A Study of HMPL-306 in Patients With IDH1 and/or IDH2 Mutation of Relapsed/Refractory Myeloid Leukemia/Neoplasms

Study Overview
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Brief Summary
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Phase I, multicenter study to evaluate the safety, pharmacokinetics, pharmacodynamics and efficacy of HMPL-306 in Patients of Relapsed/Refractory Myeloid Leukemia/Neoplasms with IDH1 and/or IDH2 Mutation.

Detailed Description
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The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and efficacy of HMPL-306 in Patients of Relapsed/Refractory Myeloid Leukemia/Neoplasms with IDH1 and/or IDH2 Mutation. The first stage of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of HMPL-306 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second stage of the study is a dose expansion phase where three cohorts of patients will receive HMPL-306 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose.

Official Title
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A Phase I, Open-Label, Multicenter Study to Assess the Safety, Pharmacokinetics and Efficacy of HMPL-306 in Patients of Relapsed/Refractory Myeloid Leukemia/Neoplasms With IDH1 and/or IDH2 Mutation

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: HMPL-306


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age; Signed Informed Consent Form; Relapsed/refractory Acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia(CMML) and others myeloid neoplasm; IDH1 and/or IDH2 mutated disease status as assessed by local laboratory; Cooperative Oncology Group (ECOG) performance status of 0-2; Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study. Exclusion Criteria: Previously treated with any prior IDH1 inhibitor, IDH2 inhibitor, or IDH1/IDH2 double-targeted therapy and had disease progression during treatment; with known involvement or clinical symptoms of central nervous system (CNS); Patients who have undergone HSCT within 60 days; Without adequate liver or kidney function; With known infection with active hepatitis B or C; With known infection with human immunodeficiency virus (HIV); History of clinically significant or active cardiac disease; Active clinically significant infection; Taking known strong cytochrome P450 (CYP) 2C8 inducers or inhibitors; Pregnancy or breast-feeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HMPL-306<br>HMPL-306 administered continuously as a single agent orally every day in a 28-day cycle. | Drug: HMPL-306<br>* HMPL-306 administered continuously as a single agent starting at 25 mg orally every day in a 28-day cycle and dose escalation is planned up to 200mg. Subjects may continue treatment with HMPL-306 until disease progression, development of other unacceptable toxicity or hematopoietic stem cell transplant.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability: Incidence of adverse events | Incidence of adverse events. | Baseline up to the last patient has completed the 24 weeks of treatment | 
| Maximum tolerated dosage (MTD) and/or recommended phase 2 dosage (RP2D) | Measured by adverse event profile. | Baseline up to the last patient has completed the 24 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (Cycle 1 Day 1) of HMPL-306 | Cmax: maximum observed drug concentration in measured matrix after single dose administration. | Pre-dose, 10 minutes, 1, 1.5, 2, 3, 5, 8, 11, 24, 48, 72, 120 and 168 hours after start | 
| AUC(0-24) (Cycle 1 Day 1) of HMPL-306 | AUC: area under the concentration vs. time curve from zero to infinity after single (first) dose. | Pre-dose, 10 minutes, 1, 1.5, 2, 3, 5, 8, 11, 24, 48, 72, 120 and 168 hours after start | 
| AUC(0-tlast) (Cycle 1 Day 1) of HMPL-306 | AUC from time zero to the last data point. | Pre-dose, 10 minutes, 1, 1.5, 2, 3, 5, 8, 11, 24, 48, 72, 120 and 168 hours after start | 
| Objective Response Rate (ORR) | proportion of patients with confirmed complete response (CR) and partial response (PR). | Baseline up to the last patient has completed the 24 weeks of treatment | 
| Duration of response (DOR) | DOR is defined as the time from the date of first observed tumor response (Complete response (CR) or Partial response (PR)) until first subsequent disease progression or until death (if death occurs before progression is documented) due to any cause. | Baseline up to the last patient has completed the 24 weeks of treatment | 
| Progression-free survival (PFS) | PFS is defined as the time from enrollment (i.e., date of treatment assignment) to disease progression. | Baseline up to the last patient has completed the 24 weeks of treatment | 
| Overall survival (OS) | OS is defined as the time from enrollment (i.e., date of treatment assignment) until death from any cause or until the last date the patient is known to be alive. | Baseline up to the last patient has completed the 24 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IDH2 Mutation, HMPL-306, IDH1 Mutation, Acute myeloid leukemia, Myelodysplastic symdrome, Chronic myelomonocytic leukemia, Myeloid Leukemia/Neoplasms