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

Phase 3

Terminated

Conditions: Cutaneous Melanoma

Interventions: Drug: PV-10 (10% rose bengal disodium)
Drug: Dacarbazine, temozolomide or talimogene laherparepvec

Registration Number: NCT02288897

Lead Sponsor: Provectus Biopharmaceuticals, Inc.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 20

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PV-10	PV-10 (10% rose bengal disodium)	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.
Chemotherapy or Oncolytic Viral Therapy	Dacarbazine, temozolomide or talimogene laherparepvec	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.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	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.	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.

Secondary Outcome Measures

Name	Time	Method
Complete Response Rate (CRR)	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.	CRR was assessed using RECIST v1.1 criteria, and required disappearance of all target and non-target lesions.
Duration of Complete Response (DCR)	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.	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.
Overall Survival (OS)	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.	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.
Number of Participants With Adverse Events	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.	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.

Trial Locations

Locations (23): Sharp Memorial Hospital - Clinical Oncology Research
🇺🇸
San Diego, California, United States
M.D. Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Neurociencias Estudios Clínicos S.C.
🇲🇽
Culiacán, Sinaloa, Mexico
Mount Sinai Comprehensive Cancer Center
🇺🇸
Miami Beach, Florida, United States
Moffitt Cancer Center and Research Institute
🇺🇸
Tampa, Florida, United States
Wake Forest Baptist Health
🇺🇸
Winston-Salem, North Carolina, United States
Washington University School of Medicine - Dermatology
🇺🇸
Saint Louis, Missouri, United States
Penn State Hershey Cancer Institute
🇺🇸
Hershey, Pennsylvania, United States
Unité Cancéro-Dermatologie, Hôtel-Dieu CHU Nantes
🇫🇷
Nantes, France
St Luke's University Hospital and Health Network
🇺🇸
Easton, Pennsylvania, United States
Huntsman Cancer Institute
🇺🇸
Salt Lake City, Utah, United States
Institut Claudius Regaud, IUCT ONCOPOLE
🇫🇷
Toulouse, France
Klinik für Dermatologie Universitätsklinikum Essen Studienzentrum
🇩🇪
Essen, Germany
Klinik für Dermatologie, Venerologie und Allergologie Charite Universitätsmedizin Berlin
🇩🇪
Berlin, Germany
Klinik für Dermatologie, Venerologie und Allergologie Universitätsklinikum Schleswig-Holstein Hautkrebszentrum
🇩🇪
Kiel, Germany
Hautklinik Klinikum der Johannes Gutenberg Universität Hautkrebszentrum
🇩🇪
Mainz, Germany
IRCCS Instituto Nazionale Tumori "Fondazione Giovanni Pascale"
🇮🇹
Napoli, Italy
Azienda Sanitaria Azienda Ospedaliera Universitaria Senese
🇮🇹
Siena, Italy
Istituto Dermopatico dell'Immacolata (IDI IRCCS)
🇮🇹
Rome, Italy
Centro de Estudios y Prevención del Cancer A.C.
🇲🇽
Juchitán de Zaragoza, Oaxaca, Mexico
Oklahoma Cancer Specialists and Research Institute
🇺🇸
Tulsa, Oklahoma, United States
Dartmouth-Hitchcock Medical Center
🇺🇸
Lebanon, New Hampshire, United States
Atlantic Health System
🇺🇸
Morristown, New Jersey, United States