A Phase I clinical trial that will investigate the safety and tolerability of combining the modified vaccinia virus BT-001 with systemic pembrolizumab in patients with localised pMMR rectal cancer

Inclusion Criteria:

• Histological diagnosis of primary, localised rectal adenocarcinoma (cT2N0M0 to cT3bN2M0, TNM classification version 8

• Diagnosis of Proficient Mismatch Repair (pMMR) rectal adenocarcinoma (using biopsy from the initial diagnostic endoscopy)

• Suitable for potentially curative surgical resection

• No contraindications for treatment with pembrolizumab

• Not requiring neoadjuvant therapy

• Aged > 18 years at the time of inclusion

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

• Have baseline laboratory results as follows:

  • Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
  • Platelets ≥ 100 ×109/L (without platelet transfusion)
  • Haemoglobin ≥ 6.2 mmol/L or 10.0 g/dL (with or without red blood cell (RBC) transfusion)
  • Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
  • Bilirubin < 1.5 × ULN (or < 2.5 x ULN in patients with Gilbert's syndrome)
  • ALT, AST and alkaline phosphatase < 3 × ULN

• Provide written informed consent in accordance with all applicable regulations and follow the study procedures. Subjects must be capable of understanding the investigational nature, potential risks, and benefits of the study.

Exclusion Criteria:

• Have impending bowel obstruction or other indications for acute surgical intervention

• Have had concurrent immunotherapy in the 3 months before the start of the study therapy.

• Have acute or chronic hepatitis B or hepatitis C infection

• Evidence of immunosuppression for any reason:

  • Known HIV disease
  • Chronic oral or systemic steroid medication use at a dose of > 10 mg/day of prednisolone or equivalent
  • Other signs or symptoms of clinical immune system suppression

• Have an autoimmune disorder (except thyroiditis with replacement therapy and type I diabetes mellitus)

• Have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease

• Ongoing antiviral therapy active on vaccinia virus, e.g., ribavirin, cidofovir, interferon/ pegylated interferon

• History of severe exfoliative skin conditions (e.g., eczema or atopic dermatitis) requiring systemic therapy for more than 4 weeks within 2 years prior to BT-001 initiation

• Live virus vaccination within 28 days of BT-001 administration

• A history of hypersensitivity to egg or to any excipient of BT-001

• Pregnant or breast-feeding female. Confirmation that women of childbearing potential are not pregnant with a negative serum β-human chorionic gonadotrophin (β-hCG) pregnancy test results must be obtained within 7 days prior to the 1st administration of BT-001

• Fertile males and females who are unwilling to employ highly effective means of contraception during study treatment and for 4 months after the last dose of study treatment

Individual participant data (IPD) that underlie the results of this study may be shared after de-identification. Access to trial IPD can be requested by qualified researchers engaging in relevant independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).

Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.

Access to trial IPD can be requested by qualified researchers engaging in relevant independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).