Re-radiotherapy Combined With Chidamide for the Treatment of Recurrent Head and Neck Squamous Cell Carcinoma After Radiotherapy

A Prospective, Single-arm Clinical Study on Re-irradiation Combined With Chidamide in the Treatment of Patients With Recurrent Head and Neck Squamous Cell Carcinoma After Radiotherapy

To evaluate the safety and tolerability of re-irradiation combined with chidamide in patients with recurrent head and neck squamous cell carcinoma after radiotherapy.

The aim of this clinical trial is to systematically evaluate the safety and tolerability of combining the Histone Deacetylase(HDAC) inhibitor chidamide with salvage re-irradiation (re-RT), and to explore its preliminary anti-tumor activity in adults with recurrent squamous cell carcinoma of the head and neck (HNSCC) at West China Hospital of Sichuan University. Specifically, it aims to determine the incidence of Dose-Limiting Toxicity (DLT) during the dose-escalation phase.

Participants will undergo a 6-week course of intensity-modulated radiation therapy (IMRT) combined with chidamide, utilizing a 3+3 dose-escalation design. The regimen consists of chidamide (20 mg or 30 mg orally twice weekly, with an interval of at least 3 days between doses) plus fixed-dose IMRT (60 Gy in 30 fractions of 2 Gy each, administered once daily, 5 days a week). Participants will also undergo protocol-specified safety monitoring, with adverse events graded according to CTCAE v5.0, alongside routine clinical evaluations and laboratory tests. Finally, safety follow-up and long-term monitoring for disease status and survival outcomes will be conducted as defined by the protocol.

Inclusion Criteria:

1. Age and Life Expectancy: Aged ≥18 and ≤75 years, with a life expectancy of ≥3 months, regardless of gender.

2. Diagnosis and History: Patients with histologically confirmed head and neck squamous cell carcinoma meeting the following conditions:

   1. Primary tumor site located in the oral cavity, oropharynx, larynx, or hypopharynx.
   2. History of prior radical or adjuvant radiotherapy with local/regional recurrence (confirmed by MRI/PET-CT).
   3. The interval between the completion of the last radiotherapy and recurrence is ≥6 months (to ensure partial recovery of normal tissues).

3. Surgical Status: The recurrent lesion is deemed unresectable by a head and neck surgeon, or the patient refuses surgery, or is medically unfit to tolerate surgery.

4. Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1.

5. Organ and Marrow Function: Adequate organ and bone marrow function, defined as follows:

   1. Hematology: Absolute Neutrophil Count (ANC) ≥1.5×10⁹/L; Platelets (PLT) ≥80×10⁹/L; Hemoglobin ≥8 g/dL.
   2. Liver Function: Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and Alkaline Phosphatase (ALP) ≤2.5× Upper Limit of Normal (ULN); Total Bilirubin (TBIL) ≤1.5×ULN.
   3. Albumin: Serum Albumin ≥2.8 g/dL.
   4. Renal Function: Serum Creatinine (Cr) ≤1.5×ULN OR Creatinine Clearance (CrCl) >60 mL/min.
   5. Coagulation: International Normalized Ratio (INR) ≤1.5; Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN.

6. Consent: Willingness to participate in the study, evidenced by signing the Informed Consent Form (ICF), and ability to comply with scheduled visits and related procedures.

Exclusion Criteria:

1. Metastatic Disease: Presence of distant metastasis (Stage M1).

2. Prior Therapy: Receipt of any of the following treatments:

   1. Prior treatment with HDAC inhibitors (e.g., chidamide, vorinostat), etc.
   2. Major surgery or severe trauma within 4 weeks prior to the first dose.

3. Second Primary Malignancy: History of a second primary malignancy (excluding basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, cervical carcinoma in situ, or carcinoma of the gastrointestinal tract in situ that has been cured with no recurrence for 5 years, or other malignancies deemed eligible by the Investigator).

4. Prior Toxicity: Occurrence of Grade ≥3 radiation necrosis or myelosuppression following the initial radiotherapy.

5. Medical Comorbidities: Presence of severe medical illnesses, such as:

   1. Cardiac insufficiency Class II or higher (NYHA criteria);
   2. Ischemic heart disease (e.g., myocardial infarction or angina pectoris);
   3. Clinically significant supraventricular or ventricular arrhythmias;
   4. Left Ventricular Ejection Fraction (LVEF) <50% as determined by echocardiogram;
   5. QTc interval >450 msec for males or >470 msec for females;
   6. Abnormal Electrocardiogram(ECG) findings that the Investigator considers to pose an additional risk for the investigational drug.

6. Infectious Disease: Presence of active Hepatitis B (Hepatitis B Virus Deoxyribonucleic Acid ≥2000 IU/ml or 10⁴ copies/ml) or Hepatitis C (Hepatitis C Virus antibody positive and Hepatitis C Virus Ribonucleic Acid above the lower limit of detection of the assay), or a known history of positive Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS).

7. Psychiatric Disorders: Any severe neurological or psychiatric illness that may prevent the patient from providing informed consent or complying with study procedures.

8. Reproductive Status: Women who are pregnant or breastfeeding; subjects (and their partners) who plan to conceive during the screening period up to 3 months after the end of the study; or women of childbearing potential who are not using effective contraceptive methods.

9. Investigational Drugs: Receipt of any investigational drug within 4 weeks prior to the first dose of the study drug, or concurrent enrollment in another clinical study, unless it is for observational or interventional clinical study follow-up.

10. Investigator Discretion: Other factors determined by the Investigator that may affect the subject's ability to complete the study medication and follow-up.