The UNSCARRed Study: UNresctable Squamous Cell Carcinoma Treated With Avelumab and Radical Radiotherapy
The UNSCARRed Study: UNresctable Squamous Cell Carcinoma Treated With Avelumab and Radical Radiotherapy
The purpose of this study is to find out what effects the combination of radiation therapy
 and Avelumab have on you and your cancer. The effectiveness of this treatment as well as what
 side effects occur will both be studied.

 Squamous cell carcinoma of the skin is the most commonly diagnosed cancer. Risk factors for
 the development of squamous cell cancer include ultraviolet (sun) exposure, as well as
 increasing age. In the majority of instances, a minor surgical procedure is curative. Less
 commonly, squamous cell carcinoma cannot be removed surgically, due to the location and/or
 extent of the cancer, or due to patient-specific factors which would make surgery unsafe (for
 instance, the presence of unrelated medical illnesses such as heart disease or stroke).

 When squamous cell carcinoma cannot be removed surgically, radiation therapy may serve as an
 effective alternative treatment. Squamous cell carcinomas are typically very sensitive to
 radiation, and in some instances radiation therapy may also cure a person of their cancer.

 While some people may be cured by radiation therapy, not all people are. This study is
 investigating the combination of radiation therapy and immune therapy. When given together,
 more patients may be cured of their cancer.

 Immune therapy is effective for the treatment of squamous cell carcinoma. In clinical trials,
 more than half of patients benefit from immune therapy. Immune therapy is not chemotherapy.
 Instead, immune therapy involves the infusion of antibodies which target a person's own
 immune system. Immune therapy "re-activates" a person's own immune system against their
 cancer.

 The treatment offered within this clinical trial includes daily radiation treatments as well
 as immunotherapy treatments administered once every two weeks. The immunotherapy in use is a
 drug called Avelumab, which is an antibody that helps your body's immune system fight cancer.

 Health Canada, the regulatory body that oversees the use of natural health products, drugs
 and devices in Canada, has not approved the sale or use of this product to treat this kind of
 cancer, although they have allowed its use in this study
The treatment of patients with unresectable cuSCC is challenging, and represents an area of
 high unmet need. Treatment options within this patient population are limited; hence most
 patients undergo monotherapy with radiation leading to suboptimal outcomes. Inadequately
 treated disease may cause high morbidity, negatively impacting quality of life and leading to
 increased costs for supportive care. To address the unmet needs of these patients, we propose
 an exploratory trial combining Avelumab with radiation therapy, with an investigational plan
 to study clinical and health services outcomes. Cutaneous squamous cell carcinoma also
 represents a unique opportunity for correlative studies, given the accessibility of disease.
 The schedule of patient biopsies has been designed to allow analyses following treatment with
 Avelumab monotherapy as well as concurrent Avelumab/RT. We therefore propose additional
 biomarker outcomes, which may improve the care of patients with cuSCC as well as those with a
 host of solid tumors already sensitive to immunotherapy.

 -  Patients with cuSCC deemed unresectable (TxNxM0 - stage I-IV, M0);

 -  Prior to screening, patients will be reviewed at a bi-monthly multi-disciplinary
 cutaneous tumor board to determine unresectability; representatives from dermatology,
 pathology, medical oncology, radiation oncology, general surgery, and if deemed
 necessary, plastic surgery will be included;

 -  Patients must possess an Eastern Co-operative Oncology Group (ECOG) performance status ≤
 2 This study has been designed as an open-label, non-randomized, single-arm phase II
 study to investigate the feasibility and efficacy of Avelumab in combination with
 radiation therapy in patients with unresectable cuSCC.

 All evaluable patients will be evaluated using identical instruments, and analysis will be by
 intent-to-treat. Toxicity will be assessed using standardized criteria (CTCAE version 4.03)
 by trained trial staff. Quality of life instruments will be administered to patients prior to
 their medical assessments. Every effort will be made to limit lost or missing data and
 incomplete follow-up.

 Based on the primary objective of the study sample size of 20 patients is proposed.

 This sample size calculation is based on the historical response rate associated with
 radiation therapy of 50%. The investigators predict an improvement in response using Avelumab
 and radiation therapy of 30%, in other words a net overall response rate of 80%. Utilizing a
 one-sided, binomial hypothesis test with a target p value of 0.05, the total sample size
 would be 18 to achieve a power of 80% for the study. The null hypothesis will be rejected if
 13 out of 18 patients demonstrate an objective tumor response following treatment, indicating
 further study is warranted. Assuming a dropout rate of 10% (patient dropout defined as
 voluntary withdrawal from active therapy prior to completion of treatment), an additional 2
 patients would have to be enrolled, bringing the total target enrollment to 20 patients.

 The total duration of accrual is anticipated to last 26 months. With a maximum follow-up of
 24 months following treatment of the eighteenth patient enrolled to study, the maximum study
 duration is not anticipated to exceed 50 months.

 The provision of a tumor biopsy is optional, but strongly encouraged. For those patients who
 consent to tumor biopsy, samples (either punch, needle-core or shave-biopsy) will be obtained
 in advance of treatment, 2 weeks post first cycle of Avelumab (but before the initiation of
 radiation therapy) and in conjunction with the 30-day safety analysis.

