by non-compartmental analysis. Eventually, the patients discontinued as they progressed in the study. Hence, fewer patients at each cycle and no patients returned on Cycle 1 Day 28 in dose expansion stage: MZL arm.

Blood samples were collected to determine MRAUCtau. The metabolites of HMPL-523 were M1 (HM5023222) and M44 (HM5025866) only. The PK parameters were determined by non-compartmental analysis. Eventually, the patients discontinued as they progressed in the study. Hence, fewer patients at each cycle and no patients returned on Cycle 1 Day 28 in dose escalation stage: HMPL-523 800 mg QD and dose expansion stage: MZL arms.

Blood samples were collected to determine RA(Cmax) of HMPL-523. The PK parameters were determined by non-compartmental analysis. Eventually, the patients discontinued as they progressed in the study. Hence, fewer patients at each cycle and no patients returned on Cycle 1 Day 28 in dose expansion stage: MZL arm.

Blood samples were collected to determine RA(AUC) of HMPL-523. The PK parameters were determined by non-compartmental analysis. Eventually, the patients discontinued as they progressed in the study. Hence, fewer patients at each cycle and no patients returned on Cycle 1 Day 28 in dose escalation stage: HMPL-523 800 mg QD and dose expansion stage: MZL arms.

An AE was any untoward medical occurrence in a clinical study patient temporally associated with the use of a study treatment, whether or not considered related to the treatment. TEAEs were defined as AEs with an onset date on or after the first dose of study treatment and no later than 30 days after the date of last study treatment administration or start of a new treatment of anti-neoplasm therapy, whichever was earlier. Treatment related AEs were the TEAEs that were reported as related to study treatment by the Investigator.

ORR: percentage of patients who had BOR with CR, CRi, nPR or PR for CLL patients; CR, VGPR, PR or MR for WM patients; CR or PR for patients with disease type other than CLL and WM. BOR: best response from start of treatment until progression or any further anticancer therapy. 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, 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.

CR rate was defined as the percentage of patients who had BOR with CR or CRi for CLL patients, and CR only for other patients. BOR was defined as the best response from start of treatment until progression or any further anticancer therapy. CR was defined as the absence of serum monoclonal IgM, normal serum IgM, complete resolution of extramedullary disease, morphologically normal bone marrow aspirate and trephine biopsy. CRi was defined as the criteria fulfilled for CR but persistent cytopenia, anemia, thrombocytopenia or neutropenia.

CBR was defined as the percentage of patients who had BOR of SD or better. BOR was defined as the best response from start of treatment until progression or any further anticancer therapy. SD was defined as detectable monoclonal IgM, \<25% reduction and \<25% increase in serum IgM level, no progression in extramedullary disease, no new signs/symptoms of active disease.

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. 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 disease.

TTR was defined as the time from the first dose of study treatment to the first occurrence of CR, CRi, PR, nPR, VGPR, PR-L, or MR. 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. Kaplan Meier analysis included only the responders.

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