Radiotherapy Plus Putelimab and Vibostolimab for Advanced Anal Squamous Cell Carcinoma

Inclusion Criteria:

• Has provided written informed consent for the clinical study and biobank informed consent prior to initiation of any study-related procedures;

• Male or female patients aged between 18 and 75 years inclusive;

• Histologically confirmed squamous cell carcinoma of the anal canal (SCCAC);

• Patients with unresectable or metastatic disease who have experienced disease progression during or after first-line systemic therapy. For patients with locally limited disease, curative-intent radiotherapy combined with radiosensitising chemotherapy is considered first-line therapy; patients with disease progression during treatment or within 6 months after completion of such treatment are also eligible;

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;

• Expected survival of ≥ 12 months;

• Adequate organ function, with participants meeting all of the following laboratory criteria:

  1. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, without granulocyte colony-stimulating factor (G-CSF) administration in the preceding 14 days;
  2. Platelet count ≥ 100 × 10⁹/L, without blood transfusion in the preceding 14 days;
  3. Haemoglobin > 9 g/dL, without blood transfusion or erythropoietin administration in the preceding 14 days;
  4. Total bilirubin ≤ 1.5 × upper limit of normal (ULN). Participants with total bilirubin > 1.5 × ULN but direct bilirubin ≤ ULN are also eligible;
  5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN;
  6. Serum creatinine ≤ 1.5 × ULN, or creatinine clearance (calculated using the Cockcroft-Gault formula) ≥ 60 mL/min;
  7. Adequate coagulation function, defined as international normalised ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN;
  8. No clinically significant thyroid dysfunction as assessed by the investigator;
  9. Cardiac function: New York Heart Association (NYHA) functional class < III; left ventricular ejection fraction (LVEF) ≥ 50%;

• Agrees to provide adequate archived tumour tissue specimens from prior sampling or agrees to undergo biopsy to collect tumour tissue for correlative biomarker testing;

• Has at least one lesion at baseline that has not been previously irradiated and qualifies as a target lesion (TL) per RECIST version 1.1. Tumour assessment by imaging must be performed within 28 days prior to study treatment initiation;

• For female participants of childbearing potential: a negative urine or serum pregnancy test obtained within 3 days before the first dose of study drug (Cycle 1 Day 1). If the urine pregnancy test cannot be confirmed negative, a serum pregnancy test is required. Non-childbearing potential is defined as post-menopausal status for at least 1 year, or status following surgical sterilisation or hysterectomy;

• All participants (male and female) with reproductive potential must use contraceptive methods with an annual failure rate of <1% throughout the treatment period and for 120 days after the last dose of study drug (or 180 days after the last dose of chemotherapy, as applicable).

Exclusion Criteria:

• Diagnosis of another malignancy other than squamous cell carcinoma of the anal canal within 5 years prior to the first dose (excluding radically treated basal cell carcinoma of the skin, cutaneous squamous cell carcinoma, and/or radically resected carcinoma in situ);
• Known high risk of tumour obstruction, bleeding and/or perforation demonstrated endoscopically, requiring urgent surgery or stent placement;
• Currently receiving treatment in an interventional clinical study, or having received other medicinal therapies for gastrointestinal malignancies within 4 weeks before the first dose;
• Having received systemic treatment with Chinese patent medicines with anti-tumour indications or immunomodulatory agents (including thymopeptides, interferons, interleukins, excluding local administration for control of pleural effusion) within 2 weeks prior to the first dose;
• History of active autoimmune disease requiring systemic therapy (e.g., disease-modifying agents, glucocorticoids or immunosuppressants) within 2 years before the first dose of study treatment. Replacement therapy (e.g., thyroxine, insulin, or physiological glucocorticoids for adrenal or pituitary insufficiency) is not considered systemic therapy;
• Receiving systemic glucocorticoid therapy (excluding intranasal, inhaled or other locally administered glucocorticoids) or any other form of immunosuppressive therapy within 7 days before the first study dose.

Note: Physiological doses of glucocorticoids (≤10 mg prednisone per day or equivalent) are permitted.

• Known history of allogeneic solid organ transplantation (corneal transplantation excluded) or allogeneic haematopoietic stem cell transplantation;
• Known hypersensitivity to putelimab, chemotherapy agents, platinum compounds used in this study, or any of their excipients;
• Has not adequately recovered from toxicities and/or complications caused by prior interventions before treatment initiation (i.e., ≤ Grade 1 or return to baseline, excluding fatigue or alopecia);
• Known history of human immunodeficiency virus (HIV) infection (i.e., positive HIV-1/2 antibody);
• Untreated active hepatitis B (defined as positive HBsAg together with HBV-DNA copy number above the upper limit of normal of the local laboratory at the study site).

Note: Participants with hepatitis B meeting the following criteria are eligible:

1. HBV viral load < 1000 copies/mL (200 IU/mL) before the first dose. Participants shall receive anti-HBV prophylaxis throughout chemotherapy in this study to prevent viral reactivation;

2. For participants with anti-HBc (+), HBsAg (-), anti-HBs (-) and undetectable HBV viral load, prophylactic anti-HBV therapy is not required, but close monitoring for viral reactivation is mandatory.

   • Participants with active HCV infection (positive HCV antibody and HCV-RNA level above the lower limit of detection);
   • Received a live vaccine within 30 days before the first dose (Cycle 1 Day 1). Note: Inactivated injectable seasonal influenza vaccines administered within 30 days prior to the first dose are permitted; intranasal live attenuated influenza vaccines are not allowed.
   • Pregnant or breastfeeding women;
   • Presence of any severe or uncontrolled systemic disease, such as:

（1） Significant, symptomatic and poorly controlled abnormalities in rhythm, conduction or morphology on resting electrocardiogram, including complete left bundle branch block, second-degree or higher atrioventricular block, ventricular arrhythmia or atrial fibrillation; （2） Unstable angina, congestive heart failure, chronic heart failure with New York Heart Association (NYHA) functional class ≥ II; （3） Any arterial thrombosis, embolism or ischaemic event occurring within 6 months before enrolment, such as myocardial infarction, unstable angina, cerebrovascular accident or transient ischaemic attack; （4） Poorly controlled hypertension despite pharmacological treatment; （5） History of non-infectious pneumonitis requiring glucocorticoid therapy within 1 year before the first dose, or currently clinically active interstitial lung disease; （6） Active pulmonary tuberculosis; （7） Active or uncontrolled infection requiring systemic therapy; （8） Clinically active diverticulitis or intra-abdominal abscess; （9） Hepatic diseases such as decompensated liver disease, acute or chronic active hepatitis; （10） Poorly controlled diabetes mellitus; （11） Psychiatric disorder rendering the participant unable to comply with treatment;

• Presence of gastrointestinal physiological dysfunction or malabsorption syndrome; Any medical history, disease condition, treatment or abnormal laboratory finding that may interfere with study results, prevent the participant from completing the study, or any other condition deemed by the investigator to confer potential risks or render the participant unsuitable for study participation.