A Study to Evaluate Safety, PK and Efficacy of GH55 in Combination With GH21 in Patients With Solid Tumors

Phase I/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Efficacy of GH55 Capsule in Combination With GH21 Capsule in Subjects With Locally Advanced or Metastatic Solid Tumors Harboring Aberrantly Activated MAPK Signaling Pathway.

GH55 Capsule is a novel, highly selective small molecule dual mechanism ERK1/2 inhibitor. GH21 Capsule is a potent, orally active human SHP2 allosteric inhibitor. The combination of an ERK1/2 inhibitor and an SHP2 inhibitor achieves a dual effect: synergistic upstream and downstream blockade of the aberrantly activated RTK MAPK signaling pathway, as well as complementation of resistance mechanisms.

This study will evaluate the safety, tolerability and pharmacokinetic (PK) characteristics of GH55 Capsule in combination with GH21 Capsule in patients with advanced solid tumors with aberrantly activated MAPK signaling pathway, and investigate the efficacy of this combination regimen in the same patient population.

Inclusion Criteria:

• 1. Aged 18-80 years (inclusive), regardless of gender.

• 2. Histologically or cytologically confirmed locally advanced or metastatic solid tumor with aberrantly activated MAPK signaling pathway (RAS/RAF/MEK/ERK).

• 3. Failed standard treatment, has no standard treatment options, refuses standard treatment, or is not eligible for standard treatment at the current stage.

• 4. Has at least one measurable tumor lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

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

• 6. Estimated survival time ≥ 3 months.

• 7. Essential organ function is basically normal, with screening laboratory results meeting the following criteria:

  • Hematological system (no blood transfusion or hematopoietic stimulants within 14 days)
  • Absolute Neutrophil Count (ANC) ≥1.5×109/L
  • Platelet (PLT) ≥75×109/L
  • Hemoglobin (Hb) ≥90g/L
  • Liver function
  • Albumin (ALB) ≥3.0g/dL
  • Total Bilirubin (TBIL) ≤1.5×Upper Limit of Normal (ULN); <br/>For patients with --Gilbert syndrome: ≤3×ULN
  • Alanine Aminotransferase (ALT) ≤2.5×ULN; <br/>For patients with liver metastasis or liver cancer: ≤5×ULN
  • Aspartate Aminotransferase (AST) ≤2.5×ULN; <br/>For patients with liver metastasis or liver cancer: ≤5×ULN
  • Renal function
  • Creatinine (Cr) ≤1.5×ULN
  • Creatinine Clearance (Ccr) ≥50ml/min (calculated by Cockcroft-Gault formula)
  • Coagulation function
  • Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN
  • International Normalized Ratio (INR) ≤1.5×ULN
  • Cardiac function
  • Left Ventricular Ejection Fraction (LVEF) ≥50%
  • Fridericia-corrected QT interval (QTcF) Male<450ms; Female<470ms

• 8. Eligible patients of childbearing potential (male and female) must agree to use reliable contraceptive methods (hormonal, barrier, or abstinence) with their partners during the trial and for at least 3 months after the last dose; female patients of childbearing potential must have a negative serum pregnancy test within 1 week before the first dose.

• 9. Must understand the study requirements, voluntarily sign a written informed consent form before the trial.

Exclusion Criteria:

• 1. Received chemotherapy within 3 weeks, or radiotherapy, biological therapy, endocrine therapy, targeted therapy, immunotherapy, or other anti-tumor treatments within 4 weeks before the first dose, except:
• - Nitrosourea or mitomycin C: within 6 weeks before the first dose;
• - Oral fluoropyrimidines, small-molecule targeted drugs, or traditional Chinese medicine with anti-tumor indications: within 2 weeks before the first dose;
• - Local palliative radiotherapy: within 2 weeks before the first dose.
• 2. Received other unmarketed clinical research drugs or treatments within 4 weeks before the first dose.
• 3. Underwent major organ surgery (excluding needle biopsy) or suffered significant trauma within 4 weeks before the first dose.
• 4. Used strong inhibitors or inducers of CYP3A4 or P-gp within 1 week before the first dose.
• 5. Previously received other selective ERK inhibitors and/or SHP2 inhibitors.
• 6. Previously received hematopoietic stem cell transplantation or organ transplantation.
• 7. Adverse reactions from previous anti-tumor treatment have not recovered to NCI CTCAE v5.0 Grade ≤ 1 (except for toxicities judged by investigators to be safe, such as alopecia, Grade 2 peripheral neuropathy, or hypothyroidism stabilized with hormone replacement therapy).
• 8. Symptomatic parenchymal brain metastasis or meningeal metastasis, deemed unsuitable for enrollment by investigators.
• 9. Has an active infection requiring intravenous anti-infective treatment.
• 10. Has a history of immunodeficiency, including positive HIV antibody test.
• 11. Active hepatitis B (HBsAg positive and HBV-DNA > 500 IU/ml, 1000 cps/ml, or the study center's lower limit of detection [if higher]); antiviral therapy (excluding interferon) is allowed. Active hepatitis C (patients with positive HCV antibody but HCV-RNA < the study center's lower limit of detection are eligible).
• 12. Has a history of severe cardiovascular and cerebrovascular diseases, including but not limited to:
• - Severe cardiac arrhythmia or conduction abnormalities requiring clinical intervention (e.g., ventricular arrhythmia, third-degree atrioventricular block);
• - Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other Grade ≥ 3 cardiovascular and cerebrovascular events within 6 months before the first dose;
• - New York Heart Association (NYHA) cardiac function class ≥ III;
• - Clinically uncontrolled hypertension;
• - Any factors increasing the risk of QTc prolongation or arrhythmia (e.g., heart failure, intractable hypokalemia, congenital long QT syndrome, family history of long QT syndrome, use of any known drugs that prolong the QT interval [see Appendix 8]).
• 13. Has a history of other malignant tumors (except cured in situ cancers with no recurrence for 5 years, such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix, as deemed eligible by investigators; eligible in the dose escalation phase at the discretion of investigators).
• 14. Has a history of retinal vein occlusion or central serous chorioretinopathy.
• 15. Unable to swallow oral medications, or has conditions severely affecting gastrointestinal absorption (e.g., chronic diarrhea, intestinal obstruction) as judged by investigators.
• 16. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once a month or more frequently).
• 17. Has a history of interstitial pneumonia within 6 months before the first dose, or any evidence of clinically active interstitial lung disease.
• 18. Has aberrantly activated PI3K-mTOR pathway (including PI3K activating mutations, AKT activating mutations, and PTEN deletion or inactivation).
• 19. Has known alcohol or drug dependence.
• 20. Has a mental disorder or poor compliance.
• 21. Has a history of severe allergies or allergies to multiple drugs.
• 22. Is pregnant or lactating.
• 23. Deemed unsuitable for the study by investigators for other reasons.