A Study of SIGX1094R in Patients With Advanced Solid Tumors

A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Anti-tumor Activity and Food Effect of SIGX1094R in Patients With Advanced Solid Tumors

This is a phase I clinical, first-in-human study of SIGX1094R monotherapy. The goal of this trial is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), anti-tumor activity and food effect of SIGX1094R in patients with advanced solid tumors.

The study consists of two parts: SIGX1094R dose escalation study; food effect and SIGX1094R multiple-dose expansion study.

Part of SIGX1094R dose escalation study:

• the primary objective is to evaluate the safety and tolerability of SIGX1094R, and to define the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D).
• the secondary objective is to evaluate the PK profile and preliminary efficacy of SIGX1094R, and to explore the relationship between PD parameters and efficacy.

Part of food effect and SIGX1094R multiple-dose expansion study:

• the primary objective is to evaluate the food effect on PK profile of SIGX1094R.
• the secondary objective is to further evaluate the anti-tumor activity, safety and tolerability of SIGX1094R, and to further evaluate the relationship between PD parameters and efficacy.

Inclusion Criteria:

Patients must meet all of the following criteria before being enrolled in the study.

1. Patients must be able to understand the procedures and methods of this clinical study, voluntarily participate in the study and sign the ICF.

2. Patients aged ≥18 years when signing the ICF, male or female.

3. Patients with histologically, cytologically, or clinically proven advanced solid tumors (locally advanced or metastatic) that do not have standard treatment available, have disease progression on/after standard treatment, or cannot tolerate standard treatment.

4. Patients with at least one evaluable tumor lesion according to the RECIST v1.1; patients who have no measurable lesions but have evaluable lesions are allowed to be enrolled as judged by the investigator.

5. Patients (according to patients' option) will provide a pre-treatment tumor specimen (archival or fresh biopsy samples). If a fresh biopsy is required, procedures more invasive than a core biopsy or significant risk procedures for which the procedure-associated absolute risk of mortality or major morbidity in the patient's clinical setting and specific institution is 2% or higher, should not be utilized. The tumor tissue is used for pFAK status confirmation, without restriction on enrollment.

6. ECOG score ≤ 1.

7. Life expectancy ≥ 3 months

8. Patients with adequate organ function, including:

   • Liver function (no history of liver protection therapy 7 days before screening): total bilirubin (TBIL) ≤ 1.5×ULN, alanine aminotransferase (ALT)

     • 3×ULN, aspartate aminotransferase (AST) ≤ 3×ULN (no liver metastasis); if there is liver metastasis, ALT and AST ≤ 5×ULN; albumin ≥ 30 g/L.

   • Renal function: Creatinine clearance ≥ 50 mL/min (calculated according to Cockcroft-Gault formula).

   • Hematology (no blood transfusion or hematopoietic stimulating factor treatment within 14 days; no treatment with erythropoietin or thrombopoietin within 7 days): absolute neutrophil count (ANC) ≥ 1.5×10^9/L, platelet (PLT) ≥ 100×10^9/L, and hemoglobin (Hb) ≥ 90 g/L.

   • Coagulation function: activated partial thromboplastin time ≤ 1.5 × ULN and international normalized ratio ≤ 1.5 × ULN.

9. Women of reproductive age must have a negative blood pregnancy test result within 7 days prior to the first dose and promise to adhere to fully effective contraception or abstinence from the beginning of the screening period until 6 months after the last dose of study treatment; male patients must promise to adhere to fully effective contraception or abstinence from the beginning of the screening period until 6 months after the last dose of study treatment.

Exclusion Criteria:

Patients who meet any of the following criteria cannot be enrolled in this study.

