Immunotherapy and SBRT for Metastatic Head and Neck Carcinomas

Inclusion Criteria:

1. Pathologically (histologically or cytologically) confirmed diagnosis HNSCC at ametastatic site. This includes histologic variants of SCC such as spindle cellcarcinoma, poorly differentiated keratin-positive carcinoma, and lymphoepithelioma.The pathology can come from the most accessible site and does not need to be fromthe time of diagnosis.

2. ≥2 locoregional and/or extracranial metastatic lesions (no brain metastases) thatare treatable by SBRT. Lesions that are not measurable per RECIST v1.1 must showprogression on 2 consecutive imaging studies with a minimum increase of 1 mm, andmust be a mimimum size of 5 mm at time of enrollment. .

3. ≤ 4 prior treatment lines with systemic therapy

4. ≥2 measurable disease (RECIST) consisting of extracranial metastatic lesions (nobrain metastasis) that are treatable by SBRT.

5. ≤ 10 metastatic lesions

6. Life expectancy > 24 weeks

7. Evaluation by a radiation oncologist within 45 days prior to study registration

8. Evaluation by a medical oncologist within 45 days prior to study registration

9. Body weight >30kg

10. The following imaging workup to document metastases within 45 days prior to studyregistration:

• CT scans of the chest, abdomen and pelvis OR whole body PET/CT

11. ≥ 18 years of age at time of study entry

12. Up to 4 prior treatment lines with systemic therapy are allowed

13. Eastern Cooperative Oncology Group/World Health Organisation (ECOG/WHO) performancestatus score of ≤ 1

14. Patients with locoregional recurrence(s) can be included only if they have evidenceof distant metastasis; patients with locoregional recurrences which are symptomaticand/or potentially affect quality of life may undergo palliative radiation therapyto this region prior to enrollment on the protocol at the discretion of the treatingphysician. However, a minimum of 6 weeks must elapse before receiving protocoltreatment.

15. Adequate normal organ and marrow function as defined below:

• Haemoglobin ≥ 9.0 g/dL

• Absolute neutrophil count (ANC ≥ 1.5 (or 1.0) x (> 1500 per mm3)

• Platelet count ≥ 100 (or 75) x 109/L (>75,000 per mm3)

• Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This willnot apply to subjects with confirmed Gilbert's syndrome (persistent orrecurrent hyperbilirubinemia that is predominantly unconjugated in the absenceof hemolysis or hepatic pathology), who will be allowed only in consultationwith their physician.

• AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless livermetastases are present, in which case it must be ≤ 5x ULN

• Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft andGault 1976) or by 24-hour urine collection for determination of creatinineclearance (calculated by study site staff)

16. Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Women will be considered post-menopausal if theyhave been amenorrheic for 12 months without an alternative medical cause. Thefollowing age-specific requirements apply:

• Women <50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy).

• Women ≥50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses >1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy).

17. Patient is willing and able to give written informed consent, prior to performingany protocol-related procedures, including screening evaluations.

18. Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

19. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4, includingdurvalumab and tremelimumab if the following are fulfilled:

• Must not have experienced a toxicity that led to permanent discontinuation ofprior immunotherapy.

• All AEs of prior immunotherapy must have completely resolved or resolved tobaseline prior to screening for this study.

• Must not have experienced a ≥ Grade 3 immune related AE or an immune relatedneurologic or ocular AE of any grade while receiving prior immunotherapy.

• Must not have required the use of additional immunosuppression other thancorticosteroids for the management of an AE and not have experienced recurrenceof an AE if re-challenged.

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZenecastaff and/or staff at the study site)

2. Nasopharyngeal carcinoma

3. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study.

4. >4 prior treatment lines with systemic therapy

5. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,endocrine therapy, targeted therapy, biologic therapy, tumour embolization,monoclonal antibodies) ≤ 30 days prior to the first dose of study drug. Ifsufficient wash-out time has not occurred due to the schedule or PK properties of anagent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmuneand the investigator.

6. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria

• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basisafter consultation with the Study Physician.

• Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab or tremelimumab may be included only afterconsultation with the Study Physician.

7. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (eg. hormonereplacement therapy) is acceptable.

8. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks of the first dose of study drug

9. Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of IP. Note: Local surgery of isolated lesions for palliative intentis acceptable.

10. History of allogenic organ transplantation.

11. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions tothis criterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (eg, following Hashimoto syndrome) stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

• Patients with celiac disease controlled by diet alone

12. Uncontrolled undercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent

13. History of another primary malignancy except for

• Malignancy treated with curative intent and with no known active disease ≥5years before the first dose of IP and of low potential risk for recurrence

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease

• Adequately treated carcinoma in situ without evidence of disease

14. History of leptomeningeal carcinomatosis

15. Brain metastases or spinal cord compression. Patients with suspected brainmetastases at screening should have an MRI (preferred) or CT each preferably with IVcontrast of the brain prior to study entry.

16. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab or tremelimumab. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (eg, CT scanpremedication)

17. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP andup to 30 days after the last dose of IP.

18. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of durvalumab monotherapy or180 days afterthe last dose of durvalumab + tremelimumab combination therapy.

19. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

20. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which requiredsteroid treatment, or any evidence of clinically active interstitial lung disease.

21. Judgment by the investigator that the patient is unsuitable to participate in thestudy and the patient is unlikely to comply with study procedures, restrictions andrequirements.

22. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 180 days after the last dose of durvalumab + tremelimumab combinationtherapy or 90 days after the last dose of durvalumab monotherapy, whichever is thelonger time period.