A Single-Arm, Open-Label Phase Ia/Ib Clinical Trial Evaluating the Safety, Tolerability, Pharmacokinetic Profile, and Preliminary Efficacy of FS-207 in Patients With Advanced Solid Tumors With High Microsatellite Instability (MSI-H)

Обзор

This is a Phase Ia/Ib clinical study of FS-207, an investigational oral tablet, in patients with advanced solid tumors that are microsatellite instability-high, also called MSI-H. MSI-H tumors have specific changes in DNA repair pathways and may depend on the WRN protein to survive. FS-207 is designed to inhibit WRN. The main purpose of this study is to evaluate the safety and tolerability of FS-207 and to understand how the drug moves through the body. The study will also look for early signs of anti-tumor activity. This study has two parts. In the first part, called dose escalation, small groups of patients will receive increasing dose levels of FS-207 to help identify a safe and appropriate dose for further study. In the second part, called dose expansion, additional patients with selected MSI-H advanced solid tumors will receive FS-207 at dose level(s) chosen based on the earlier safety and clinical data. Participants will take FS-207 orally once daily. Study doctors will monitor participants closely through physical examinations, blood and urine tests, electrocardiograms, heart function tests, imaging scans, and blood samples for pharmacokinetic testing. Tumor assessments will be performed regularly to evaluate whether the cancer has responded to treatment, remained stable, or progressed. This is an open-label study, which means that both the participants and study doctors will know that FS-207 is being given. There is no placebo group in this study.

Вмешательства

• Препарат FS-207
  FS-207 will be administered orally

Первичные конечные точки

• Number of Participants with a Dose Limiting Toxicity (DLT) [Срок оценки: Up to 21 days]
• Number of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Срок оценки: Up to 3 years]

Вторичные конечные точки (9)

• Maximum Serum Concentration (Cmax) of FS-207 [Срок оценки: up to 60 days]
• Minimum Serum Concentration (Cmin) of FS-207 [Срок оценки: Up to 60 days]
• Area Under the Concentration-time Curve (AUC) Over the Dosing Interval of FS-207 [Срок оценки: Up to 60 days]
• Time to Achieve Cmax (Tmax) of FS-207 [Срок оценки: Up to 60 days]
• Confirmed Objective Response Rate(ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [Срок оценки: Up to 5 years]
• Duration of Response (DOR) per RECIST v1.1 [Срок оценки: Up to 5 years]
• Disease Control Rate (DCR) per RECIST v1.1 [Срок оценки: Up to 5 years]
• Progression-free Survival (PFS) per RECIST v1.1 [Срок оценки: Up to 5 years]
• Overall Survival (OS) per RECIST v1.1 [Срок оценки: Up to 5 years]

Критерии участия

Критерии включения

• 1\) Male or female patients aged ≥18 years at the time of signing the Informed Consent Form; 2) Patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors, whose disease has progressed or who have experienced intolerable toxicity following prior standard therapy. Additionally, participants must meet the following criterion: they have previously received treatment with at least one immune checkpoint inhibitor (ICI), and this treatment was deemed a failure due to disease progression or was discontinued due to intolerable toxicity; 3) Participants must provide a test report confirming a positive MSI-H/dMMR status in their tumor tissue; 4) Eastern Cooperative Oncology Group (ECOG) Performance Status score: 0-1; 5) Anticipated life expectancy of ≥3 months; 6) Presence of at least one measurable lesion (according to RECIST v1.1 criteria, a measurable lesion is defined as a non-lymph node lesion with a longest diameter of ≥10 mm, or a lymph node lesion with a short axis of ≥15 mm, as measured by CT or MRI); 7) Female or male participants of childbearing potential must agree not to conceive, donate ova, or donate sperm from the date of signing the Informed Consent Form until 3 months after the last treatment administered in the study; furthermore, during this period, they must agree to utilize effective contraception (including one or more non-pharmacological contraceptive methods) or safety measures; 9) Agrees to comply with all requirements and procedures of the clinical trial and voluntarily signs the Informed Consent Form.

