Phase Ib Study of Oral R01 Monotherapy in Advanced Solid Tumors

A Phase Ib Dose-Escalation and Expansion Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile, and Efficacy of R01 Administered Orally as a Single Agent in Patients With Advanced Solid Tumors, Including Squamous Cell Lung Cancer, Gastric Cancer, and Esophageal Cancer

This is a Phase I（Ib）, open-label, single-arm clinical study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of R01 administered orally as monotherapy twice daily (BID) in patients with advanced solid tumors, including squamous cell lung cancer, gastric cancer , and esophageal cancer.

Patients with advanced squamous cell lung cancer, gastric cancer , and esophageal cancer will be enrolled. All subjects will receive oral R01 monotherapy and will undergo physical examinations, laboratory tests, radiographic tumor response assessments, biological sample collection, and safety follow-ups as specified in the protocol.

The study comprises two consecutive sub-stages: a dose-bridging escalation stage (i.e., a dose escalation stage designed to bridge from the highest dose evaluated in Phase Ia) and a dose expansion stage. The dose escalation follows a classic '3+3' design at three dose levels (240, 320, and 400 mg BID). The 400 mg dose may be initiated after the Safety Review Committee (SRC) review based on safety and PK data. The primary objectives of this stage are to characterize dose-limiting toxicities (DLTs), determine the maximum tolerated dose (MTD), and establish the recommended Phase II dose (RP2D).

The dose expansion stage will be conducted at the RP2D in selected indication cohorts, with a planned enrollment of at least 6 subjects per cohort (including subjects with the corresponding indications enrolled at the same dose level during the dose escalation stage), to further evaluate the safety, tolerability, PK characteristics, and preliminary antitumor efficacy at this dose level.

With respect to study endpoints: during the dose escalation stage, the primary endpoints are the incidence of DLTs, the MTD, and/or the determination of the expansion dose (RP2D); secondary endpoints include PK parameters of R01 and its metabolites, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). During the dose expansion stage, the primary endpoints are ORR and the incidence and severity of treatment-related adverse events (TRAEs); secondary endpoints include duration of response (DOR), time to response (TTR), DCR, PFS, OS, and steady-state PK parameters.

Inclusion Criteria:

• Patients must meet all of the following inclusion criteria to be eligible for enrollment in this study:

• 1. Age: 18 to 75 years (inclusive), of any sex.

• 2. Patients with unresectable squamous cell lung cancer, gastric cancer, or esophageal cancer confirmed by histology or cytology, specifically including those in whom existing standard therapy has failed (≥1 line) or who cannot tolerate standard therapy, or who have evidence of locoregional recurrence or metastasis and are not suitable for curative-intent surgical resection or radiotherapy; the investigator comprehensively assesses that the clinical trial participant is not suitable to receive standard treatment.

• 3. Tumor type: advanced squamous cell lung cancer, gastric cancer (including signet-ring cell gastric cancer), and esophageal cancer.

• 4. At screening, presence of measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumor lesions previously treated with radiotherapy or other locoregional therapy are considered measurable only if progressive disease (PD) at the treated site has been clearly documented after completion of the treatment.

• 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

• 6. Expected survival of at least 12 weeks.

• 7. Essentially normal function of major organs, with laboratory values at screening meeting the following criteria:

  1. . ANC ≥1500/mm³ (1.5×10⁹/L);
  2. . PLT ≥75,000/mm³ (75×10⁹/L);
  3. . Hb ≥9 g/dL (90 g/L) (most recent test during the screening period, and within 7 days before the first dose);
  4. . Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both ≤2.5× the upper limit of normal (ULN); if liver metastases are present, both ALT and AST ≤5.0× ULN;
  5. . Total bilirubin (TBIL) ≤1.5× ULN;
  6. . Serum creatinine (SCr) ≤1.5× ULN or estimated creatinine clearance (CrCl) ≥50 mL/min (according to the Cockcroft-Gault formula);
  7. . Albumin (ALB) ≥28 g/L;
  8. . Serum potassium ≥3.5 mmol/L and ≤5.5 mmol/L.

• 8. Prior to the first dose, all acute toxicities from prior anticancer therapy or surgery must have resolved to baseline severity or to Grade ≤1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 6.0, with the exception of alopecia, skin pigmentation changes, and toxicities judged by the investigator to be clinically insignificant; peripheral neuropathy of Grade ≤2 is permitted.

