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

Study Overview
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Brief Summary
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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, MTD, and objective antitumor efficacy of ascending dose strengths of VP-315 when administered intratumorally to adults with biopsy proven basal cell carcinoma (BCC). The study is expected to enroll approximately 80 subjects with a histological diagnosis of BCC in at least 1 eligible target lesion (confirmed by punch or shave biopsy).

Detailed Description
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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 80 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).

Official Title
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A Phase 2, Multicenter, Open-label, Proof-of-concept Study With Safety Run-in to Evaluate the Safety, Pharmacokinetics, and Efficacy of VP-315 in Adult Subjects With Basal Cell Carcinoma

Conditions
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Basal Cell Carcinoma, Skin Cancer, Cancer of the Skin, Basal Cell, Cancer of the Skin, Carcinoma

Intervention / Treatment
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* Drug: LTX-315 Part 1
* Drug: VP-315 Part 2


Participation Criteria
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Eligibility Criteria
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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 Inclusion Criterion 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 28 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 28 days prior to Screening.) 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 History of cerebrovascular or cardiac disorders, or subjects at particular risk of sequelae following a short hypotensive episode, including subjects with systolic BP <110 mmHg and/or diastolic BP <70 mmHg at screening or Day 1 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

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is an open-label, multicenter, dose-escalating study. Eligible subjects will be enrolled sequentially.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 LTX-315 Safety Run-in<br>Part 1: Starting total daily dose of LTX-315 will be 2 mg for the first subject. Subjects will receive ascending once daily doses increasing in 1 mg increments for up to 3 days in a 7-day treatment week until the first lesion is necrosed or a DLT occurs | Drug: LTX-315 Part 1<br>* LTX-315 once-daily dosing; starting total daily dose of 2 mg for the first subject. Ascending once-daily 1 mg dosing increments (eg, 2 mg on Day 1, 3 mg on Day 2). Subjects may be treated for a maximum of 2 weeks and a maximum total daily dose of 8 mg in Part 1. The starting dose will be escalated between subject cohorts in 1-mg increments after the previous cohort has completed Week 1 dosing (the DLT observation period).<br>* Other names: VP-315;|
| Experimental: Part 2 VP-315 Regimen Finding<br>Part 2: VP-315 once-daily dosing; total daily dose of 8 mg in up to 5 cohorts Cohort 1: VP-315 once-daily dosing of 8 mg with half the target dose of 8 mg only on W1D1; all remaining doses will be the full target dose Cohort 2: VP-315 once-daily dosing of 8 mg on all treatment days for up to 3 consecutive daily doses/week. Cohort 3: has been removed, advance from Cohort 2 to 4 and 5. Cohorts 4 and 5, the total daily dose of VP-315 (8.0 mg) will be divided into a split dose; the first dose is not to exceed 2.4 mg (30% of 8 mg dose), and the remaining dose will not exceed 5.6 mg (70% of 8 mg dose) and administered 15 minutes apart (not to exceed 30 minutes). Cohort 4: (Two times weekly dosing) VP-315 once-daily dosing of 8 mg, administered on 2 consecutive days in one week. Cohort 5: (Three times weekly dosing) VP-315 once-daily dosing of 8 mg, administered on 3 consecutive days in one week. PK data will be collected in the Cohorts 4 and 5 expansion groups. | Drug: VP-315 Part 2<br>* VP-315 once-daily dosing; Part 2 will be initiated upon completion of Part 1 to determine the optimal dosing regimen of VP-315. There were no DLTs observed in Part 1 of the study and the maximum dose of 8 mg was achieved. Therefore, the dose to be evaluated in Part 2 will be a total daily dose of 8 mg in 4 Cohorts.<br>* Other names: LTX-315;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Percentage of subjects with discontinuations due to adverse events | Subjects who discontinued the study due to adverse event | Up to 9 weeks | 
