Trial Outcomes & Findings for A Study of HMPL-306 in Advanced Hematological Malignancies With mIDH (NCT NCT04764474)

This Phase 1, 2-part, open-label study was conducted in patients with advanced relapsed/refractory or resistant hematological malignancies that harbor isocitrate dehydrogenase mutations. The study consisted of dose escalation part (Part 1) and dose expansion part (Part 2). A total of 46 patients were enrolled in this study.

As only 1 patient was enrolled in dose expansion part, all data of patient were pooled in dose escalation part at Dose Level 8 cohort (Cohort 8) for the data analysis. Thus, no separate participant flow period was created for dose expansion part. Study was terminated based on strategic evaluation of clinical development of HMPL-306 with no safety concerns. Dose levels increase from 1 to 8, with Dose Level 1 being the lowest dose and Dose Level 8 the highest dose.

A Study of HMPL-306 in Advanced Hematological Malignancies With mIDH

RP2D determination took the following criteria under consideration: determination of maximum tolerated dose (MTD) achieved during the dose escalation part and assessment of safety, PK and pharmacodynamics (PD).

DLT was defined as occurrence of any of the following treatment-emergent adverse events (TEAEs) during the DLT assessment window, unless clearly unrelated to the study drug as per investigator's discretion: nonhematologic toxicity: TEAEs of Grade \>=4, Grade \>=3 with the exception of those that resolved within 72 hours (h) of onset; hematologic toxicity with the exception of neutropenia or thrombocytopenia that occurred with active leukemic disease: Grade 3 or 4 neutropenia lasting more than 7 days, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or any requirement for platelets (PLT) transfusion, Grade 3 or greater febrile neutropenia defined as absolute neutrophil count (ANC) 1000 per cubic millimeter with a single temperature of \>38.3 degree Celsius (°C) or a sustained temperature of \>=38°C for more than 1 h; any TEAE requiring a dose delay of \>=14 days or cases of confirmed Hy's law.

AE:unfavorable and unintended sign,symptom or disease temporally associated with use of study drug or other protocol-imposed intervention, whether or not considered related to study drug. SAE:AE that resulted in death,life-threatening AE,inpatient hospitalization/prolongation of existing hospitalization,persistent/significant incapacity or substantial disruption of ability to conduct normal life functions, abnormal pregnancy outcome in child born to female patient or female partner of male patient exposed to study drug or was important medical event that jeopardized patient and required medical/surgical intervention to prevent above outcome. TEAE:AE with onset on/after start of study drug until 30 days after last dose or prior to start of subsequent anti-tumor therapy, or AE with onset before start of study drug but worsened in severity after study drug administration, or AE onset after 30 days after last dose or after start of subsequent anti-tumor therapy and treatment-related SAEs.

BOR was defined as the best response during the anti-tumor evaluation period, which was determined using time point responses (TPRs) from date of the first dose of study drug from Cycle 1 in continuous cycle up until the last evaluable TPR prior to or on the date of PD/relapse according to the 2017 European LeukemiaNet criteria, or death; or withdrawal of consent or lost to follow-up; or receiving subsequent anti-cancer therapy, whichever was earlier. Number of patients with BOR \[complete response (CR), CR with negative minimal residual disease (CRmrd-), CR with partial hematological recovery (CRh), CR with incomplete count (CRi), morphologic leukemia-free state (MLFS), partial response (PR), stable disease (SD), and PD\] are reported.

ORR was defined as the percentage of patients with BOR being CRmrd-, CR, CRh, CRi, MLFS or PR. CR: myeloblast \<5%, blast cells without Auer bodies, no blast cells in peripheral blood, no extramedullary lesion, ANC \>=1.0x10\^9/L, PLT \>=100x10\^9/L. CRmrd-: CR with negative RT-qPCR or CR with negative MFC. CRi: met all other criteria of CR but ANC \<1.0x10\^9/L or PLT \<100x10\^9/L. MLFS: myeloblast \<5%, blast cells without Auer bodies, no extramedullary lesion, no hematological recovery requirements. PR: met all hematological criteria for CR, percentage of myeloblasts decreased from baseline by least 50% and reached 5% to 25%.

TTOR was defined as the time from the date of first study drug administration from Cycle 1 in continuous cycle to the date of first objective response (CRmrd-, CR, CRh, CRi, MLFS, or PR). CR: myeloblast \<5%, blast cells without Auer bodies, no blast cells in peripheral blood, no extramedullary lesion, ANC \>=1.0x10\^9/L, PLT \>=100x10\^9/L. CRmrd-: CR with negative RT-qPCR or CR with negative MFC. CRi: met all other criteria of CR but ANC \<1.0x10\^9/L or PLT \<100x10\^9/L. MLFS: myeloblast \<5%, blast cells without Auer bodies, no extramedullary lesion, no hematological recovery requirements. PR: met all hematological criteria for CR, percentage of myeloblasts decreased from baseline by least 50% and reached 5% to 25%.

