MAGE-A3

1. Written (signed and dated) informed consent for both pre-screening and the main trial and capable of co-operating with any investigational medicinal product (IMP) administration and follow-up.

2. Histologically or cytologically proven Stage IIIB, IIIC or IV squamous NSCLC or Stage IIIB or IV non-squamous NSCLC scheduled to receive pembrolizumab and chemotherapy as standard of care at the time of enrolment or randomisation. Patients can receive up to two cycles of SoC pembrolizumab in combination with chemotherapy prior to enrolment or randomisation to the trial.

Or (when included in the trial)

Histologically proven inoperable Stage III or IV Oesophageal or Gastro-oesophageal Junction cancer scheduled to receive or continue to receive chemotherapy and an immune checkpoint inhibitor as standard of care at the time of enrolment.

3. For non-squamous NSCLC patients, EGFR and ALK mutation testing has been performed and both are negative.

4. NSCLC patients with no prior immune checkpoint inhibitor therapy prior to the pembrolizumab they are receiving in combination with chemotherapy at time of enrolment or randomisation.

a. For non-squamous NSCLC patients, the patient has not received previous systemic therapy for advanced/metastatic disease. Completion of treatment with chemotherapy and/or radiotherapy as part of neoadjuvant therapy is allowed as long as the therapy was completed at least 6 months prior to the diagnosis of recurrent locally advanced or metastatic disease.

b. For squamous NSCLC patients, the patient has not received previous cytotoxic chemotherapy for advanced/metastatic disease. Completion of treatment for earlier stage disease with chemotherapy with or without radiotherapy as part of neoadjuvant/concurrent/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of recurrent locally advanced or metastatic disease.

Or (when included in the trial)

Patients with GO cancer who are treatment naïve patients with no prior immune checkpoint inhibitor therapy or chemotherapy prior to the chemotherapy and immune checkpoint inhibitor they are receiving at time of enrolment to the trial.

5. Have at least one measurable lesion according to RECIST v1.1. Note: A measurable lesion may be biopsied at screening and on trial, however that lesion cannot be selected as a target lesion for disease assessment according to RECIST v1.1.

6. PD-L1 status between 1% and 50% tumour proportion score for NSCLC patients.

Or (when included in the trial)

A confirmed PD-L1 combined positive score (CPS) for patients with Oesophageal or Gastro-oesophageal Junction cancer.

7. Archival tumour tissue or new biopsy expressing MAGE-A3 as demonstrated by RT PCR.

8. Life expectancy of at least 12 weeks.

9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 2).

10. Haematological and biochemical indices within the ranges shown below. These measurements should be performed to confirm the patient’s eligibility.

Laboratory Test Value Required

Haemoglobin (Hb) > = 90 g/L (no prior transfusion within last 4 weeks)

OR

> = 100 g/L (transfusion within last 4 weeks)

Absolute neutrophil count (ANC) > = 1.5×10^9/L

(growth factor support (G-CSF) is allowed when used as part of routine supportive therapy for SoC)

Platelet count > = 100×10^9/L

International normalized ratio (INR)

AND

prothrombin time (PT)

OR

Activated partial thromboplastin time (aPTT) < = 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

Bilirubin < = 1.5 x upper limit of normal (ULN)

OR

< 3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia)

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < = 3.0 x ULN

OR

< = 5.0 x ULN in presence of liver metastases

Calculated creatinine clearance (using the Cockcroft & Gault [C&G] formula) > = 50 mL/min or serum creatinine < = 1.5 x ULN

11. Aged 18 years or over at the time pre-screening consent is given. 

1. For non-squamous NSCLC patients, patients who have received previous systemic therapy for advanced/metastatic disease prior to the pembrolizumab they are receiving in combination with chemotherapy at time of enrolment or randomisation. Completion of treatment with chemotherapy and/or radiotherapy as part of neoadjuvant therapy is allowed as long as the therapy was completed at least 6 months prior to the diagnosis of recurrent locally advanced or metastatic disease.

For squamous NSCLC patients, patients who have received previous cytotoxic chemotherapy for advanced/metastatic disease prior to the pembrolizumab they are receiving in combination with chemotherapy at time of enrolment or randomisation. Completion of treatment for earlier stage disease with chemotherapy with or without radiotherapy as part of neoadjuvant/concurrent/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of recurrent locally advanced or metastatic disease.

Or (when included in the trial)

For patients with GO cancer - patients who have previously received treatment for their current GO cancer apart from the SoC treatment outlined in this clinical trial.

2. Previous therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor (e.g., anti-CTLA-4, OX 40, anti-CD137). This does not include the immune checkpoint inhibitor patients receive in combination with chemotherapy commencing during screening prior to enrolment or randomisation to the trial.

3. Current or prior malignancy which could affect safety or efficacy assessment of the IMP or compliance with the protocol or interpretation of results. Patients with curatively-treated non-melanoma skin cancer, non-muscle-invasive bladder cancer, or carcinomas-in-situ are eligible.

4. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with symptomatically active brain metastases or leptomeningeal metastases. Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during trial screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.

5. Female patients who are able to become pregnant (or are already pregnant or lactating). However, those patients who meet the points described in the protocol are considered eligible.

6. Male patients with partners of child-bearing potential. However, those patients who meet the points described in the protocol are considered eligible.

7. Major thoracic or abdominal surgery from which the patient has not yet recovered. Patients who have undergone other types of surgery which the Chief Investigator (CI) and Sponsor agree would not compromise patient safety on trial are eligible.

8. Electrocardiogram (ECG) with clinically significant abnormalities or with QTcF interval (QT corrected using Fridericia’s formula) > 480 msec.

9. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.

10. Historically known to be serologically positive for hepatitis B or human immunodeficiency virus (HIV). Patients with previous Hepatitis C exposure but no current infection are eligible to participate.

11. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

12. Has received AZD1222 (previously named ChAdOx1-nCoV-19) vaccine within six weeks of commencing chemotherapy and an immune checkpoint inhibitor.

13. Has received any other live vaccination within four weeks before enrolment or randomisation to the trial.

14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.

15. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. Participants who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of graft versus host disease (GVHD).

16. Has previously experienced severe hypersensitivity (> = Grade 3) to an immune checkpoint inhibitor, ChAdOx1 or MVA vaccines and/or any of their excipients.

17. History of a severe allergy to eggs or history of severe allergic reaction to any previous vaccination. 

Research Nurse: Lizzie Coates (x2031) Elizabeth.Coates@LTHTR.nhs.uk