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

Sponsor

Hutchison Medipharma Limited (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04764474

Collaborator

(none)

Enrollment

Locations

Arm

23.1

Anticipated Duration (Months)

10.7

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Isocitrate Dehydrogenase Gene Mutation	Drug: HMPL-306	Phase 1

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 hematological malignancies including, but not limited to, AML, MDS/MPN, AITL.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

75 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 28, 2021

Anticipated Primary Completion Date :

Jan 31, 2023

Anticipated Study Completion Date :

Jan 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment All patients will be administered HMPL-306 orally QD	Drug: HMPL-306 Administered orally QD in a 28-day continuous dosing treatment cycle

Arm

Intervention/Treatment

Experimental: Treatment

All patients will be administered HMPL-306 orally QD

Drug: HMPL-306

Administered orally QD in a 28-day continuous dosing treatment cycle

Outcome Measures

Primary Outcome Measures

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.
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

Number of Subjects with Complete Response (CR) [From 1st dose of study drug to the time of progressive disease, assessed up to 36 months]
Number of Subjects with Complete Response with Incomplete Marrow Recovery (CRi [From 1st dose of study drug to the time of progressive disease, assessed up to 36 months]
Number of Subjects with Complete Response with Negative Minimal Residual Disease (CRMRD-) [From 1st dose of study drug to the time of progressive disease, assessed up to 36 months]
Number of Subjects with Partial Response (PR) [From 1st dose of study drug to the time of progressive disease, assessed up to 36 months]
Number of Subjects with Stable Disease (SD) [From 1st dose of study drug to the time of progressive disease, assessed up to 36 months]
Subjects who have not achieved a CR, CRi, CRMRD-, morphologically leukemia-free state (MLFS), or PR but have no evidence of progression of disease in >8 weeks.
Objective Response Rate (ORR) [From 1st dose of study drug to the time of progressive disease, assessed up to 36 months]
ORR is defined as the proportion of subjects achieving PR and better response during the study [CR + CRi + marrow CR/MLFS + PR].
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 first dose of study drug to end of study or death, assessed up to 36 months]
OS is defined as the time from the start of the study drug until death from any cause.
Proportion of non-blood transfusion dependent subjects [From the first dose of study drug to last dose of study drug, assessed up to 36 months]
It is defined as the proportion of subjects who do not need blood transfusion for any sequential period ≥8 weeks during the study treatment period.
Maximum serum drug concentration [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 maximum serum concentration of HMPL-306
Time to maximum concentration [PK weeks at screening through safety follow-up, assessed up to 36 months]
Blood samples will be obtained from all patients for determination time to maximum 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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.
Subjects must have received at least 2 prior lines of therapy for their hematologic malignancy.
Subjects with MDS must have a Revised International Prognostic Scoring System (IPSS-R) score of >4.5 (high and very high risk).
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30322
2	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
3	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
4	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
5	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
6	Institut Catala d'Oncologia de l'Hospitalet de Llobregat - Hospital Duran i Reynals	Barcelona		Spain	08908
7	Hospital Universitario 12 de Octubre	Madrid		Spain	28041