Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of AST-3424 in Treatment of Patients With Advanced Solid Tumors and Its Correlation With AKR1C3 Enzyme Expression
Overview
- Phase
- Phase 1
- Intervention
- AST-3424
- Conditions
- Advanced Solid Tumors
- Sponsor
- Ascentawits Pharmaceuticals, Ltd
- Enrollment
- 51
- Locations
- 7
- Primary Endpoint
- Incidence and severity of adverse events(AEs)
- Status
- Active, Not Recruiting
- Last Updated
- last year
Overview
Brief Summary
An open-label, Phase I/II study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of AST-3424 administered as a single agent
Detailed Description
This is an open-label phase I/II clinical study to evaluate the safety, tolerability, MTD/RP2D, pharmacokinetics, preliminary efficacy, and the relationship between AKR1C3 expression and efficacy of AST-3424 monotherapy in advanced solid tumors. The study is divided into phase I and Phase II. The maximum tolerated dose will be explored in phase I. In phase II, participants will be treated with AST-3424 according to the Phase I confirmed dose. Phase II clinical study will first be conducted in hepatocellular carcinoma (HCC).
Investigators
Eligibility Criteria
Inclusion Criteria
- •phase I: dose escalation phase
- •Male or female, 18-70 years old.
- •Histologically and/or cytologically confirmed malignant solid tumors (including but not limited to hepatocellular carcinoma, intrahepatic cholangiocarcinoma, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, renal cell carcinoma, non-small cell lung cancer, and castration-resistant prostate cancer) that are metastatic or unresectable and have failed standard treatment or no standard treatment, pr not suitable for standard treatment at this stage.
- •Once MTD is confirmed, participant in the Extended Dose group (MTD group) need to have at least one measurable lesion that meets the RECIST 1.1 criteria. Previously irradiated lesions are not measurable unless they show clear radiographic progression after radiotherapy.
- •The physical status score of the Eastern Cancer Collaboration Group (ECOG) is 0 or
- •Life expectancy≥12 weeks.
- •All toxicities (except alopecia, fatigue, or peripheral neuropathy) from previous anticancer therapy must have returned to grade 1 or baseline levels prior to initiation of the investigational drug (NCI CTCAE 5th Edition).
- •The heart QTcF interval ≤450 ms in males or ≤ 470 ms in females.
- •Laboratory tests must meet the following criteria. the indicators could not be corrected by blood transfusion or hematopoietic stimulating factors for 14 days prior to the screening laboratory examination.
- •Hemoglobin ≥90 g/L
Exclusion Criteria
- •phase I: dose escalation phase
- •Untreated active central nervous system (CNS) metastases or leptomeningeal disease. Participant may participate in the study if their CNS metastases have been adequately treated and are stable for at least 4 weeks as confirmed by clinical examination and brain imaging (MRI or CT) during screening.
- •Major surgery other than diagnostic surgery was performed within 4 weeks prior to initial dosing.
- •Radiotherapy, surgery, chemotherapy, immunotherapy, cancer biotherapy, targeted therapy, or hormonal therapy within 4 weeks prior to the first dose (lomustine or mitomycin C treatment, requiring a 6-week washout period; Oral fluorouracil, requiring a 2-week washout period; Small molecule targeted therapy requires a 2-week washout period).
- •Participated in an investigational drug (diagnostic or therapeutic) or device study within 4 weeks prior to initial dosing.
- •Combined use of strong potent CYP3A4 inhibitors or inducers need to be used during the study.
- •Uncontrolled, active bacterial, viral or fungal infections requiring systemic treatment.
- •Known to be positive for human immunodeficiency virus (HIV) or syphilis.
- •Women who are pregnant, breast-feeding, or planning to become pregnant.
- •Concomitant diseases or symptoms that may interfere with the conduct of the study, or physical abnormalities that the investigator believes pose an excessive risk to the patient, including but not limited to active peptic ulcer or gastritis, changes in mental status, or mental abnormalities that may interfere with the patient's understanding of the informed consent form.
Arms & Interventions
Phase I: dose escalation phase
AST-3424 (1.0 mg/m\^2 to 10.0 mg/m\^2 or higher doses) will be administered by IV infusion on Day1 and Day8 of each 21-day cycle. 1mg/m\^2 and 2mg/m\^2 cohort will enroll 1 participant respectively . 4mg/m\^2 or higher dose cohorts will use 3+3 dose escalation design to determine the MTD and RP2D.
Intervention: AST-3424
Phase II: cohort expansion phase
6mg/m\^2, administrated on Day1 and Day 8 of each 21-day cycle
Intervention: AST-3424
Outcomes
Primary Outcomes
Incidence and severity of adverse events(AEs)
Time Frame: measure begins from informed consent to 30 days after last dose of study drug.
Adverse events will be noted and graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 or severity (if not covered by CTCAE)
Safety changes in electrocardiogram (ECG)
Time Frame: Day 1 Cycles 1 and 2 (each cycle is 21 days)
Resting 12-lead ECGs will be obtained from all subjects' pre-AST-3424 infusion and within 30 minutes post-AST-3424 infusion in order to assess any impact AST-3424 may have on the QT interval as assessed by the Fridericia's Correction Formula (QTcF).
Safety Changes of body weight
Time Frame: Day 1 of each cycle (there are 34 cycles; 21 days for each cycle)
If during treatment a participant's body weight changes by \>10%, the dose should be adjusted.
Dose limiting toxicities (DLTs) in phase I
Time Frame: Throughout Cycle 1 (21 days for each cycle) in phase I (dose escalation phase).
Number of participants with dose limiting toxicities (DLTs)
Maximum Tolerated Dose(MTD)/Recommended Phase 2 Dose (RP2D) in phase I
Time Frame: Day 1 and Day 8 of each cycle (all 34 cycles and there are 21 days for each cycle)
Determination of the MTD, based on the frequently of DLTs observed in Cycle 1 in participants enrolled to the Dose Escalation Phase.
Pharmacokinetics (PK) - Time to maximum concentration (Tmax)
Time Frame: Days 1 and 8 of Cycle 1 (first cycle of 34 cycles and there are 21 days for each cycle)
Tmax of AST-3424 and AST-2660 will be computed for each subject where possible.
PK - Maximum peak plasma concentration (Cmax)
Time Frame: Days 1 and 8 of Cycle 1 (first cycle of 34 cycles and there are 21 days for each cycle)
Cmax of AST-3424 and AST-2660 will be computed for each subject where possible.
PK - The magnitude of the slope of the linear regression of the log concentration vs. time profile during the terminal phase (Kel)
Time Frame: Days 1 and 8 of Cycle 1 (first cycle of 34 cycles and there are 21 days for each cycle)
Kel of AST-3424 and AST-2660 will be computed for each subject where possible.
PK - Half-life (T1/2)
Time Frame: Days 1 and 8 of Cycle 1 (first cycle of 34 cycles and there are 21 days for each cycle)
T1/2 computed as ln (2)/Kel of AST-3424 and AST-2660 will be computed for each subject where possible.
PK - Area under the concentration-time curve (AUClast)
Time Frame: Days 1 and 8 of Cycle 1(first cycle of 34 cycles and there are 21 days for each cycle)
AUClast from Hour 0 through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was drawn
Objective response rate(ORR)
Time Frame: Approximately 36 months
Disease control rate(DCR)
Time Frame: Approximately 36 months
Duration of response (DOR)
Time Frame: Approximately 36 months
Progress free survival (PFS)
Time Frame: Approximately 36 months