| Part 1: Percentage of subjects with dose-limiting toxicities (DLTs) | Subjects with pre-determined dose-limiting toxicities such as hypotension (specific criteria); significant elevation of serum tryptase; Grade 2 or higher adverse event (with specific criteria) | Day 4 (Safety Assessment) | 
| Part 1: Percentage of subjects with Cutaneous Reaction by severity | Evaluation of the tissue condition at the treatment site for the presence and severity of each of the following cutaneous reactions; Erythema, Induration, Swelling, Blister Formation, Desquamation, Erosion, Ulceration, Necrosis by a scale of None; Mild; Moderate; Severe. | Up to 9 weeks | 
| Part 2: Percent of subjects with adverse events | Subjects with adverse events | Up to 15 weeks | 
| Part 2: Percentage of subjects with discontinuations due to adverse events | Subjects that discontinued study due to adverse events | Up to 15 weeks | 
| Part 2: Percent of subjects with Treatment Related Adverse Events of Special Interest (TRAEs SI) | Subjects with pre-determined TRAEs of SI such as hypotension (specific criteria); significant elevation of serum tryptase; Grade 2 or higher adverse event (with specific criteria) | Treatment Week 1 Day 1 | 
| Part 2: Percent of subjects with Treatment Related Adverse Events of Special Interest (TRAEs SI) | Subjects with pre-determined TRAEs of SI such as hypotension (specific criteria); significant elevation of serum tryptase; Grade 2 or higher adverse event (with specific criteria) | Treatment Week 1 Day 2 | 
| Part 2: Percent of subjects with Treatment Related Adverse Events of Special Interest (TRAEs SI) | Subjects with pre-determined TRAEs of SI such as hypotension (specific criteria); significant elevation of serum tryptase; Grade 2 or higher adverse event (with specific criteria) | Treatment Week 1 Day 3 | 
| Part 2: Percent of subjects with Treatment Related Adverse Events of Special Interest (TRAEs SI) | Subjects with pre-determined TRAEs of SI such as hypotension (specific criteria); significant elevation of serum tryptase; Grade 2 or higher adverse event (with specific criteria) | Treatment Week 2 Day 1 | 
| Part 2: Percent of subjects with Treatment Related Adverse Events of Special Interest (TRAEs SI) | Subjects with pre-determined TRAEs of SI such as hypotension (specific criteria); significant elevation of serum tryptase; Grade 2 or higher adverse event (with specific criteria) | Treatment Week 2 Day 2 | 
| Part 2: Percent of subjects with Treatment Related Adverse Events of Special Interest (TRAEs SI) | Subjects with pre-determined TRAEs of SI such as hypotension (specific criteria); significant elevation of serum tryptase; Grade 2 or higher adverse event (with specific criteria) | Treatment Week 2 Day 3 | 
| Part 2: Percentage of subjects with Cutaneous Reaction by severity | Evaluation of the tissue condition at the treatment site for the presence and severity of each of the following cutaneous reactions; Erythema, Induration, Swelling, Blister Formation, Desquamation, Erosion, Ulceration, Necrosis by a scale of None; Mild; Moderate; Severe. | Up to 105 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Percentage of subjects with clinical clearance of treated lesion(s) at excision | Clinical clearance of treated lesion at excision as determined by visual assessment (no residual tumor seen on visual inspection) | Day 84-91 | 
| Part 2: Percentage of subjects with histological clearance of treated lesion(s) at excision | Subjects with histological clearance of treated lesion(s) at excision | Day 84-91 | 
| Part 2: Percentage of subjects with abscopal effect at excision | Abscopal effect as determined by clinical and histological clearance of nontreated lesions at excision | Day 84-91 | 
| Part 2: Mean estimated remaining tumor volume at excision | Estimate of remaining tumor volume (necrotic cells:tumor cells) at excision | Day 84-91 | 
| Part 2: Percent of subjects with Physician's Global Assessment by scale | Physician's global assessment of improvement per lesion as measured by the following scale: 100% improvement, no visible tumor; 75% to <100% improvement; 50% to <75% improvement; 25% to <50% improvement; up to 25% improvement; no change; worse | Up to 105 days | 
| Part 2 (Cohorts 4 and 5 expansion groups): Plasma concentrations of VP-315 | Pharmacokinetics (PK) of an 8 mg dose of VP-315 administered with the optimal dosing regimen | Day 1-2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCC, Skin Cancer, Neoplasm, Epithelial