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

Study Overview
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Brief Summary
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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
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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 hematological malignancies including, but not limited to AML, HR-MDS, AITL.

Official Title
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A Phase 1, Open-Label, Multicenter Study of HMPL-306 in Advanced Hematological Malignancies With Isocitrate Dehydrogenase (IDH) Mutations

Conditions
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Isocitrate Dehydrogenase Gene Mutation

Intervention / Treatment
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* Drug: HMPL-306


Participation Criteria
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Eligibility Criteria
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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. An established standard of care with proven benefit for which the patient is eligible, must not be available at the time of enrollment. Subjects with MDS must have a Revised International Prognostic Scoring System (IPSS-R) score of >4.5 (high and very high risk). 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. Patients with relapsed/refractory AML/HR-MDS/AITL include the following: i. Subjects who relapse after transplantation; ii. Subjects in second or later relapse; iii. Subjects who are refractory to initial induction or re-induction treatment. Subjects must not have progressed on prior IDH treatment unless isoform switching of the IDH mutation has been documented following progression on the prior IDH inhibitor. 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.

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: Treatment<br>All patients will be administered HMPL-306 orally QD | Drug: HMPL-306<br>* Administered orally QD in a 28-day continuous dosing treatment cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Subjects with Dose Limiting Toxicities (DLTs) | DLT is defined as an adverse event (AE) that meets protocol defined DLT criteria during cycle 1 and is at least possibly related to study drug. | Up to 28 days after first dose of study drug | 
| Part 1 and Part 2: Frequency and severity of AEs |  | From the first dose of the study drug to 37 days after the last dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects with best overall response | Subjects with AML will be evaluated according to the 2017 ELN criteria Subjects with HR-MDS subjects will be evaluated according to the International Working Group response criteria in myelodysplasia Subjects with AITL will be evaluated according to the Lugano Classification for Hodgkin and Non-Hodgkin's Lymphoma Subjects with AML will be evaluated according to the 2017 ELN criteria Subjects with HR-MDS subjects will be evaluated according to the International Working Group response criteria in myelodysplasia Subjects with AITL will be evaluated according to the Lugano Classification for Hodgkin and Non-Hodgkin's Lymphoma Subjects with AML will be evaluated according to the 2017 ELN Criteria. Subjects with HR-MDS subjects will be evaluated according to the International Working Group response criteria in myelodysplasia Subjects with AITL will be evaluated according to the Lugano Classification for Hodgkin and Non-Hodgkin's Lymphoma | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Objective Response rate (ORR) | It is defined to include subjects who have the objective response. | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Clinical Benefit Rate (CBR) | CBR is defined as the proportion of subjects achieving objective response or SD. | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Overall survival (OS) | OS is defined as the time from the start of the study drug until death from any cause. | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Progression-free survival (PFS) | PFS is defined as the time from the start of study treatment to disease progression, or death due to any cause, whichever occurs first. | From first dose of study drug to earlier of progression or death, assessed up to 36 months | 
| Subjects with baseline transfusion dependence | It is defined as requiring transfusions of red blood cells (RBCs) or platelets within 56 days prior to the first dose of treatment. | From the first dose of study drug to last dose of study drug, assessed up to 36 months | 
| Subjects with post-baseline transfusion independence | It is defined as no RBC or platelet transfusion for at least ≥4 weeks (and separately ≥8 weeks) during treatment period. | From 1st dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Maximum serum drug concentration | Blood samples will be obtained from all patients for determination of the maximum serum concentration of HMPL-306. | PK weeks at screening through end of treatment, assessed up to 36 months | 
| Time to maximum concentration | Blood samples will be obtained from all patients for determination time to maximum concentration of HMPL-306. | PK weeks at screening through end of treatment, assessed up to 36 months | 
| Area under the concentration-time curve (AUC) | Blood samples will be obtained from all patients for determination of the AUC of HMPL-306 | PK weeks at screening through safety follow-up, assessed up to 36 months | 
| Concentration of 2-HG in plasma and/or bone marrow | Blood or bone marrow sample to determine the concentration of 2-HG | PK weeks at screening through safety follow-up, assessed up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Myelodysplastic Syndrome, Angio-Immunoblastic T-Cell Lymphoma, IDH Mutation