This is single arm Phase 2, single center study of talimogene laherparepvec (TVEC) to treat low risk cutaneous squamous cell carcinomas (cSCC).

The purpose of this study is to assess the effect of Talimogene laherparepvec (TVEC) in patients diagnosed with lower risk cSCC in need of alternative therapeutic approaches.

Immune recognition and cytotoxic responses play an important role in the pathogenesis and progression of cutaneous squamous cell carcinoma (cSCC). TVEC is an HSV-1 oncolytic immunological agent FDA approved for the local treatment of unresectable recurrent melanoma. It is proposed that T-VEC directly destroys cancer cells and induces production of GM-CSF to enhance systemic antitumor immune priming. This proposed mechanism of action supports the novel approach to implement TVEC in the management of cSCC. Particularly, in patients with increased burden of primary tumors.

The study subjects enrolled in the study were Immunocompetent, > 18 years of age, and diagnosed with at least one histologically confirmed primary low-risk cSCC according to the Brigham and Women staging system. Unresectable lesions or patients unable/unwilling to undergo standard of care treatment were eligible to participate. Study lesions included target lesions injected (TLIs) and target non-injected lesions (TNILs). TNILs were selected to evaluate for abscopal effect when feasible. The TLIs were treated according to TVEC FDA approved protocol and followed for 1yr after the 1st injection. The primary endpoint of the study was to evaluate the overall response rate, defined as the proportion of subjects who achieved complete response and partial response in the TLIs. Safety and adverse effect profile (AEs), duration of response, time to response, durable response rate, and time to progression, were the some of the secondary endpoints included.

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 cutaneous SCC (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 criteria are 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 be included 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) to determine the histological differentiation of the tumor or other adverse histological 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 as follows:

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 or transfusion support)

9. Renal

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

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 and partial thromboplastin time (PTT)/ activated PTT (aPTT) must be within therapeutic range of intended use of anticoagulants.
    • PTT or aPTT ≤ 1.5 x ULN unless the subject is receiving anticoagulant therapy as long as PT and PTT/aPTT is within therapeutic range of intended use of anticoagulants.

12. Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If urine test is positive or cannot 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 exception of 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 disease that has required systemic treatment (ie, use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) in past 2 months prior to enrollment. Replacement therapy (eg, thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment for autoimmune disease.

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

   • Primary immunodeficiency state such as Severe Combined Immuno deficiency Disease
   • Acquired immunodeficiency syndrome
   • Concurrent opportunistic infection
   • Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment.

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 an antiherpetic 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 drug study(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 disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician
    • adequately treated non-melanoma skin cancer, lentigo maligna, stage I or II cutaneous 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 in situ

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

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

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

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

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