Study of TVEC in Patients With Cutaneous Squamous Cell Cancer

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

Detailed Description
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The purpose of this study is to find out more about talimogene laherparepvec (also known as OncoVEXGM-CSF or IMLYGIC®) in people with a healthy immune system with confirmed low-risk squamous cell carcinoma. Usually, low-risk SCC is treated with a surgical procedure, but surgery can be challenging when patients have: multiple SCCs on their body, when the SCC is on a challenging place on the body to remove or when patients are older or have diseases that place them at risk for surgery related complications. Immune therapy is a treatment that uses certain parts of a person's immune system to fight disease. Immune therapy is a proven therapeutic approach in many cancers, including melanoma, another type of skin cancer. Talimogene laherparepvec (TVEC) is made from a modified herpes simplex virus type 1 (HSV-1, the cold sore virus). The virus' genes were modified in a laboratory so that it produces a protein called human granulocyte macrophage colony-stimulating factor (GM-CSF), which multiplies and grows in tumor cells. Human GM-CSF is normally produced by various cells within the body and is used as a medicine to treat patients with white blood cell counts that are too low. This modified HSV-1 produces a protein that acts on tumor cells and stimulates the immune system. TVEC is administered by injection with a needle directly into one or more tumors and works by directly destroying cancer cells and enhancing immune response to destroy cancer cells.

Official Title
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A Single Arm Phase 2 Study of Talimogene Laherparepvec in Patients With Cutaneous Squamous Cell Cancer

Conditions
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Squamous Cell Carcinoma, Skin Cancer, Keratoacanthoma, Cutaneous Tumor, Skin Cancer, Squamous Cell, Lesion Skin

Intervention / Treatment
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* Drug: Injection of TVEC into target lesions - week 1-2
* Drug: Injection of TVEC into target lesions 3wks after 1st injection
* Drug: Injection of TVEC into target lesions 2wks after 2nd injection
* Drug: Injection of TVEC into target lesions 2wks after 3rd injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to give informed consent in English or Spanish Age > 18 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. 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 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. Maximum of 5 lesions per patient can be selected for treatment Adequate organ function determined within 28 days prior to enrollment, defined as follows: 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) 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) 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 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. 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: 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. Subjects on acitretin, capecitabine, topical chemotherapies or treatments. 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. 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. Active herpetic skin lesions or prior complications of herpetic infection (e.g., herpetic keratitis or encephalitis). Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (e.g., acyclovir), other than intermittent topical use. Previous treatment with talimogene laherparepvec or any other oncolytic virus Prior therapy with tumor vaccine Received live vaccine within 28 days prior to enrollment. 24 | Page Version 6-26-2018 Currently receiving treatment with another investigational device or drug study, or < 28 days since ending treatment with another investigational device or drug study(s) Other investigational procedures while participating in this study are excluded. Known to have acute or chronic active hepatitis B infection Known to have acute or chronic active hepatitis C infection 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 Subject has known sensitivity to talimogene laherparepvec or any of its components to be administered during dosing. 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 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 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (talimogene laherparepvec)<br>The subject participation period will be approximately 48 weeks. This will include a screening visit, 4 injection visits and 5 follow up visits. Total length of study/patient is 8.5 to 10.5 months. TVEC will be administered by injection with a needle directly into one or more tumors. | Drug: Injection of TVEC into target lesions - week 1-2<br>* Target lesions are identified and documented with measurements and photographs. Photographs will be taken with regional and close up view of the anatomical area and lesion. Inject 0.5ml - 4ml (based on lesion size - section 7.1, Table 5) Talimogene laherparepvec at nominal concentration of 106 plaque forming units (PFU)/mL with approximately 1.15 mL in a 2 mL vial for the initial dose. This will be administered intralesionally to 1-3 cSCC lesions per anatomical site with a maximum of 5 injectable lesions per patient.<br>Drug: Injection of TVEC into target lesions 3wks after 1st injection<br>* Target lesions are identified and documented with measurements and photographs. Photographs will be taken with global and close up view of the anatomical area and lesion. Inject 0.5ml - 4ml (based on lesion size) and number of lesions selected. Talimogene laherparepvec at nominal concentration of 108 PFU/mL withapproximately 1.15 mL in a 2 mL vial for the second and subsequent doses.<br>Drug: Injection of TVEC into target lesions 2wks after 2nd injection<br>* Target lesions are identified and documented with measurements and photographs. Photographs will be taken with global and close up view of the anatomical area and lesion. Inject 0.5ml - 4ml (based on lesion size) and number of lesions selected.Talimogene laherparepvec at nominal concentration of 108 PFU/mL with approximately 1.15 mL in a 2 mL vial for the subsequent doses.<br>Drug: Injection of TVEC into target lesions 2wks after 3rd injection<br>* Target lesions are identified and documented with measurements and photographs. Photographs will be taken with global and close up view of the anatomical area and lesion. Inject 0.5ml - 4ml (based on lesion size) and number of lesions selected. Talimogene laherparepvec at nominal concentration of 108 PFU/mL with approximately 1.15 mL in a 2 mL vial for the subsequent doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | The primary end point is to evaluate the overall response rate (ORR) defined as proportion of subjects who achieved complete response (CR) and partial response (PR) in the cSCC Target injected lesions (TILs). | 8.5-10.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with events requiring the discontinuation of study drug | 1. Number of participants with events requiring the discontinuation of study drug 75% or greater number of Target injection lesions (TILs) meeting criteria for withdrawal. Identification of high-risk features in one or more TILs during study participation. Persistent discomfort (consecutive weeks of lesion pain, burning, or itching of Grade 2 or more). | 8.5-10.5 months | 
| Time of response. | To measure time of response in cSCC TILs. | 8.5-10.5 months | 
| Duration of overall response. | To measure the duration of overall response (DOR) of TILs. | 8.5-10.5 months | 
| Assess durable response. | Assess durable response rate (DRR) of TILs. | 8.5-10.5 months | 
| Time to progression. | To measure the time to progression (TTP) of TILs | 8.5-10.5 months | 
| Overall response rate by ultrasound. | Overall response rate (ORR) (CR+PR) assessed by imaging technique (high frequency ultrasound). | 8.5-10.5 months | 
| Overall clinical response rate - targeted lesions. | Overall clinical response rate (CR+PR) of individual TILs with talimogene laherparepvec (not as overall subject response). | 8.5-10.5 months | 
| Overall clinical response rate - non-injected lesion(s). | Overall clinical response rate (CR+PR) in cSCC Target non-injected lesion(s) (TNILs). | 8.5-10.5 months | 
| Number of safety adverse events (SAE) as assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.0 | 1. Number of safety adverse events (SAE) as assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.0 a. Clinically significant laboratory values i. Clinically significant laboratory values are based on participant condition and side effect. These will vary and will be determined by the clinical judgement of the research healthcare provider. Note: laboratory values will be collected for initial participant screening and side effects only, no other clinical laboratory values are scheduled in this protocol. | 8.5-10.5 months | 
| Number of adverse effects to tumors according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.0 | Local effects on the tumor as assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.0 Pain Inflammation Ulceration | 8.5-10.5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Skin cancer, Squamous cell, Squamous Cell Carcinoma, Skin lesion, Keratoacanthoma, talimogene laherparepvec