A Study of HMPL-306 in Advanced Hematological Malignancies With mIDH
- Registration Number
- NCT04764474
- Lead Sponsor
- Hutchmed
- 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
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 46
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:
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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.
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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.
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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
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment HMPL-306 All patients will be administered HMPL-306 orally QD
- Primary Outcome Measures
Name Time Method 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 Part 1: Number of Subjects with Dose Limiting Toxicities (DLTs) Up to 28 days after first dose of study drug 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.
- Secondary Outcome Measures
Name Time Method Time to maximum concentration PK weeks at screening through end of treatment, assessed up to 36 months Blood samples will be obtained from all patients for determination time to maximum concentration of HMPL-306.
Number of Subjects with best overall response From 1st dose of study drug to the time of progressive disease, assessed up to 36 months Subjects with AML will be evaluated according to the 2017 ELN criteria
Progression-free survival (PFS) From first dose of study drug to earlier of progression or death, assessed up to 36 months PFS is defined as the time from the start of study treatment to disease progression, or death due to any cause, whichever occurs first.
Maximum serum drug concentration PK weeks at screening through end of treatment, assessed up to 36 months Blood samples will be obtained from all patients for determination of the maximum serum concentration of HMPL-306.
Area under the concentration-time curve (AUC) PK weeks at screening through safety follow-up, assessed up to 36 months Blood samples will be obtained from all patients for determination of the AUC of HMPL-306
Concentration of 2-HG in plasma and/or bone marrow PK weeks at screening through safety follow-up, assessed up to 36 months Blood or bone marrow sample to determine the concentration of 2-HG
Objective Response rate (ORR) From 1st dose of study drug to the time of progressive disease, assessed up to 36 months It is defined to include subjects who have the objective response.
Clinical Benefit Rate (CBR) From 1st dose of study drug to the time of progressive disease, assessed up to 36 months CBR is defined as the proportion of subjects achieving objective response or SD.
Overall survival (OS) From 1st dose of study drug to the time of progressive disease, assessed up to 36 months OS is defined as the time from the start of the study drug until death from any cause.
Subjects with baseline transfusion dependence From the first dose of study drug to last dose of study drug, assessed up to 36 months It is defined as requiring transfusions of red blood cells (RBCs) or platelets within 56 days prior to the first dose of treatment.
Subjects with post-baseline transfusion independence From 1st dose of study drug to the time of progressive disease, assessed up to 36 months It is defined as no RBC or platelet transfusion for at least ≥4 weeks (and separately ≥8 weeks) during treatment period.
Trial Locations
- Locations (15)
University of California Irvine Medical Center (UCIMC) - Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
Institut Catala d'Oncologia de l'Hospitalet de Llobregat - Hospital Duran i Reynals
🇪🇸Barcelona, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
Hospital Universitario La Fe
🇪🇸Valencia, Spain
Winship Cancer Institute - Emory University
🇺🇸Atlanta, Georgia, United States
University of Massachusetts Medical School
🇺🇸Worcester, Massachusetts, United States
Froedtert-Medical College of WI
🇺🇸Milwaukee, Wisconsin, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
The Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Clinica Universidad de Navarra
🇪🇸Pamplona, Navarra, Spain
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
START Madrid - Hospital Universitario Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain