Endostatin Adenovirus With Checkpoint Inhibitor in Advanced Head and Neck or Esophageal Cancer

Cohort A will enroll patients with recurrent or metastatic head and neck cancer. Cohort B will enroll patients with ESCC with superficial lymph node metastasis. Both cohorts will receive intratumoral injection of recombinant human endostatin adenovirus combined with intravenous an immune checkpoint inhibitor.

The primary objectives are to assess the safety profile, incidence of dose-limiting toxicities (DLTs), and treatment-related adverse events (TRAEs) of the combination therapy. The secondary objectives include evaluation of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Each cohort plans to enroll approximately 20 patients, with a total of 40 participants.

• recombinant human endostatin adenovirus (Biological): Recombinant Human Endostatin Adenovirus: Administered via intratumoral injection twice every 3 weeks for a total of eight doses, or until disease progression, the occurrence of unacceptable toxicity, or death from any cause, whichever occurs first.
• PD-1 Inhibitor (Drug): PD-1 inhibitor: Administered via intravenous infusion once every 3 weeks.

Primary outcomes

• Incidence of treatment-related adverse effects (TRAEs) [Through study completion, an average of 1.5 year]: This study will collected any adverse medical events that occurred during the study drug treatment, and the treatment related adverse events as assessed by CTCAE v5.0.
• Incidence of Dose-Limiting Toxicities (DLTs) [During the first cycle of treatment （21 days）]: DLTs are defined as treatment-related adverse events occurring during the DLT evaluation period that meet protocol-specified criteria for severity and duration, as assessed by NCI CTCAE v5.0.

Secondary outcomes

• Objective Response Rate (ORR) [up to 12 months]: It is defined as the proportion of patients with complete response (CR) or partial response (PR), as assessed by RECIST 1.1.
• Disease Control Rate (DCR) [up to 12 months]: DCR refers to the proportion of patients who achieve complete response (CR), partial response (PR), or stable disease (SD) for a specified minimum duration after treatment, based on RECIST 1.1.
• Progression-Free Survival (PFS) [up to 12 months]: Time from the start of treatment to the first documentation of disease progression based on RECIST 1.1.
• Overall Survival (OS) [up to 24 months]: Time from the start of treatment to death from any cause

Sex: All, ages: 18 Years to 75 Years

* Cohort A (Head and Neck Cancer)
* Cohort B (Esophageal Squamous Cell Carcinoma)

Inclusion Criteria:

1. Age ≥18 years

   * Cohort A (Head and Neck Cancer): ≤70 years
   * Cohort B (Esophageal Squamous Cell Carcinoma): ≤75 years
2. Histologically or cytologically confirmed recurrent or metastatic:

   * Cohort A: Head and Neck Cancer
   * Cohort B: ESCC, AJCC 9th edition stage IV
3. Prior treatment:

   * Cohort A: ≥1 prior platinum-based chemotherapy regimen or platinum-refractory/intolerant
   * Cohort B: Prior immune checkpoint inhibitor (ICI) therapy with documented acquired resistance after prior PR or SD
4. At least one lesion accessible for intratumoral injection

   * Cohort A: measurable lesion ≥2 cm by RECIST 1.1
   * Cohort B: superficial metastatic lymph nodes (cervical or supraclavicular)
5. ECOG performance status

   * Cohort A: 0-2
   * Cohort B: 0-1
6. Adequate organ function
7. Life expectancy ≥12 weeks (Cohort A)
8. No anti-tumor therapy (chemotherapy, radiotherapy, biotherapy, antiviral) within 4 weeks prior to enrollment (Cohort A)
9. Availability of fresh tumor tissue specimen or pathological slides from the injection target lesion (Cohort B)
10. Male/female patients of childbearing potential must use effective contraception during study and for at least 6 months after treatment
11. Voluntary participation with signed informed consent

Exclusion Criteria:

1. Known allergy or hypersensitivity to study drugs
2. Lesions unsuitable for injection due to proximity to major blood vessels, nerves, or hollow organs, or with extensive necrosis
3. Deeply located lesions with high procedural difficulty (Cohort B)
4. Concurrent radiotherapy to target lesion(s) (Cohort A)
5. Prior anti-angiogenic therapy (Cohort A)
6. Immunosuppressive therapy or systemic corticosteroids >10 mg/day prednisone (or equivalent) within 2 weeks prior to enrollment
7. Active autoimmune disease or history of autoimmune disease
8. Congenital or acquired immunodeficiency
9. Severe coagulopathy, bleeding tendency, or high-risk lesions (Cohort B)
10. Poor nutritional status (Cohort B)
11. Interstitial lung disease with symptoms or radiographic evidence (Cohort B)
12. Severe uncontrolled systemic disease or recent myocardial infarction (<3 months)
13. Acute infection
14. Pregnancy or breastfeeding
15. Other malignancy besides ESCC (Cohort B)
16. Patients unlikely to comply with follow-up or participation requirements
17. Any condition deemed unsuitable for enrollment by the investigator