Clinical trial NCT04764474: A Study of HMPL-306 in Advanced Hematological Malignancies With mIDH
Official title: A Phase 1, Open-Label, Multicenter Study of HMPL-306 in Advanced Hematological Malignancies With Isocitrate Dehydrogenase (IDH) Mutations
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Isocitrate Dehydrogenase Gene Mutation
Keywords: Acute Myeloid Leukemia
IDH Mutation
Lead sponsor: Hutchmed
Sponsor class: INDUSTRY
First posted: 2021-02-21
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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 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.
* 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 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.
* 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

Primary outcomes:
measure: Part 1: Number of Subjects with Dose Limiting Toxicities (DLTs)
timeFrame: Up to 28 days after first dose of study drug
measure: Part 1 and Part 2: Frequency and severity of AEs
timeFrame: From the first dose of the study drug to 37 days after the last dose of study drug
Secondary outcomes:
measure: Number of Subjects with best overall response
timeFrame: From 1st dose of study drug to the time of progressive disease, assessed up to 36 months
measure: Objective Response rate (ORR)
timeFrame: From 1st dose of study drug to the time of progressive disease, assessed up to 36 months
measure: Clinical Benefit Rate (CBR)
timeFrame: From 1st dose of study drug to the time of progressive disease, assessed up to 36 months
measure: Overall survival (OS)
timeFrame: From 1st dose of study drug to the time of progressive disease, assessed up to 36 months
measure: Progression-free survival (PFS)
timeFrame: From first dose of study drug to earlier of progression or death, assessed up to 36 months
measure: Subjects with baseline transfusion dependence
timeFrame: From the first dose of study drug to last dose of study drug, assessed up to 36 months
measure: Subjects with post-baseline transfusion independence
timeFrame: From 1st dose of study drug to the time of progressive disease, assessed up to 36 months
measure: Maximum serum drug concentration
timeFrame: PK weeks at screening through end of treatment, assessed up to 36 months
measure: Time to maximum concentration
timeFrame: PK weeks at screening through end of treatment, assessed up to 36 months
measure: Area under the concentration-time curve (AUC)
timeFrame: PK weeks at screening through safety follow-up, assessed up to 36 months
measure: Concentration of 2-HG in plasma and/or bone marrow
timeFrame: PK weeks at screening through safety follow-up, assessed up to 36 months
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California Irvine Medical Center (UCIMC) - Chao Family Comprehensive Cancer Center
state: California
city: Atlanta
country: United States
facility: Winship Cancer Institute - Emory University
state: Georgia
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert-Medical College of WI
state: Wisconsin
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia de l'Hospitalet de Llobregat - Hospital Duran i Reynals
city: Madrid
country: Spain
facility: START Madrid - Hospital Universitario Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
Study officials:
affiliation: Hutchison Medipharma Limited
name: Bo Zhang
role: STUDY_DIRECTOR
References: