Phase Ib Study of Oral R01 Monotherapy in Advanced Solid Tumors

Number of Participants with Dose-Limiting Toxicities (DLTs)

Dose-limiting toxicity (DLT) is defined as a toxicity occurring during the observation window at any dose level, judged by the investigator to be related to R01, and meeting any of the following criteria: Hematologic toxicities: Grade 4 hematologic toxicity; Grade 4 neutropenia persisting for \>7 days despite G-CSF treatment; Grade 4 anemia not recovering to ≤Grade 2 within 14 days despite transfusion support; Grade 4 thrombocytopenia regardless of bleeding; Febrile neutropenia ; Grade 3 thrombocytopenia with clinically significant bleeding. Non-hematologic toxicities: Grade ≥3 non-hematologic toxicity; QTcF \>500 ms or increase of \>60 ms from baseline confirmed by repeat ECG; Grade ≥3 hypoxemia or Grade ≥3 dyspnea; Actual dosing in Cycle 1 \<75% of planned dose or dosing delay \>14 days due to study drug-related toxicity. DLTs will be assessed according to CTCAE v6.0 during the DLT observation window.

Determination of Maximum Tolerated Dose (MTD) and/or Expansion Dose

The maximum tolerated dose (MTD) is defined as the highest dose level at which ≤1 of 6 participants experiences a dose-limiting toxicity (DLT) during the DLT observation window. DLTs will be assessed according to CTCAE v6.0. The MTD will be determined using a standard 3+3 dose escalation design. The expansion dose will be selected based on the MTD, pharmacokinetic exposure, safety, tolerability, and preliminary efficacy observed during the dose escalation phase, and will not exceed the MTD.

Objective Response Rate (ORR)

Objective response rate (ORR) is defined as the proportion of participants who achieve a confirmed best overall response of complete response (CR) or partial response (PR), as assessed by the investigator according to RECIST version 1.1. CR is defined as the disappearance of all target lesions and any pathological lymph nodes (short axis \<10 mm). PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. All responses must be confirmed by a repeat assessment performed no less than 4 weeks after the initial response is first documented. ORR will be reported for each dose cohort and for the overall study population. The 95% confidence interval (CI) for ORR will be calculated using the Clopper-Pearson exact method.

Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs)

Treatment-emergent adverse events (TEAEs) are defined as adverse events that start or worsen in severity after the first dose of study drug (R01) through 30 days after the last dose of study drug, or until initiation of another antineoplastic therapy, whichever occurs first. Treatment-related adverse events (TRAEs) are defined as TEAEs for which the investigator assesses a causal relationship to the study drug as possibly, probably, or definitely related. The incidence and severity of TEAEs and TRAEs will be summarized by dose cohort and for the overall safety population. Severity will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.

Pharmacokinetic (PK) parameters of R01 and its metabolites

Single-dose PK parameters of R01 and its metabolites include maximum plasma concentration (Cmax), time to maximum concentration (Tmax), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC₀-ₜ), area under the plasma concentration-time curve from time zero to infinity (AUC₀-∞), and terminal elimination half-life (t½). Steady-state PK parameters include area under the plasma concentration-time curve over one dosing interval (AUCτ), maximum plasma concentration at steady state (Cmax,ss), trough plasma concentration at steady state (Ctrough,ss), and accumulation ratio (Rac).

Objective response rate (ORR)

Objective response rate (ORR) is defined as the proportion of participants who achieve a confirmed best overall response of complete response (CR) or partial response (PR), as assessed by the investigator according to RECIST version 1.1. CR is defined as the disappearance of all target lesions and any pathological lymph nodes (short axis \<10 mm). PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. All responses must be confirmed by a repeat assessment performed no less than 4 weeks after the initial response is first documented. ORR will be reported for each dose cohort and for the overall study population. The 95% confidence interval (CI) for ORR will be calculated using the Clopper-Pearson exact method.

Disease control rate (DCR)

DCR is defined as the proportion of participants who achieve a best overall response of complete response (CR), partial response (PR), or stable disease (SD), as assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PRI nor sufficient increase to qualify for progressive disease (PD), maintained for at least \[X\] weeks.

Progression-free survival (PFS)

PFS is defined as the time from the date of first dose to the date of first documented disease progression (PD) per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death due to any cause, whichever occurs first. Participants who have not progressed or died at the time of analysis will be censored at the date of their last evaluable tumor assessment.

Change from Baseline in Functional Pharmacodynamic Parameters (Hemoglobin, Red Blood Cell Count, and Reticulocyte Count)

Functional pharmacodynamic (PD) parameters, including hemoglobin (Hb), red blood cell count (RBC), and reticulocyte count (Ret), will be measured at scheduled time points throughout the study. The change from baseline in each parameter will be calculated and summarized by dose cohort and for the overall study population. Baseline is defined as the last available measurement prior to the first dose of study drug (R01). Descriptive statistics will be provided for absolute values and change from baseline at each scheduled assessment time point. These parameters will be explored as potential indicators of pharmacodynamic activity of R01.

Exploratory Biomarker Analysis and Association with Drug Exposure and Clinical Efficacy

At baseline, metastatic lymph node samples may be collected from participants eligible for biopsy to evaluate the effect of R01 on tumor tissue-specific PD biomarkers.Baseline is defined as the tumor tissue sample collected prior to the first dose of R01.