1. Patients with hypersensitivity to the active ingredient or excipient ingredient of SIGX1094R, or a history of severe allergy.
2. Having a history of a second primary malignant tumor, excluding cervical carcinoma in situ, cutaneous squamous cell carcinoma, or basal cell carcinoma that has been cured or stabilized as assessed by the investigator;
3. Patients who have received cytotoxic chemotherapeutic drugs or small molecule targeted drugs within 4 weeks prior to the first dose. Note: For mitomycin C or nitrosoureas, 6-week washout is required; for small-molecule targeted drugs and oral fluorouracil drugs, a washout period of 2 weeks or 5 T1/2 of the drug (whichever is shorter) is required.
4. Anti-tumor endocrine therapy, radiotherapy, interventional embolization, radiofrequency, proton therapy, radioimmunotherapy, immunotherapy or other biotherapies within 4 weeks prior to the first dose (if 5 T1/2 of the drug/therapy used by the patient is confirmed to be < 4 weeks, 5 T1/2 shall prevail).
5. Patients who have received anti-tumor treatment with medicine/proprietary medicine within 2 weeks prior to the first dose. Note: This criterion is relevant to China study only.
6. Patients who have received other clinical investigational drugs or therapies that are not on the market within 4 weeks or 5 T1/2 prior to the first dose, whichever is longer.
7. Prior treatment with focal adhesion kinase (FAK) inhibitors.
8. Patients who have received strong cytochrome P450(CYP)3A4, CYP3A5 inhibitors, or strong CYP3A4 or CYP3A5 inducers, or strong P-gp and BCRP inhibitors, within 14 days prior to the first dose; or cannot stop using such drugs during the study.
9. Patients who have received an anti-acid drug or gastric acid reducing agents within 14 days prior to the first dose and cannot be discontinued for the duration of the study. Allow enrollment if administration interval between antacids/gastric acid inhibitors and the study drug is no less than 2 hours during the study period.
10. Pregnant or lactating women.
11. Patients whose adverse reactions of prior anti-tumor therapy assessed according to CTCAE v5.0 at the time of screening have not returned to Grade ≤ 1 (except for toxicities that are of no safety risk as judged by the investigator, such as alopecia, gasping, γ-glutamyl transferase (GGT) increased, Alkaline phosphatase (ALP) increased, grade 2 peripheral neurotoxicity, and decreased thyroid function stabilized by hormone replacement therapy).
12. Presence of clinically symptomatic metastases to central nervous system or meninges or other evidence showing that metastatic lesions in central nervous system or meninges have not yet been controlled at screening, which, at the investigator's discretion, is not suitable for enrollment. Note: Patients with central nervous system or meningeal metastases who are asymptomatic or stable after treatment prior to the first dose may be considered for enrollment.
13. A history of severe neurological or psychiatric disorders, including epilepsy, dementia, and moderate to severe depression.
14. History of drug abuse or dependence.
15. Clinically serious and uncontrolled cardiovascular diseases.
16. Patients with hyperglycemia that cannot be stably controlled with medication at screening.
17. Patients with pulmonary embolism within 6 months prior to the first dose, or interstitial pneumonia at screening.
18. Prior allogeneic stem cell transplantation, bone marrow transplantation or vital organ transplantation.
19. Patients who have undergone surgery on vital organs (other than aspiration biopsy) or suffered major trauma within 4 weeks prior to the first dose, or patients who have not recovered from any surgical effect at screening, or who are scheduled for major surgery during the study period.
20. Patients with uncontrolled infectious diseases, congenital immunodeficiency diseases, acquired immunodeficiency syndrome [human immunodeficiency virus antibody (HIV-Ab) positive], syphilis (syphilis antibody-positive), or active hepatitis B [hepatitis B virus (HBV) - deoxyribonucleic acid (DNA) >500 IU/ml]; hepatitis C virus (HCV) infection (HCV antibody positive and HCV ribonucleic acid amplification quantitative test positive). Patients with well controlled HIV, HBV, and HCV infections may be enrolled with no significant safety risk in the judgment of the investigator; see https://www.fda.gov/media/121319/download for definition of well controlled.
21. Patients with severe active infection, including but not limited to bacteremia and severe pneumonia within 2 weeks prior to the first dose; patients with an active infection requiring intravenous antibiotics within 2 weeks prior to the first dose.
22. Patients with conditions that may affect drug absorption as judged by the investigator, such as dysphagia, chronic diarrhea, or prior small bowel resection.
23. Patients with active autoimmune diseases, such as rheumatic disorder and rheumatoid disease.
24. The investigator considers that the patient is not suitable for participating in this study (e.g., study drug is not in the best interest of patient, patients with mental disorder, patients with poor compliance, etc.).