Safety and Pharmacokinetics of NM6603 in Chinese Patients With Advanced Solid Tumors

A Phase I, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of NM6603 in Patients With Advanced Solid Tumors

This study is to assess the MTD and PK of NM6603 in adult patients with advanced solid tumors.

This is a Phase 1, open label, 3+3 dose escalation study designed to evaluate the safety profile, the maximum tolerated dose (MTD), the pharmacokinetic and the preliminary antitumor activity of NM6603 in patients with advanced solid tumors.

Inclusion Criteria:

• Advanced solid tumors (primarily advanced colorectal cancer or triple-negative breast cancer) confirmed by histology or cytology

• Prior adequate standard therapy with documented progression or intolerance, or lack of available standard therapy options, or contraindications to standard therapy

• At least one evaluable tumor lesion per RECIST version 1.1

• Age 18 to 75 years at the time of informed consent

• Body weight 45 kg or greater for men and 40 kg or greater for women

• ECOG performance status 0 or 1

• Expected survival time greater than 12 weeks

• Adequate organ and bone marrow function as defined below:

  • Absolute neutrophil count 1500 per mm3 or greater
  • Platelet count 100000 per mm3 or greater with no transfusion or growth factor use within 14 days before first dose
  • Hemoglobin 9.0 g/dL or greater with no transfusion or stimulating factors within 14 days before first dose
  • Total bilirubin 1.5 times upper limit of normal (ULN) or less (patients with Gilbert syndrome allowed)
  • AST and ALT 2.5 times ULN or less without liver metastasis, or 5 times ULN or less with liver metastasis
  • Creatinine clearance 60 mL/min or greater (Cockcroft-Gault formula)
  • INR 1.5 times ULN or less and APTT 1.5 times ULN or less

• Male subjects and female subjects of childbearing potential agree to use effective contraception from signing consent until 6 months after last dose; men must not donate sperm; women of childbearing potential require a negative pregnancy test within 7 days prior to first dose

• Able and willing to comply with study visits, procedures, and provide written informed consent

Exclusion Criteria:

• Known hypersensitivity to NM6603 or its components

• Prior treatment with a drug targeting the same mechanism of action or molecular target

• Participation in another drug or device clinical trial within 4 weeks before first dose

• Major surgery within 4 weeks before first dose or planned surgery during the study

• Chemotherapy, biologic therapy, macromolecular targeted therapy, or radiotherapy within 4 weeks before first dose

• Oral fluoropyrimidines or other small molecule targeted agents received within 2 weeks or 5 half-lives before first dose (whichever is longer)

• Use of traditional Chinese medicine or herbal products with antitumor activity within 2 weeks before first dose

• Use of medications known to prolong QT interval or strong inhibitors or inducers of CYP1A2, CYP2A6, or CYP3A4 within 7 days before first dose, or requirement for continued use

• Systemic corticosteroids or immunosuppressive drugs at doses greater than 10 mg/day prednisone or equivalent within 4 weeks before first dose (physiologic replacement and topical/inhaled forms allowed)

• History of another malignancy within 5 years except for curatively treated carcinoma in situ of the cervix, non-melanoma skin cancer, localized prostate cancer, or ductal carcinoma in situ

• Active central nervous system metastases, including symptomatic brain metastases, leptomeningeal disease, spinal cord compression, or unstable brain metastasis

• Treated brain metastases allowed if stable for 4 weeks or longer, no neurologic symptoms, and not receiving systemic corticosteroids above replacement dose for 4 weeks

• Untreated asymptomatic brain metastases 1.5 cm or smaller allowed if not requiring corticosteroids

• Uncontrolled disease including:

  • Active infection
  • Acute coronary syndrome, symptomatic heart failure (NYHA class 2 or greater), cerebrovascular accident, transient ischemic attack, stroke, deep vein thrombosis, pulmonary embolism, aneurysm, arterial dissection, or other grade 3 or higher cardiovascular or cerebrovascular events within 6 months
  • Left ventricular ejection fraction less than 50 percent, uncontrolled hypertension (systolic over 160 mmHg or diastolic over 100 mmHg), uncontrolled hyperglycemia, ventricular arrhythmias requiring intervention, second or third degree AV block, congenital long QT syndrome, QTcF greater than 450 ms
  • Active peptic ulcer, gastritis, or bleeding disorder
  • Risk factors for pancreatitis including history of pancreatitis, uncontrolled hyperlipidemia, excessive alcohol use, uncontrolled diabetes, gallbladder disease, or medications associated with elevated triglycerides or pancreatic toxicity
  • Psychiatric or social conditions that may affect study compliance or ability to provide informed consent

• Family history of long QT syndrome or unexplained sudden death before age 40 in a first-degree relative

• Inability to swallow oral medication or gastrointestinal disease or major GI surgery likely to impair drug absorption, metabolism, or excretion

• Known alcohol or substance dependence

• Active syphilis; positive HIV antibody; positive HCV antibody with detectable HCV RNA; active hepatitis B infection (HBsAg positive with HBV DNA 1000 IU/mL or greater)

• Not recovered to grade 1 or less from prior therapy toxicity (NCI CTCAE v5.0), except for alopecia, irreversible grade 1 fatigue, or clinically insignificant lab abnormalities such as lymphocyte count decrease

• Pregnant or breastfeeding women or women planning pregnancy during the study

• Any condition that, in the investigator's judgment, makes the subject unsuitable or may affect compliance