• 9. Voluntarily participate in the clinical trial and sign the informed consent form (ICF).

Exclusion Criteria:

• Patients meeting any of the following criteria will not be enrolled in this study:
• 1. Patients with advanced disease at risk of life-threatening complications in the short term (patients with visceral crisis).
• 2. Known or symptomatic active CNS metastases, manifesting as clinical symptoms, cerebral edema, spinal cord compression, carcinomatous meningitis, leptomeningeal disease, and/or progressive growth.
• 3. Major surgery, chemotherapy, radiotherapy, any investigational drug, or other anti-cancer therapy within 4 weeks before the first dose.
• 4. Patients who have not been withdrawn from another clinical trial within 4 weeks before study entry, or who are currently participating in another clinical trial involving an investigational drug or device.
• 5. Known history of allergy or suspected allergic symptoms to any component of the R01 formulation.
• 6. Use, within 14 days or 5 drug half-lives before the first dose (whichever is shorter), of: drugs known to be strong inhibitors/inducers of CYP3A4 or CYP2D6; drugs known to significantly prolong the QT interval.
• 7. At screening, a mean corrected QT interval (QTcF) >480 msec based on the average of 3 ECG assessments at rest (repeat testing and averaging of 3 values is required only if the first ECG indicates QTcF >480 msec); history of long QT syndrome or a confirmed family history of long QT syndrome; history of clinically significant ventricular arrhythmia, or current use of antiarrhythmic drugs, or an implanted defibrillation device used to treat ventricular arrhythmia.
• 8. Uncontrolled electrolyte disturbances that may affect the action of drugs that prolong the QTcF interval (e.g., hypocalcemia below the lower limit of normal (LLN), hypokalemia <3.5 mmol/L, hyperkalemia >5.5 mmol/L).
• 9. Concurrent severe/unstable angina pectoris; persistent arrhythmia of NCI CTCAE version 6.0 grade ≥2; atrial fibrillation of any grade; symptomatic congestive heart failure; cerebrovascular accident (including transient ischemic attack or symptomatic pulmonary embolism); myocardial infarction within 6 months, or prior coronary/peripheral artery bypass surgery.
• 10. Clinically significant active infections, including hepatitis B, hepatitis C, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related diseases, syphilis, active tuberculosis infection, and other diseases posing a risk of transmission, as well as uncontrolled systemic bacterial/fungal/other viral infections. Active hepatitis B is defined as: positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B e antigen (HBeAg), with hepatitis B virus deoxyribonucleic acid (HBV-DNA) ≥2000 IU/mL (equivalent to 10⁴ copies/mL); active hepatitis C is defined as a positive HCV RNA test result; active syphilis is defined as a positive rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test or the presence of clinical symptoms; active tuberculosis infection is defined as a positive T-SPOT.TB test or positive tuberculin skin test with purified protein derivative (PPD).
• 11. Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities, that may increase the risk of participating in the study or the risk associated with administration of the investigational drug, or that may interfere with the study results, as well as any other condition that the investigator considers to make the patient unsuitable for participation in this study.
• 12. Diabetic patients whose blood glucose is not effectively controlled (repeated fasting blood glucose [FBG] >7.0 mmol/L).
• 13. Persistently elevated corrected serum calcium levels on the 2 most recent independent tests (interval ≥24 h), ≥2.7 mmol/L (10.8 mg/dL) or exceeding the upper limit of the laboratory reference range.
• 14. Female clinical trial participants of childbearing potential with a positive pregnancy test at screening, or who do not agree to use highly effective contraception during the study and for 6 months after the last dose; male clinical trial participants who do not agree to use contraception during the study and for 6 months after the last dose, or who do not agree to refrain from donating sperm.
• 15. Recent or active suicidal ideation or behavior.
• 16. Conditions affecting the intake or absorption of oral drugs, including but not limited to: inability to swallow oral medications; persistent nausea or vomiting of ≥ CTCAE grade 2; severe aversion to fatty food or active malabsorption syndrome; Crohn's disease, ulcerative colitis, or short bowel syndrome in an acute episode.
• 17. History of major small intestinal or colonic surgery that may significantly affect the absorption of oral drugs.
• 18. Use of erythropoietin (EPO) or erythropoiesis-stimulating agents (ESA) within 28 days before the first dose.