Study of TVEC in Patients With Cutaneous Squamous Cell Cancer

Inclusion Criteria:

1. Able to give informed consent in English or Spanish

2. Age > 18

3. Have at least one >0.5 cm to <5.0 cm, histologically confirmed low risk cutaneousSCC (including kerathoacanthomas)

• Size >0.5 cm on trunk or extremities (excluding face, neck feet, nail units,and ankles)

• Clinically consistent with primary tumors.

• Lesion considered unresectable (as defined in Section 1.2)

• Recurrent lesions will be considered eligible if additional inclusion criteriaare met.

• No immunosuppression

• Not a site of previous radiation therapy or chronic significant inflammation

• Fast growing lesions (doubling in size over a 4 week period of time) will beincluded if they are clinically suggestive of cSCC of the keratoacanthoma type.

• Well or moderately differentiated tumor as confirmed by skin biopsy

• Depth less than 2 mm (for non KA type cSCC )

• No perineural or vascular involvement in preliminary biopsy.

4. Partial biopsy of squamous cell skin cancer identified as a target lesion(s) todetermine the histological differentiation of the tumor or other adversehistological features

5. In patients with multiple lesions, up to 3 lesions in a similar anatomical site, (trunk, limbs etc) that is at least 10 cm apart can be selected.

6. Maximum of 5 lesions per patient can be selected for treatment

7. Adequate organ function determined within 28 days prior to enrollment, defined asfollows:

8. Hematology:

• Absolute neutrophil count ≥ 1500/mm3 (1.5x109/L)

• Platelet count ≥ 75,000/mm3 (7.5x109/L)

• Hemoglobin ≥ 8 g/dL (without need for hematopoietic growth factor ortransfusion support)

9. Renal

• Serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR 24-hour creatinineclearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note:Creatinine clearance need not be determined if the baseline serum creatinine iswithin normal limits. Creatinine clearance should be determined per institutionalstandard)

10. Hepatic

• Serum bilirubin ≤ 1.5 x ULN

• Aspartate aminotransferase (AST) ≤ 2.5 x ULN 23 | Page Version 6-26-2018

• Alanine aminotransferase (ALT) ≤ 2.5 x ULN

11. Coagulation

• International normalization ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN,unless the subject is receiving anticoagulant therapy, in which case PT andpartial thromboplastin time (PTT)/ activated PTT (aPTT) must be withintherapeutic range of intended use of anticoagulants.

• PTT or aPTT ≤ 1.5 x ULN unless the subject is receiving anticoagulant therapyas long as PT and PTT/aPTT is within therapeutic range of intended use ofanticoagulants.

12. Female subject of childbearing potential should have a negative urine or serumpregnancy test within 72 hours prior to enrollment. If urine test is positive orcannot be confirmed as negative, a serum pregnancy test will be required.

Exclusion Criteria:

1. Any patient with diagnosis of invasive cancer in the last 3 years with the exceptionof stage I and II melanoma, cutaneous BCC and SCCs will be excluded.

2. Subjects on acitretin, capecitabine, topical chemotherapies or treatments.

3. History or evidence of symptomatic autoimmune disease (eg, pneumonitis,glomerulonephritis, vasculitis, or other), or history of active autoimmune diseasethat has required systemic treatment (ie, use of corticosteroids, immunosuppressivedrugs or biological agents used for treatment of autoimmune diseases) in past 2months prior to enrollment. Replacement therapy (eg, thyroxine for hypothyroidism,insulin for diabetes or physiologic corticosteroid replacement therapy for adrenalor pituitary insufficiency) is not considered a form of systemic treatment forautoimmune disease.

4. Evidence of clinically significant immunosuppression such as the following:

• Primary immunodeficiency state such as Severe Combined Immuno deficiencyDisease

• Acquired immunodeficiency syndrome

• Concurrent opportunistic infection

• Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroiddoses > 10 mg/day of prednisone or equivalent within 2 months prior toenrollment.

5. Active herpetic skin lesions or prior complications of herpetic infection (e.g.,herpetic keratitis or encephalitis).

6. Requires intermittent or chronic systemic (intravenous or oral) treatment with anantiherpetic drug (e.g., acyclovir), other than intermittent topical use.

7. Previous treatment with talimogene laherparepvec or any other oncolytic virus

8. Prior therapy with tumor vaccine

9. Received live vaccine within 28 days prior to enrollment. 24 | Page Version 6-26-2018

10. Currently receiving treatment with another investigational device or drug study, or < 28 days since ending treatment with another investigational device or drugstudy(s)

11. Other investigational procedures while participating in this study are excluded.

12. Known to have acute or chronic active hepatitis B infection

13. Known to have acute or chronic active hepatitis C infection

14. History of other malignancy within the past 3 years with the following exceptions:

• adequately treated mucosa associated lymphoid tissue (MALT) tumor

• malignancy treated with curative intent and with no known active diseasepresent for ≥ 3 years before enrollment and felt to be at low risk forrecurrence by the treating physician

• adequately treated non-melanoma skin cancer, lentigo maligna, stage I or IIcutaneous melanoma, without evidence of disease.

• adequately treated cervical carcinoma in situ without evidence of disease

• adequately treated breast ductal carcinoma in situ without evidence of disease

• prostatic intraepithelial neoplasia without evidence of prostate cancer

• adequately treated urothelial papillary noninvasive carcinoma or carcinoma insitu

15. Subject has known sensitivity to talimogene laherparepvec or any of its componentsto be administered during dosing.

16. Female subject is pregnant or breast-feeding, or planning to become pregnant duringstudy treatment and through 3 months after the last dose of talimogene laherparepvec

17. Female subject of childbearing potential who is unwilling to use acceptablemethod(s) of effective contraception during study treatment and through 3 monthsafter the last dose of talimogene laherparepvec. (Note: Women not of childbearingpotential are defined as: Any female who is post-menopausal [age > 55 years withcessation of menses for 12 or more months or less than 55 years but not spontaneousmenses for at least 2 years or less than 55 years and spontaneous menses within thepast 1 year, but currently amenorrheic (eg, spontaneous or secondary tohysterectomy), and with postmenopausal gonadotropin levels (luteinizing hormone andfollicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal range" for the laboratoryinvolved] or who have had a hysterectomy, bilateral salpingectomy, or bilateraloophorectomy). 25 | Page Version 6-26-2018

18. Sexually active subjects and their partners unwilling to use male latex condom toavoid potential viral transmission during sexual contact while on treatment andwithin 30 days after treatment with talimogene laherparepvec.

19. Subject who is unwilling to minimize exposure with his/her blood or other bodyfluids to individuals who are at higher risks for HSV-1 induced complications suchas immunosuppressed individuals, individuals known to have HIV infection, pregnantwomen, or children under the age of 1 year, during talimogene laherparepvectreatment and through 30 days after the last dose of talimogene laherparepvec.