DoOR was defined as the time from the first occurrence of objective response (CRmrd-, CR, CRh, CRi, MLFS, or PR) until PD, relapse, or death due to any cause, whichever came first. CR: myeloblast \<5%, blast cells without Auer bodies, no blast cells in peripheral blood, no extramedullary lesion, ANC \>=1.0x10\^9/L, PLT \>=100x10\^9/L. CRmrd-: CR with negative RT-qPCR or CR with negative MFC. CRi: met all other criteria of CR but ANC \<1.0x10\^9/L or PLT \<100x10\^9/L. MLFS: myeloblast \<5%, blast cells without Auer bodies, no extramedullary lesion, no hematological recovery requirements. PR: met all hematological criteria for CR, percentage of myeloblasts decreased from baseline by least 50% and reached 5% to 25%.

CBR was defined as the percentage of patients with BOR being CRmrd-, CR, CRh, CRi, MLFS, PR, or SD lasting for 3 cycles. CR: myeloblast \<5%, blast cells without Auer bodies, no blast cells in peripheral blood, no extramedullary lesion, ANC \>=1.0x10\^9/L, PLT \>=100x10\^9/L. CRmrd-: CR with negative RT-qPCR or CR with negative MFC. CRi: met all other criteria of CR but ANC \<1.0x10\^9/L or PLT \<100x10\^9/L. MLFS: myeloblast \<5%, blast cells without Auer bodies, no extramedullary lesion, no hematological recovery requirements. PR: met all hematological criteria for CR, percentage of myeloblasts decreased from baseline by least 50% and reached 5% to 25%. SD: Not met criteria for CR, CRi, CRmrd-, MLFS, PR, or PD.

PFS was defined as the time from the start of study drug from Cycle 1 in continuous cycle to PD, or relapse, or death due to any cause, whichever occurred first. PD was defined as increase in bone marrow blast percentage and/or absolute peripheral blood blast cells: a) myeloblasts percentage increased from baseline by \>50% (if blast cells at baseline were \<30%, net increased value needs to be \>=15%) or myeloblasts percentage \>70% continued for at least 3 months; ANC was not seen to be improved by at least 100%, reached (\>0.5x10\^9/L and/or PLT reached \>50x10\^9/L, without blood transfusion); b) the absolute peripheral blood blast cell count (WBCxblast cell ratio) increased by \>50% and reached \>25x10\^9/L (without differentiation syndrome); or new extramedullary diseases.

OS was defined as the time from the start of study drug from Cycle 1 in continuous cycle until the date of death due to any cause.

EFS was defined as the time from date of first study drug administration from Cycle 1 in continuous cycle to treatment failure, relapse from CR (including CRmrd-, CR, CRh and CRi), or death due to any cause, whichever occurred first. CR: myeloblast \<5%, blast cells without Auer bodies, no blast cells in peripheral blood, no extramedullary lesion, ANC \>=1.0x10\^9/L, PLT \>=100x10\^9/L. CRmrd-: CR with negative RT-qPCR or CR with negative MFC. CRi: met all other criteria of CR but ANC \<1.0x10\^9/L or PLT \<100x10\^9/L. Treatment failure was defined as failure to achieve CR (including CRmrd-, CR, CRh, CRi) by Week 24. Patients who did not achieve CR (including CRmrd-, CR, CRh, CRi) by Week 24 were considered to have had an event at Day 1 of first study drug administration from Cycle 1 (excluding single oral dose from PK week). For remaining CR responders (including CRmrd-, CR, CRh and CRi), event time was time of either disease relapse or death due to any cause, whichever occurred first.

Post-baseline TI was defined as the absence of red blood cell and platelet transfusions for a pre-specified time during treatment period which was defined from the first dose of study drug administration from Cycle 1 in continuous cycle to 30 days after the last dose date or prior to the start of a subsequent anti-tumor therapy (whichever came first). Number of patients with post-baseline TI for \>=4 weeks and \>=8 weeks is presented.

Blood samples were collected at the specified timepoints to determine plasma concentrations of HMPL-306.

Blood samples were collected at the specified timepoints to determine Cmax of HMPL-306.

Blood samples were collected at the specified timepoints to determine Tmax of HMPL-306.

Blood samples were collected at the specified timepoints to determine AUC0-24 of HMPL-306.

Blood samples were collected at the specified timepoints to determine plasma concentrations of 2-HG which was a PD marker. The maximum inhibition rate for patients in different dose groups are presented.