Критерии исключения

• 1\) Known diagnosis of Werner syndrome; 2) Prior treatment with any medication targeting Werner syndrome helicase (WRN); 3) Receipt of any anti-tumor therapy within 3 weeks or 5 half-lives (whichever is longer) prior to the first dose; 4) Patients with adverse events related to prior anti-tumor therapy that have not resolved to Grade ≤1 (according to NCI CTCAE v6.0), excluding toxicities deemed by the investigator to pose no safety risk-such as alopecia, Grade 2 peripheral neuropathy, hypothyroidism stable on hormone replacement therapy, mild rash, hyperpigmentation, etc.-with specific cases subject to the investigator's judgment; 5) Undergone, or scheduled to undergo during the study period, major surgery (excluding procedures for vascular access placement, or biopsies performed via laparoscopy, mediastinoscopy, or thoracoscopy) within 4 weeks prior to the first dose; or undergone radical radiotherapy (palliative radiotherapy within 2 weeks prior to the first dose); 6) Leptomeningeal metastases; central nervous system (CNS) metastases with clinical symptoms; or other evidence indicating that CNS metastases are not adequately controlled, as determined by the investigator to render the participant unsuitable for enrollment. 7) Patients with symptomatic and unstable pleural effusion, ascites, or pericardial effusion, as determined by the investigator (patients whose clinical symptoms stabilize following therapeutic drainage of pleural fluid, ascites, or pericardial fluid may be enrolled); 8) Patients with other severe or uncontrolled systemic diseases, as determined by the investigator, including but not limited to interstitial lung disease, non-infectious pneumonitis; uncontrolled diabetes, renal disease requiring dialysis, severe hepatic disease (Child-Pugh Class B or C), acute pancreatitis, etc.; 9) Patients with cardiovascular diseases of significant clinical relevance;

10\) Patients with dysphagia, or gastrointestinal dysfunction or disease that could significantly affect the absorption of FS-207 tablets (e.g., severe ulcerative disease, poorly controlled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, etc.); 11) Patients with active autoimmune disease requiring systemic treatment, or a history of autoimmune disease with a potential for recurrence; 12) Patients with active Hepatitis B; active Hepatitis C; or Human Immunodeficiency Virus (HIV) infection; 13) Patients who have received a live vaccine or attenuated live vaccine within 4 weeks prior to the first dose of study medication; administration of inactivated vaccines is permitted; 14) Patients who have received treatment with other investigational drugs not yet approved for marketing, or who have participated in clinical trials involving interventional medical devices, within 4 weeks prior to the first dose of study medication; 15) Patients with active pulmonary tuberculosis (TB) (patients suspected of having active TB must undergo further evaluation by an infectious disease specialist to establish a definitive diagnosis) or a history of active TB; 16) Patients with any active infection requiring systemic treatment occurring within 2 weeks prior to the first dose of study medication; 17) Participants with a known or suspected history of severe allergic reactions to any component of the investigational drug, or a history of uncontrolled allergic asthma; 18) Patients who have previously undergone organ transplantation or allogeneic hematopoietic stem cell transplantation; 19) History of substance abuse, or known medical, psychological, or social conditions-such as a history of alcoholism or drug abuse; 20) Women who are pregnant or breastfeeding, or women of childbearing potential who have a positive pregnancy test result during the screening period; 21) Any other conditions that the investigator deems render the participant unsuitable for participation in this trial.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 17 центров

• The First Affiliated Hospital of Anhui Medical University — Хэфэй
• Fujian Cancer Hospital — Фучжоу
• Guangdong Provincial People's Hospital — Гуанчжоу
• The First Affiliated Hospital of Zhengzhou University — Чжэнчжоу
• Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & T — Ухань
• Hunan Cancer Hospital — Чанша
• Jiangxi Cancer Hospital — Nanchang
• Jilin Cancer Hospital — Changchun
• … и ещё 9 центров

Идентификаторы

NCT: NCT07593144 · ForesightTx

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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