 An electronic data capture system will be used in this trial. A case report form (CRF) will
 have to be completed for each consented patient. The site maintains a separate source of
 data. This data will be entered by the site into the electronic data capture system This
 study is proposed as a phase II study with objective response rate as the primary endpoint.
 Refer to section 3.3.1 for the estimated calculation of study sample size.

 If the study conduct (e.g. recruitment rate, drop-out rate, data quality, protocol
 compliance) does not suggest a proper completion of the study within a reasonable time frame
 the trial will be terminated. This will be done in consultation with the CCI DSMB.

 The trial activities performed at the CCI will be monitored by the Cross Cancer Institute,
 Investigator Initiated Trials Data Safety Monitoring Board. The DSMB is independent of the
 investigator and is composed of representatives from both medical and radiation oncology.
 Further details about its charter can be found by contacting the Project Manager,
 Investigator Initiated Clinical Trials at the Cross Cancer institute.
Inclusion Criteria:

 1. Patients must be 18 years of age or older.

 2. Patients with histologically confirmed, unresectable cuSCC, stage I-IV (M0).

 3. Patients must be capable of providing consent to enrolment and treatment.

 4. Patients with a performance status of ECOG 0-2 will be eligible for enrolment

 5. Measurable disease must be present according to RECIST 1.1 criteria.

 6. Women of child bearing potential (WOCBP) must have a negative serum (or urine)
 pregnancy test at the time of screening. WOCBP is defined as any female who has
 experienced menarche and who has not undergone surgical sterilization (hysterectomy or
 bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal.
 Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the
 absence of other biological or physiological causes. In addition, females under the
 age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40
 mIU/mL to confirm menopause.

 7. Patients of childbearing / reproductive potential should use highly effective birth
 control methods, as defined by the investigator, during the study treatment period and
 for a period of 30 days after the last dose of study drug. A highly effective method
 of birth control is defined as those that result in low failure rate (i.e. less than
 1% per year) when used consistently and correctly.

 Note: abstinence is acceptable if this is established and preferred contraception for
 the patient and is accepted as a local standard.

 8. Female patients who are breast-feeding should discontinue nursing prior to the first
 dose of study treatment and until 30 days after the last dose of study drug.

 9. Male patients should agree to not donate sperm during the study and for a period of at
 least 30 days after last dose of study drug.

 10. Absence of any condition hampering compliance with the study protocol and follow- up
 schedule; those conditions should be discussed with the patient before registration in
 the trial.

 11. The following adequate organ function laboratory values must be met:

 Hematological:

 -  Absolute neutrophil count (ANC) >1.5 x109/L

 -  Platelet count >100 x109/L

 -  Hemoglobin >9 g/dL (may have been transfused)

 Renal:

 o Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or
 local institutional standard method)

 Hepatic:

 -  Total serum bilirubin <1.5x ULN

 -  AST and ALT <2.5x ULN

 Coagulation:

 -  International Normalized Ratio (INR) <1.5x ULN (unless patient is receiving
 anticoagulant therapy as long as prothrombin time (PT) or activated partial
 thromboplastin time (PTT) is within therapeutic range of intended use of
 anticoagulants)

 -  PTT <1.5x ULN (unless patient is receiving anticoagulant therapy as long as PT or PTT
 is within therapeutic range of intended use of anticoagulants)

 Exclusion Criteria:

 1. History of pneumonitis requiring treatment with steroids.

 2. History of active interstitial lung disease.

 3. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
 accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
 prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
 Association Classification Class II), or serious cardiac arrhythmia requiring
 medication.

 4. History of another malignancy or a concurrent malignancy; Exceptions include patients
 who have been disease-free for 3 years, or patients with a history of completely
 resected non-melanoma skin cancer or successfully treated in situ carcinoma are
 eligible, for example cervical cancer in situ.

 5. Diagnosis of immunodeficiency.

 6. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,
 inhaled, topical steroids, or local steroid injection (e.g., intra-articular
 injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone
 or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT
 scan premedication).

 7. Prior organ transplantation including allogeneic stem-cell transplantation.

 8. Known history of human immunodeficiency virus (HIV).

 9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
 HBV surface antigen or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test
 positive).

 10. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
 agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid
 diseases not requiring immunosuppressive treatment are eligible.

 11. Active infection requiring systemic therapy.

 12. Vaccination within 4 weeks of the first dose of Avelumab and while on trials is
 prohibited except for administration of inactivated vaccines.

 13. Patient will not be eligible if the patient is or has an immediate family member
 (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or
 sponsor staff directly involved with this trial, unless prospective independent ethics
 committee (IEC) approval (by chair or designee) is given allowing exception to this
 criterion for a specific subject.

 14. Known prior severe hypersensitivity to investigational product or any component in its
 formulations, including known severe hypersensitivity reactions to monoclonal
 antibodies (CTCAE v4.03 Grade ≥ 3).

 15. Other severe acute or chronic medical conditions including inflammatory bowel disease,
 immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent
 (within the past year) or active suicidal ideation or behavior; or laboratory
 abnormalities that may increase the risk associated with study participation or study
 treatment administration or may interfere with the interpretation of study results
 and, in the judgment of the investigator, would make the patient inappropriate for
 entry into this study.

 16. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 grade > 1); however,
 alopecia, sensory neuropathy ≤ grade 2, or other toxicities ≤ grade 2 not constituting
 a safety risk based on investigator's judgment are acceptable.