A Phase I, Multi-center, Open-label, Single-arm Study to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of AB-218 for Treating Adult Patients With Advanced IDH1 Mutant Cholangiocarcinoma and Other Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- AB-218 capsule
- Conditions
- Cholangiocarcinoma With IDH1 Mutation
- Sponsor
- AnHeart Therapeutics Inc.
- Enrollment
- 9
- Locations
- 14
- Primary Endpoint
- TEAEs
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This is an open label, single-arm Phase I study to evaluate the safety, tolerability, PK and preliminary efficacy of AB-218, an oral IDH1 inhibitor, for the treatment of adult patients with advanced IDH1 mutant cholangiocarcinoma and other solid tumors who have failed at least one prior therapy in the advanced stage.
The study contains a dose escalation part and a dose expansion part. In the dose escalation part, participants are enrolled sequentially into one of 3 dose levels of AB-218 (125 mg BID, 250 mg BID and 500 mg BID) following a 3+3 rule. Intensive PK sampling will be performed during the dose escalation part. Participants will be followed up for DLTs from the date of first study dose to 28 days afterwards. When all participants in the dose escalation part have completed the 28-day DLT observation period, SMC will review the available data including but not limited to safety, tolerability and PK, and then recommend the dose for the study dose expansion part.
In the dose expansion part, there are 2 disease cohorts planned: cholangiocarcinoma (CCA) and other IDH1 mutant solid tumors. It is planned to enrol 30 participants in the CCA cohort and another 15 participants in other IDH1 mutant solid tumors, to assess the safety and preliminary efficacy of AB-218. Sparse PK samples will be collected to further evaluate the PK profile in the different target populations.
Each participant will undergo screening up to 28 days prior to the start of the treatment period. The treatment period consists of a visit on Day 1 of every 28-day cycle and continues until any of disease progression, unacceptable toxicity, withdrawal of consent or death. An end of treatment (or early discontinuation) visit occurs 30 days (± 7 days) after the last dose of study medication, and a survival follow call every 12 weeks until death, withdrawal of informed consent, loss to follow-up (LTFU) or termination of the study by the sponsor, whichever occurs first.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Must be ≥18 years of age at the time of signing the informed consent form.
- •Must have locally advanced or metastatic solid tumors that have recurred or progressed following treatment with at least 1 prior systemic therapy, or that have not responded to prior systemic therapy; or the patient is unfit for any intensive chemotherapy in the first line setting.
- •Must have histologically confirmed IDH1 mutation from testing of a primary or metastatic tumor before first study treatment. Patients must have archival primary tumor biopsy or surgical specimens, or biopsies of recurrence of metastasis for IDH1 mutation confirmation and status of other concurrent gene mutations. Patients shall provide formalin-fixed paraffin-embedded (FFPE) tissue slides without staining, which are shipped to the designated laboratory. The IDH1 mutation must be determined by a validated assay as performed in Clinical Laboratory Improvement Amendments (CLIA)-certified/College of American Pathologists (CAP)-accredited or locally equivalent clinical laboratories. Patients whose tumors have not been tested for IDH1 mutation, must be consented with the pre-screening ICF to allow collection of tumor tissue and testing at the designated qualified central laboratory. These patients may only be consented to the study with the full ICF if they have a documented IDH1 mutation.
- •Must have a measurable lesion(s) as per the RECIST v1.1 criteria.
- •Patients with chronic HCV infection are acceptable to enroll, if ≥ 4 weeks between achieving sustained viral response and start of study drug. Anti-viral therapy is allowed during the study treatment period.
- •Patients with chronic HBV infection may enroll in the study, if HBV DNA is \<1000 copies/mL prior to the start of study treatment. Anti-viral therapy is allowed during the study treatment period.
- •Must have life expectancy ≥ 3 months.
- •Must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤
- •Must have a Child-Pugh class A liver score within 7 days prior to first dose of study treatment.
- •Must have adequate organ functions as defined below:
Exclusion Criteria
- •Patients diagnosed with IDH1 mutant glioma or acute myeloid leukemia (AML).
- •Patients with history or complication of any of the following diseases within 3 months prior to the initial dose of the investigational drug.
- •Myocardial infarction
- •Severe or unstable angina pectoris
- •Coronary or peripheral endovascular treatment
- •Heart failure
- •Cerebrovascular disorder including transient ischemic attack, stroke, central nervous system (CNS) bleeding.
- •Uncontrolled active systemic fungal, bacterial, or other infection (despite appropriate antibiotics or other treatment).
- •HIV infection as determined by an HIV antibody test.
- •Presence of Grade 3 ascites, as defined in the Guidance on the Management of Ascites and Complications in Cirrhosis
Arms & Interventions
AB-218
AB-218 for the treatment of adult patients with advanced cholangiocarcinoma, chondrosarcoma and other solid tumors with IDH1 mutation.
Intervention: AB-218 capsule
Outcomes
Primary Outcomes
TEAEs
Time Frame: About 24 months
Treatment-Emergent Adverse Events (TEAEs) including events reported following physical examination, vital signs assessment, clinical laboratory assessment or electrocardiogram (ECG)
DLT incidence
Time Frame: Dose escalation part, about 6 months
Dose limiting toxicity incidence
Secondary Outcomes
- Overall Response Rate(About 24 months)
- Duration of Response(About 24 months)
- Disease Control Rate(About 24 months)
- Progress Free Survival(About 24 months)
- Overall Survival(About 48 months)
- Cmax(8 Days. At the Day1 and Day8 of Cycle1 for dose escalation part and dose expansion part(each cycle is 28 days))
- Tmax(8 Days. At the Day1 and Day8 of Cycle1 for dose escalation part and dose expansion part(each cycle is 28 days))
- AUC8h(8 Days. At the Day1 and Day8 of Cycle1 for dose escalation part(each cycle is 28 days))
- AUC12h(8 Days. At the Day1 and Day8 of Cycle1 for dose escalation part(each cycle is 28 days))
- AUC6h(8 Days. At the Day1 and Day8 of Cycle1 for dose expansion part(each cycle is 28 days))
- Ctrough(4 Months. At the end of Cycle 4 (each cycle is 28 days).)
- Plasma concentration of 2-HG(4 Months. At the end of Cycle 4 (each cycle is 28 days).)