PV-10 vs Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma

Study Overview
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Brief Summary
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This is an international multicenter, open-label, randomized controlled trial (RCT) of single-agent intralesional PV-10 versus systemic chemotherapy or intralesional oncolytic viral therapy to assess treatment of locally advanced cutaneous melanoma in patients who (1) are not candidates for targeted therapy and (2) are not candidates for an immune checkpoint inhibitor. Subjects in the comparator arm will receive the Investigator's choice of dacarbazine (DTIC), temozolomide (TMZ) or intralesional talimogene laherparepvec as determined by Investigator preference and standard of care in the Investigator's country or region. Effectiveness will be assessed by comparison of progression-free survival (PFS) between all intent-to-treat (ITT) subjects in the two study treatment arms.

Detailed Description
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Subjects will be randomized using a 2:1 treatment allocation (i.e. two-thirds of the subjects will receive PV-10). Subjects in the comparator arm who have completed at least 1 cycle of study treatment and who meet the study protocol definition of disease progression but do not have evidence of visceral metastases will be eligible to enter the crossover portion of the study and receive PV-10. Subjects crossing over must meet all study inclusion and exclusion criteria for clinical laboratories, thyroid function, concurrent or intercurrent illness and pregnancy at the time of crossover. Assessment of progression will be performed by an Independent Review Committee (IRC) based on Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 criteria. Events signaling progression include increase in size and/or number of lesions, distant or nodal disease progression, or death. All secondary endpoints involving disease response and progression will be based on the IRC determination. An interim assessment of efficacy and safety will be performed by the IRC when 50% of the events required for the primary endpoint have occurred.

Official Title
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PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma

Conditions
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Cutaneous Melanoma

Intervention / Treatment
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* Drug: PV-10 (10% rose bengal disodium)
* Drug: Dacarbazine, temozolomide or talimogene laherparepvec


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older, male or female Histologically or cytologically confirmed melanoma Recurrent, satellite or in-transit locally advanced cutaneous or subcutaneous melanoma metastases (i.e., American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or Stage IV M1a with no active nodal metastases) At least 1 measurable Target Lesion that can be accurately measured by calipers or computed tomography (CT) consisting of: at least one cutaneous lesion (each lesion ≥ 10 mm in longest diameter or up to 5 lesions having a sum of longest diameters ≥ 10 mm); and/or at least one subcutaneous lesion (each lesion ≥ 10 mm in longest diameter by CT); where Target Lesions should be at least 10 mm from any other lesion No lesion > 50 mm in longest diameter; and no more than 50 lesions Calculated required PV-10 dose ≤ 15 mL (based on total tumor burden) Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-2 Not a candidate for treatment with an immune checkpoint inhibitor (e.g., failed or did not tolerate prior therapy, or due to co-morbidities, pre-existing autoimmune disease, drug unavailability or standard of care) Not a candidate for targeted therapy with BRAF or combined BRAF/MEK inhibitors (e.g., failed or did not tolerate prior therapy, BRAF V600 wild-type or due to drug unavailability or standard of care) Clinical Laboratories: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L and platelet count ≥100 x 10^9/L Creatinine ≤ 3 times the upper limit of normal (ULN) Estimated creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 Total bilirubin ≤ 3 times the upper limit of normal (ULN) Aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) ≤ 5 times the upper limit of normal (ULN) Lactate dehydrogenase (LDH) ≤ 2 times the upper limit of normal (ULN). Thyroid function abnormality ≤ Grade 2 Candidate for at least one comparator drug: Subjects must be candidates for at least one of the designated comparator drugs Exclusion Criteria: Presence or history of visceral melanoma metastasis Presence of active nodal metastases (e.g., radiologic or clinical evidence of current nodal disease) Presence of more than 50 melanoma lesions Radiation therapy to any Study Lesion within 6 weeks of initial study treatment. Chemotherapy or other systemic cancer therapy within 4 weeks of initial study treatment (6 weeks for nitrosoureas or mitomycin), or regional chemotherapy (limb infusion or perfusion) within 12 weeks of initial study treatment Immunotherapy for cancer within 4 weeks of initial study treatment Local treatment (e.g., surgery, cryotherapy, laser ablation) to any Study Lesion within 4 weeks of initial study treatment Anti-tumor vaccine therapy within 6 weeks of initial study treatment. Investigational agents within 4 weeks of initial study treatment. Concurrent or Intercurrent Illness: Impaired wound healing or other extremity complications due to diabetes mellitus in subjects whose Study Lesions are located in an extremity Severe peripheral vascular disease in subjects whose Study Lesions are located in an extremity Significant concurrent or intercurrent illness, psychiatric disorders, or alcohol or chemical dependence that would, in the opinion of the Investigator, compromise the subject's safety or compliance or interfere with interpretation of study results. Uncontrolled thyroid disease or cystic fibrosis Clinically significant acute or unstable cardiovascular, cerebrovascular (stroke), renal, gastrointestinal, pulmonary, immunological, endocrine, or central nervous system disorders Pregnancy: Female subjects who are pregnant or lactating Female subjects who have positive serum pregnancy test taken within 14 days of study treatment Female subjects of child-bearing potential who are unwilling to use highly effective contraception (e.g., combined (estrogen and progestogen containing) or progestogen-only hormonal contraceptives, intrauterine devices, bilateral tubal ligation, vasectomized partner, sexual abstinence or equivalent measures) for the duration of study treatment Contraindication for all comparators: Subjects with contraindications to all of the designated comparator drugs

