Phase I Trial: T4 Immunotherapy of Head and Neck Cancer

Inclusion Criteria:

1. Histologically and/ or cytologically confirmed SCCHN.

2. 18 years or older.

3. Locally advanced and/ or recurrent head and neck cancer with or without metastaticdisease (excluding brain metastases) for whom no standard therapy remains or issuitable.

4. Regarding previous treatment, patients may have received prior systemic therapy,including platinum chemotherapy, at least one month earlier. In the presence ofmetastatic disease, recent short-course palliative radiotherapy to non-targetsite(s) is allowed.

5. Those who refuse palliative treatment may be eligible for participation. However,their reasons for not opting for palliative treatment must be explored thoroughly.

6. At least one loco-regional target lesion measurable by RECIST v1.1 criteria on CT orMRI scanning within four weeks of enrolment, and amenable to intra-tumoralinjection.

7. Eastern Co-operative Oncology Performance Status of 0-2.

8. Normal cardiac function as assessed by electrocardiography and eitherechocardiography (ECHO), or multi-gated acquisition (MUGA) scanning. Leftventricular ejection fraction must be > 50%. Assessment must take place within fourweeks of enrolment.

9. Haematology results within seven days of enrolment: neutrophils >1.5 x 109/L,platelets >100 x 109/L, haemoglobin >9g/dl, INR <1.5.

10. Biochemistry results within seven days of enrolment: • serum creatinine <1.5 upperlimit of normal • bilirubin <1.25 times normal; • ALT/ AST <2.5 times upper limit ofnormal (<5 times upper limit of normal if liver metastases present)

11. Female patients must be postmenopausal (12 months of amenorrhea), surgically sterileor they must agree to use a physical method of contraception. Oral or injectablecontraceptive agents cannot be the sole method of contraception. Women ofchildbearing potential (WOCB) who receive cyclophosphamide must adhere to thesecontraceptive requirements during the trial and until 3 months after the last doseof cyclophosphamide. Male patients, even if sterilized, must agree to use a barriermethod of contraception. Male subjects must also commit to use a barrier method ofcontraception until at least 3 months after the end of study treatment.

12. Written informed consent prior to registration.

13. Eligible for NHS care in the UK.

Exclusion Criteria:

1. The presence of or imminent occurrence of airway obstruction, unless tracheostomy inplace.

2. The presence of or imminent occurrence of tumour-mediated infiltration of majorblood vessels.

3. Positive history of HIV-1, HIV-2, HTLV-1, HTLV-2, Hepatitis B, Hepatitis C orsyphilis infection.

4. Prior splenectomy.

5. Clinically active autoimmune disease. Sub-clinical or quiescent autoimmune diseasedoes not exclude from participation.

6. Treatment in the preceding week with systemic corticosteroids (> 20mg prednisolone/day), any systemic immunomodulatory agent, radiotherapy, chemotherapy orinvestigational medicinal product.

7. Concurrent use of anticoagulant therapy is not permissible.

8. The presence of major co-morbidity likely to impair ability to undergo trialtherapy, such as recent myocardial infarction, congestive cardiac failure oruncontrolled hypertension.

9. The presence of any psychological, familial, sociological or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule.

10. Cyclophosphamide allergy (Cohort 6 only).

11. Pregnancy.

12. Breastfeeding.

13. Prior T4 immunotherapy.