Isocitrate Dehydrogenase Gene Mutation
Conditions
Keywords
Acute Myeloid Leukemia, IDH Mutation
Brief summary
An open label single-arm clinical trial to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of HMPL-306 in subjects with advanced relapsed, refractory, or resistant hematological malignancies that harbor IDH mutations.
Detailed description
HMPL-306 is a dual IDH1/2 inhibitor This is a phase 1, open-label, multicenter, single-arm study to evaluate safety, tolerability, PK, PD, and preliminary efficacy of HMPL-306 administered orally in treatment of subjects with advanced relapsed, refractory, or resistant hematological malignancies that harbor IDH mutations (or co-mutations). The study consists of 2 parts: a dose-escalation part (Part 1) and a dose-expansion part (Part 2). The dose-escalation part will determine the MTD/R2PD. The dose-expansion part will administer the MTD/RP2D to subjects with mIDH-positive AML
Interventions
DRUGHMPL-306
Administered orally QD in a 28-day continuous dosing treatment cycle
Sponsors
Hutchmed
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Subjects may be enrolled in this study only if they satisfy all the following criteria (NOTE: This is not an exhaustive list): * Subjects aged ≥18 years. * ECOG performance status ≤ 2 * Subjects with advanced relapsed, refractory, or resistant hematological malignancies, as defined below: Part 1: * Subjects with documented IDH mutation per local or institutional next generation sequence (NGS). * Subjects must be refractory to or intolerant of established therapies. * Subjects who have received prior IDH inhibitor treatment may be enrolled in the escalation phase. Part 2: * Subjects with documented IDH mutation of any of these subsets: IDH1 (R132C), IDH1 (R132H), IDH (R140Q), and IDH2 (R172K), including co-mutations and any combination thereof per local and institutional NGS. * Patients must have received at least 1 prior line of therapy with an IDH inhibitor. An established standard of care with proven benefit for which the patient is eligible, must not be available at the time of enrollment. * Patients with AML must not have standard therapeutic options available (including IDH inhibitors where approved) and have the following: * i. Relapsed AML unsuitable for intensive chemotherapy or venetoclax-based regimen or target agents; * ii. Primary refractory AML unsuitable for intensive chemotherapy or venetoclax-based regimen or target agents. * iii. Relapsed/refractory AML that has progressed on prior IDH treatment Key
Exclusion criteria
Subjects are not eligible for enrollment into this study if they meet any of the following criteria (NOTE: This is not an exhaustive list): * Subjects who received an investigational agent \<14 days prior to their first day of study drug administration. * Subjects who are pregnant or breastfeeding. * Subjects with an active severe infection, some treated infections and with an expected or with an unexplained fever \>38.3°C during screening visits or on their first day of study drug administration. * Subjects with some current or prior heart conditions. * Subjects taking medications that are known to prolong the QT interval may not be eligible. * Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation. * Some subjects with some current or prior gastrointestinal or liver diseases. * Subjects with inadequate organ function as defined by the protocol. * Subjects with a medical condition, physical examination finding, or clinical laboratory finding that, in the Investigators opinion, contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the subject at high risk from treatment complications. * Subjects with a known hypersensitivity to HMPL-306 or to any of its excipients. * Subjects with presence of second primary malignant tumors within the last 2 years, with the exception of the following, if medically controlled: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and carcinoma in situ of the breast. * Part 2 Only: The time since the last dose of prior IDH inhibitor treatment is within 30 days prior to the first day of study drug administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Part: Recommended Phase 2 Dose (RP2D) of HMPL-306 | From the first dose of study drug (Day 1) up to Day 28 of Cycle 1 | 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). |
| Dose Escalation Part: Number of Patients With Dose-Limiting Toxicities (DLTs) | From the first dose of study drug (Day 1) up to Day 28 of Cycle 1 | 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. |
| Number of Patients With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs) | From the first dose of study drug (Day 1) up to 30 days after the last dose of study drug, approximately 25.25 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Best Overall Response (BOR) | Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months | 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. |
| Objective Response Rate (ORR) | Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months | 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%. |
| Time to Objective Response (TTOR) | Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months | 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%. |
| Duration of Objective Response (DoOR) | Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months | 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%. |
| Clinical Benefit Rate (CBR) | Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months | 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. |
| Progression-Free Survival (PFS) | Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months | 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. |
| Overall Survival (OS) | From the first dose of study drug (Day 1) up to date of death due to any cause, approximately 45 months | 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. |
| Event-Free Survival (EFS) | Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months | 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. |
| Number of Patients With Post-Baseline Transfusion Independence (TI) | From the first dose of study drug (Day 1) up to 30 days after the last dose of study drug, approximately 25.25 months | 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. |
| Plasma Concentrations of HMPL-306 | PK Week: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Day 1 PK week; Cycle 2 Day 1: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Cycle 2 Day 1 | Blood samples were collected at the specified timepoints to determine plasma concentrations of HMPL-306. |
| Maximum Observed Plasma Concentration (Cmax) of HMPL-306 | PK Week: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Day 1 PK week; Cycle 2 Day 1: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Cycle 2 Day 1 | Blood samples were collected at the specified timepoints to determine Cmax of HMPL-306. |
| Time to Reach the Maximum Plasma Concentration (Tmax) of HMPL-306 | PK Week: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Day 1 PK week; Cycle 2 Day 1: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Cycle 2 Day 1 | Blood samples were collected at the specified timepoints to determine Tmax of HMPL-306. |
| Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of HMPL-306 | PK Week: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 PK week; Cycle 2 Day 1: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Cycle 2 Day 1 | Blood samples were collected at the specified timepoints to determine AUC0-24 of HMPL-306. |
| Maximum Inhibition Rate of Plasma 2-Hydroxyglutaric Acid (2-HG) | From PK Week Day 2 until end of treatment, approximately 24.25 months | 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. |
Countries
Spain, United States
Contacts
STUDY_DIRECTORBo Zhang
Hutchison Medipharma Limited
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 72.3 years STANDARD_DEVIATION 6.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized White | 7 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 3 / 3 | 7 / 11 | 5 / 7 | 5 / 6 | 3 / 4 | 2 / 4 | 4 / 8 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 10 / 11 | 7 / 7 | 6 / 6 | 3 / 4 | 3 / 4 | 8 / 8 |
| serious Total, serious adverse events | 3 / 3 | 1 / 3 | 6 / 11 | 5 / 7 | 5 / 6 | 3 / 4 | 4 / 4 | 5 / 8 |
Outcome results
None listed