A Study of HMPL-306 in Advanced Solid Tumors With IDH Mutations

Study Overview
=================
Brief Summary
-----------------
An open label single-arm clinical trial to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of HMPL-306 in advanced or metastatic solid tumors with IDH mutation.

Detailed Description
-----------------
HMPL-306 is a dual IDH1/2 inhibitor This is a phase 1, open-label, multicenter study to evaluate the safety and tolerability of HMPL-306 administered orally in the treatment of subjects with advanced or metastatic solid tumors with IDH mutation. The study consists of 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). The dose escalation part will determine the MTD/RP2D. The dose expansion part will administer the MTD/RP2D to mIDH-positive solid tumor malignancies including, but not limited to, cholangiocarcinoma, skeletal chondrosarcoma, low-grade glioma, perioperative low-grade glioma

Official Title
-----------------
A Multicenter, Open-Label, Phase I Study Evaluating the Safety and Tolerability of HMPL-306 in Subjects With Advanced or Metastatic Solid Tumors With IDH Mutations

Conditions
-----------------
Isocitrate Dehydrogenase Gene Mutation

Intervention / Treatment
-----------------
* Drug: HMPL-306


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Subjects are eligible for enrollment into this study if they meet any of the following criteria (NOTE: This is not an exhaustive list): Subjects aged ≥18 years. ECOG performance status 0 or 1 Subjects must have a documented IDH mutation per immunohistochemistry (IHC), polymerase chain reaction (PCR), or next generation sequencing (NGS) testing of tumor tissue. Subjects must have histologically or cytologically documented, advanced or metastatic solid malignancy of any type that has recurred or progressed on available standard treatment and for which no curative therapy exists. 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Dose Escalation Cohorts<br>Patients from each cohort will be administered HMPL-306 orally QD | Drug: HMPL-306<br>* Administered orally QD in a 28-day continuous dosing treatment cycle<br>|
| Experimental: Part 2 Dose Expansion Cohorts<br>Patients from each cohort will be administered HMPL-306 orally QD at the recommended phase 2 dose | Drug: HMPL-306<br>* Administered orally QD in a 28-day continuous dosing treatment cycle<br>|

What is the study measuring?
-----------------
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 |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the proportion of subjects with confirmed best overall tumor response of Complete Response (CR) or Partial Response (PR). | From first dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Clinical Benefit Rate (CBR) | CBR is the proportion of subjects with stable disease (SD), confirmed PR or confirmed CR (CR+PR+SD). | From first dose of study drug to the time of progressive disease, assessed up to 36 months | 
| Duration of response (DoR) | DoR defined as the time from the date of the first CR or PR to the first date of progressive disease (PD) or death from any cause. | From first dose of study drug to the time of disease relapse or death, whichever comes first, assessed up to 36 months | 
| Progression-free Survival (PFS) | PFS is defined as time from first dose date of study drug to date of progression or date of death from any cause, whichever occurred first. | From first dose of study drug to the time of progressive disease or death due to any causes, whichever comes first, 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 safety follow-up, 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 safety follow-up, 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cholangiocarcinoma, Skeletal chondrosarcoma, Glioma, IDH Mutation