This study will evaluate the safety, tolerability, drug levels, pharmacodynamic effects, and clinical activity of YL 17231 in patients with advanced solid tumors harboring mutations in KRAS, HRAS, or NRAS.
The study is a Phase 1, multi-center, open label study in 2 parts. Part 1 (Phase Ia): This is a 3 + 3 design dose escalation study, to evaluate the safety and tolerability, and to determine the MTD and/or RP2D of YL-17231 treatment when administered orally QD in patients with advanced solid tumors harboring mutations in KRAS, HRAS or NRAS. Up to 9 doses cohorts are planned for the dose escalation part of the study, with the starting dose of 0.25mg QD. The actual number of dose cohorts to be explored in this study will be determined by the non-tolerable dose based on dose limiting toxicities (DLTs) in conjunction with the PK and preliminary efficacy signal data. If suggested by safety and PK findings from planned dose treatment cohorts, additional dose levels may be evaluated and dosing interval may be modified under the Safety Monitoring Committee (SMC) guidance. In Part 1, the 3+3 trial design for the dose escalation will be used and a total of 9 dose levels starting dose of 0.25 mg OD is planned. One cycle is 21 days. DLT observation period is one cycle. The maximum tolerated dose (MTD) is the highest dose at which ≤1 of 6 patients experiences a DLT during the DLT observation period. The study will identify a maximum tolerated dose (MTD) if possible, with safety and tolerability data. All available data, including safety, tolerability, PK, PD and preliminary anti-tumor activity from each cohort will be reviewed by the SMC to determine the RP2D. Patients may be permitted an intra-patient dose-escalation of YL-17231 to a higher dose level that has been cleared and deemed safe by the SMC if they have completed Cycle 2 at their initial enrolled dose level and continued on-study with no treatment related ≥ Grade 2 AEs. The Investigator must consult with the Medical Monitor to confirm if the patient is permitted be dose-escalated to a dose-level already cleared by the SMC. Backfilling Additional patients (up to total of 12) may be enrolled in the dose levels which have been cleared and deemed safe by SMC to further evaluate the safety, tolerability and PK. This is referred to as backfilling. Part 2 (Phase Ib): This is a dose expansion phase to further evaluate the safety, tolerability and preliminary anti-tumor activity of YL 17231 at the RP2D selected by SMC. The number of patients to be enrolled for the expansion cohorts, the RP2D and the desired patient population will be determined by the emerging data from part 1 of the study, including safety, tolerability, PK, PD and preliminary anti-tumor efficacy, as well as any other relevant evolving clinical data, and will be clarified through a protocol amendment.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
YL-17231 will be administered orally once daily in a continuous regimen
The Lindner Center for Research & Education at The Christ Hospital
Cincinnati, Ohio, United States
RECRUITINGMD Anderson Cancer Center
Houston, Texas, United States
RECRUITINGHuntsman Cancer Institute and Hospital, University of Utah
Salt Lake City, Utah, United States
RECRUITINGOccurrence of dose limiting toxicities (DLTs)
A toxicity will be considered dose-limiting if it occurs during the first cycle (21 days) of treatment with YL-17231.
Time frame: The first cycle (21 days)
TEAEs
AEs will be coded using Medical Dictionary for Regulatory Activities current version. AEs will be regarded as treatment-emergent AEs (TEAEs) if they occur after first treatment. The frequencies will be presented including number and percentages of patients having experienced an event and the total number of events.
Time frame: Through study completion, an average of 1 year
SAEs
Serious AEs
Time frame: Through study completion, an average of 1 year
Overall Response Rate (ORR)
ORR, defined as percentage of patients with a documented CR or PR in Response Evaluation Criteria in Solid Tumors 1.1(RECIST 1.1)
Time frame: From first dose of study treatment to the first documented disease progression or death due to any cause, whichever occurs first, assessed up to 30 months.
Duration of Response (DOR)
DOR, defined as time from first documentation of a response (PR or CR) to the first documented disease progression or death due to any cause, whichever occurs first, for those patients with a PR or CR.
Time frame: From first documentation of a response (PR or CR) to the first documented disease progression or death due to any cause, whichever occurs first, assessed up to 30 months.
Progression Free Survival (PFS)
PFS, defined as time from first dose of study treatment to the first documented disease progression or death due to any cause, whichever occurs first.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: From first dose of study treatment to the first documented disease progression or death due to any cause, whichever occurs first, assessed up to 30 months.
Disease Control Rate (DCR)
DCR, defined as percentage of patients with a documented CR or PR and SD
Time frame: From first dose of study treatment to the first documented disease progression or death due to any cause, whichever occurs first, assessed up to 30 months.
AUC(0-T)
Area under the concentration-time curve from time zero to the last quantifiable concentration of YL-17231
Time frame: During Cycles 1 and 2 (each cycle is 21 days)
Cmax
Maximum observed serum concentration of YL-17231 is observed directly from data
Time frame: During Cycles 1 and 2 (each cycle is 21 days)
T1/2
Elimination half life of YL-17231 is observed directly from data
Time frame: During Cycles 1 and 2 (each cycle is 21 days)
Tmax
Time to maximum plasma concentration of YL-17231 is observed directly from data as time of Cmax
Time frame: During Cycles 1 and 2 (each cycle is 21 days)