Overview

This is a multi-center, open-label, dose escalation phase I and dose expansion phase II study aimed to evaluate the safety, tolerability, PK and PD profiles as well as to observe the efficacy of GH55 in patients with MAPK mutant advanced solid tumors.

This study is divided into two parts, namely the dose escalation phase I study and the dose expansion phase II study.

Eligibility

Inclusion Criteria:

        Subjects must meet all the following inclusion criteria to be qualified for study
        enrollment:
          1. Male or female subjects aged 18-80 years (inclusive).
          2. Patients with histologically or cytologically confirmed MAPK mutant (presence of
             RAS/RAF/MEK/ERK mutations) locally advanced or metastatic solid tumors.
          3. Patients who have failed standard treatment or have no standard treatment regimen or
             are not suitable for standard treatment currently.
          4. Dose escalation: At least one assessable tumor lesion according to RECIST version 1.1;
             Dose expansion: At least one measurable tumor lesion according to RECIST version 1.1
             (tumor lesion located in the region of previous radiotherapy or other locoregional
             treatment sites is usually not considered a measurable lesion, unless this lesion
             shows clear progression or persists for 3 months after radiotherapy).
          5. Eastern Cooperative Oncology Group (ECOG) performance status score: Phase I dose
             escalation: 0-1. Phase II dose expansion: 0-2.
          6. 3 months or longer expected survival.
          7. Major organs are functioning normally, and laboratory tests meet the following
             criteria during the screening period.
        Hematological system (has not received any blood transfusion or hematopoietic stimulating
        factor therapy within the past 14 days) Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
        Platelet Count (PLT) ≥ 75 × 109/L Hemoglobin (Hb) ≥ 90 g/L Liver function Albumin (ALB) ≥
        3.0 g/dL Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN) Liver metastasis or
        liver cancer patients: ≤ 2.5 × ULN Alanine Aminotransferase (ALT) ≤ 2.5 × ULN; Liver
        metastasis or liver cancer patients: ≤ 5 × ULN Aspartate aminotransferase (AST) ≤ 2.5 ×
        ULN; Liver metastasis or liver cancer patients: ≤ 5 × ULN Renal function Creatinine
        clearance rate (Ccr) ≥ 60 mL/min (calculated based on the 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% QT interval corrected by the Fridericia formula (QTcF) Males < 450 ms, Females
        < 470 ms 7. Qualified patients (male and female) with childbearing potential must agree to
        use reliable contraceptives (hormone or barrier or abstinence) with their partners during
        the study and until at least 3 months after the last dose; female patients with
        childbearing potential must be negative for the blood pregnancy test within 1 week before
        the first dose.
        8. Subjects must give informed consent to the study and voluntarily signed the informed
        consent form prior to study initiation.
        Exclusion Criteria:
        Subjects who meet any one of the following exclusion criteria are not eligible for study
        enrollment:
          1. Received antitumor therapy such as chemotherapy within 3 weeks before the first dose,
             radiotherapy, biotherapy, endocrine therapy, targeted therapy, and immunotherapy
             within 4 weeks before the first dose, except for the following:
               -  Use of nitrosoureas or mitomycin C within 6 weeks prior to the first dose of the
                  investigational drug;
               -  Use of oral fluorouracil(s), small molecule targeted drugs, and antitumor
                  traditional Chinese medicine within 2 weeks prior to the first dose of the
                  investigational drug;
               -  Local palliative radiotherapy within 2 weeks prior to the first dose of the
                  investigational drug.
          2. Received other unmarketed clinical investigational drug or therapy within 4 weeks
             prior to the first dose.
          3. Underwent major organ surgery (excluding needle biopsy) or had significant trauma
             within 4 weeks prior to the first dose or requires selective surgery during the study
             period.
          4. Use of strong CYP3A4 inhibitors or inducers within 1 week prior to the first dose of
             the investigational drug.
          5. Previously received other selective ERK inhibitors.
          6. Previously received allogeneic HSCT or organ transplantation.
          7. Adverse drug reactions of previous antitumor treatment have not recovered to grade ≤ 1
             as per CTCAE version 5.0 (except for toxicity without safety risk judged by the
             investigator, such as alopecia, grade 2 peripheral neurotoxicity, and hypothyroidism
             that is stable after hormone replacement therapy).
          8. Brain parenchymal metastasis or meningeal metastasis with clinical symptoms unsuitable
             for study participation as judged by the investigator.
          9. Patient with active infection and currently requires intravenous anti-infective
             therapy.
         10. History of immunodeficiency, including being positive for HIV antibody test.
         11. Active hepatitis B [HBsAg positive and HBV-DNA > 500 IU/mL or LLQ of the study site
             (when the LLQ is > 500 IU/mL)], for which antiviral therapies other than interferon
             are permitted; Active hepatitis C (patients who are positive for HCV antibody but
             whose HCV-RNA is < study site LLQ can be included).
         12. History of severe cardiovascular and cerebrovascular diseases, including but not
             limited to:
               -  Severe abnormalities in cardiac rhythm or conduction, such as ventricular
                  arrhythmia or second- or third-degree atrioventricular block requiring clinical
                  intervention;
               -  Acute coronary syndrome, congestive heart failure, aortic dissection, stroke or
                  other grade 3 or greater cardiovascular and cerebrovascular events within 6
                  months prior to the first dose;
               -  New York Heart Disease Association (NYHA) class ≥ III cardiac function or left
                  ventricular ejection fraction (LVEF) < 50%;
               -  Clinically uncontrolled hypertension;
               -  Any factors that increase the risk of QTc prolongation or arrhythmia, such as
                  heart failure, hypokalemia that is difficult to correct, congenital long QT
                  syndrome, family history of long QT syndrome, and use of concomitant medication
                  known to prolong QT interval.
         13. History of other malignant tumors (except for the cured squamous cell carcinoma in
             situ of the skin, basal cell carcinoma, and cervical carcinoma in situ that have not
             recurred within 5 years and are considered acceptable for study enrollment by the
             investigator; except for patients who are considered acceptable for enrollment by the
             investigator in the dose escalation study).
         14. History of retinal vein occlusion or central serous retinopathy, or patients with
             clinically significant abnormalities in the ophthalmological examination during the
             screening period and judged by the investigator to be unsuitable for enrollment.
         15. Unable to swallow medication or has conditions that severely impact gastrointestinal
             absorption (e.g. Chronic diarrhea or intestinal obstruction) as judged by the
             investigator.
         16. Clinically uncontrolled third space effusion judged by the investigator to be
             unsuitable for enrollment.
         17. Patients with current interstitial lung disease (except radiation-induced pulmonary
             fibrosis that does not required hormone therapy).
         18. Known alcohol or drug dependence.
         19. Mental disorder or poor compliance.
         20. Previous history of severe allergy, or allergy to any active or non-active ingredients
             of the investigational drug.
         21. Pregnant or lactating women.
         22. Other conditions judged by the investigator that render the subject unsuitable for
             participation.