Open-Label Proof of Concept Study of VP-315 in Basal Cell Carcinoma

This is a 2-part, open-label, multicenter, dose-escalation, proof-of-concept study with a safety run-in designed to assess the safety, tolerability, maximum tolerated dose (MTD), and objective antitumor efficacy of ascending dose strengths of VP-315 when administered intratumorally to adults with biopsy proven BCC.

The study is expected to enroll approximately 86 subjects with a histological diagnosis of BCC in at least 1 eligible target lesion (confirmed by punch or shave biopsy).

All enrolled subjects will receive VP-315 intradermal injection on an outpatient basis into up to 2 target lesions. In all Parts of the study (1 or 2, as below), each 7-day treatment week comprises up to 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing will commence in a single target lesion. Once a lesion is observed to be fully necrotic (Part 1, Part 2; Cohorts 1-2 only), treatment of that lesion stops, and treatment of subsequent target lesions (up to 2 total) may continue on Day 1 of the following week. In Part 2, Cohorts 4 and 5, treatment of a second target lesion begins on W2D1 (not based on status of necrosis of target lesion 1).

Inclusion criteria

• Adults ≥18 years of age
• Clinically suspected BCC with at least 1 and up to 5 eligible lesion(s) suitable for biopsy and excision
• Willing to refrain from using nonapproved topical agents on, or within 2 cm of, the target BCC lesions and surrounding areas during the treatment period. Subjects should use topical agents that are gentle (eg, Aquaphor, CeraVe) and will not irritate the skin in these areas.
• Willing to refrain from exposure to direct sunlight or ultraviolet light and to avoid the use of tanning parlors for the duration of the study
• Written informed consent obtained, including consent for tissue to be examined by the central dermatopathologist and stored by the Sponsor or designee
• Willing to undergo BCC surgical excision procedure of target and nontarget BCC lesions after study treatment
• Willing to delay surgical excision of target and nontarget BCC lesions until the end of treatment (EOT) visit
• Provides written consent to allow photographs of the target and nontarget BCC lesion to be used as part of the study data
• Willing to practice a highly effective method of birth control while on study and until 4 weeks after the last treatment. Highly effective birth control includes sexual abstinence, vasectomy, bilateral tubal ligation/occlusion, or a condom with spermicide (men) combined with hormonal birth control or intrauterine device in women.

BCC Lesion Eligibility

Eligible lesions are those that meet the BCC lesion eligibility specifications described herein, from samples that are either from:

• HISTORICAL punch or shave biopsies (i.e., samples collected according to clinical standard of care collected within the 90 days prior to W1D1);
• A 2-mm punch biopsy collected within 90 days of W1D1 for suspected BCC ≥0.5 cm to 1.0 cm, and 3-mm punch biopsy for suspected BCC >1.0 cm to 2.0 cm; or
• A shave biopsy performed according to standard of care to include superficial or middle papillary dermis collected within 90 days of W1D1.

Lesions must meet the following criteria to be eligible for treatment

BCC Lesion Inclusion Criteria

• For punch biopsies: the size of the lesion(s) must be ≥0.5 cm and </=2 cm in the longest diameter prior to punch biopsy.
• Histological diagnosis of nodular, micronodular, or superficial BCC, as confirmed by punch or shave biopsy performed within 90 days of W1D1. (NOTE: HISTORICAL punch or shave biopsies are acceptable, provided that the biopsy was performed according to clinical standard of care and was collected within the 90 days prior to Screening.) Subject Exclusion Criteria Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.

Exclusion criteria

• Presence of known or suspected systemic cancer
• Treatment with systemic chemotherapeutic agents within the 6 months prior to the screening visit
• Treatment with systemic immunotherapy, immunomodulators or immunosuppressants within the 12 weeks prior to the screening period
• Genetic or nevoid conditions (eg, Gorlin / basal cell nevus syndrome, xeroderma pigmentosum)
• Clinically significant laboratory values, as assessed by the investigator, for the tests listed in the Schedule of Assessments, including:

• serum creatinine >1.5× the upper limits of normal and
• serum tryptase concentration >11.4 ng/mL
• Chronic medical condition that in the judgment of the investigator(s) would interfere with the performance of the study or would place the subject at undue risk, such as, but not limited to:

• Uncontrolled infection or infection requiring antibiotics
• Uncontrolled cardiac failure: Classification III or IV New York Heart Association
• Subjects presenting with a systolic BP <110 mmHg and/or diastolic BP <70 mmHg at Screening or Week 1 Day 1 or a history of cerebrovascular or cardiac disorders, or subjects at particular risk of sequelae following a short hypotensive episode.
• Uncontrolled systemic or gastrointestinal inflammatory conditions
• Known bone marrow dysplasia
• History of positive tests for human immunodeficiency virus/acquired immunodeficiency syndrome or active hepatitis B or C
• History of systemic autoimmune disease requiring anti-inflammatory or immunosuppressive therapy within 3 months prior to Day 1, with the following exceptions:

i. Subjects with a history of autoimmune thyroiditis are eligible provided the subject requires only thyroid hormone replacement therapy and disease has been stable for ≥1 year

ii. Subjects with well-controlled type I diabetes (in the opinion of the investigator) are eligible

h. Known mast cell activation syndrome, mastocytosis, or chronic idiopathic urticaria

• Known sensitivity to any of the ingredients in the study medication
• Elective surgery within 4 weeks prior to the screening visit, during the study, or 4 weeks after the treatment period
• Evidence of current chronic alcohol or drug abuse
• Current enrollment in an investigational drug or device study or participation in such a study within 4 weeks of the screening visit
• In the investigator's opinion, evidence of unwillingness, or inability to follow the restrictions of the protocol and complete the study
• Females who are pregnant or breastfeeding

BCC Lesion Exclusion Criteria

• Recurrent or previously treated lesions
• Lesions within 1 cm of the eyelids or lips, or on the hands, feet, ears, nose, and genitalia
• Histological evidence of any other tumor in the biopsy specimen
• Histological evidence of infiltrative, desmoplastic, sclerosing, or morpheaform BCC subtypes in the biopsy specimen
• Medium- and high-risk basal cell carcinomas as defined by the National Comprehensive Cancer Network (NCCN) or Mohs Appropriate Use Criteria (ie, BCCs eligible for Mohs surgery).

TARGET LESION EXCLUSION ONLY:

• For subjects with severe stasis dermatitis, target BCC lesions may not be on the lower extremities
• Within 2 cm of the target BCC lesion(s):

• Treatment with the following topical agents within the 12 weeks prior to the screening visit: aminolevulinic acid, 5-fluorouracil, corticosteroids, diclofenac, imiquimod, ingenol mebutate
• Treatment with surgical excision, or curettage within the 2 weeks prior to the screening visit
• Evidence of dermatological disease or confounding skin condition that may interfere with clinical evaluation (ie, psoriasis, atopic dermatitis, eczema, propensity to form keloids or hypertrophic scarring)
• Use of topical immunomodulators during study
• Within 5 cm of the target BCC lesion(s): history of any skin cancer, except for other currently identified target and nontarget BCC lesions
• Target BCC lesion is in the area of prior resurfacing procedure with CO2 laser or any photodynamic and phototherapy treatment within the 3 months prior to the screening visit