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: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PV-10<br>Subjects will receive intralesional PV-10 to all Study Lesions on study Day 1. PV-10 should be re-administered at 28-day intervals until complete response, disease progression or study termination occurs. | Drug: PV-10 (10% rose bengal disodium)<br> <br> |
| Active Comparator: Chemotherapy or Oncolytic Viral Therapy<br>Subjects will receive (a) dacarbazine (intravenously at 850 m/m2) or temozolomide (orally at 200 mg/m2 daily for 5 consecutive days), administered at consecutive 28-day intervals, or (b) intralesional talimogene laherparepvec administered on an initial 21 interval followed by consecutive 14 day intervals, until complete response, disease progression or study termination occurs. | Drug: Dacarbazine, temozolomide or talimogene laherparepvec<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was estimated via Kaplan-Meier analysis using Response Evaluation Criteria In Solid Tumors (RECIST v1.1) criteria. Subjects who did not have an event of progression or death were censored at their last assessment date. Assessment of progression was performed by the sponsor based on review of lesion measurement and clinical progression data reported by each investigator. Events signaling progression included increase in size and/or number of study lesions, onset of visceral metastatic disease, and death. For target lesions (assigned prior to randomization), complete response (CR) required disappearance of all target lesions; partial response (PR) required >= 30% decrease in sum of the longest diameter (SLD) of all target lesions; progressive disease (PD) required >=20% increase in SLD of target lesions. Non-target lesions were followed for CR, PD, or non-CR/non-PD status using equivalent thresholds. Progression occurred when PD was observed in either target or non-target lesion. | Assessed every 12 weeks until disease progression, withdrawal of consent, or study termination; progression detected between formal assessments was documented at the time of detection; median follow-up time for PFS was 26.6 weeks, maximum was 125.8 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (CRR) | CRR was assessed using RECIST v1.1 criteria, and required disappearance of all target and non-target lesions. | Assessed every 12 weeks until disease progression, withdrawal of consent, or study termination; median follow-up time for CRR was 26.6 weeks, maximum was 125.8 weeks. | 
| Duration of Complete Response (DCR) | DCR was estimated via Kaplan-Meier analysis for participants achieving a complete response, and was defined as the interval from first complete response to disease progression or death; responders who did not have an event of progression or death were censored at their last assessment date. Complete response was assessed using RECIST v1.1 criteria, and required disappearance of all target and non-target lesions. | Assessed every 12 weeks until disease progression, withdrawal of consent, or study termination; median follow-up time for DCR was 26.7 weeks, maximum was 77.7 weeks. | 
| Overall Survival (OS) | OS was documented at 12 week intervals commencing on withdrawal from active study participation. Documentation was made by subject clinic visit or other personal contact, telephonic contact, review of medical records, or other unequivocal evidence of survival status. OS was estimated via Kaplan-Meier analysis, and was defined as the interval from randomization to death; subjects who did not have an event of death were censored at their last assessment date. | Assessed every 12 weeks upon withdrawal from active study participation until death, withdrawal of consent, or study termination; median follow-up time for survival was 82.4 weeks, maximum was 167.0 weeks. | 
| Number of Participants With Adverse Events | Safety and tolerability were assessed by monitoring the frequency, duration, severity and attribution of adverse events and evaluating changes in laboratory values and vital signs. | Assessed every 4 weeks until 28 days after last treatment; median duration of treatment was 11.8 and 9.5 weeks in each treatment group, respectively. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage IV (M1a), Stage 3, Stage 4, IVM1a, IV(M1a), IV-M1a, in-transit, in transit, intransit, satellite, recurrent, Stage III, Stage IIIB, Stage IIIC