Clinical trial NCT02288897: PV-10 vs Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma
Official title: PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Cutaneous Melanoma
Keywords: Stage III
Stage IIIB
Stage IIIC
Stage IV (M1a)
Stage 3
Stage 4
IVM1a
IV(M1a)
IV-M1a
in-transit
in transit
intransit
satellite
recurrent
Lead sponsor: Provectus Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2014-11-11
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Age 18 years or older, male or female
2. Histologically or cytologically confirmed melanoma
3. 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)
4. 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
5. No lesion \> 50 mm in longest diameter; and no more than 50 lesions
6. Calculated required PV-10 dose ≤ 15 mL (based on total tumor burden)
7. Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-2
8. 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)
9. 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)
10. 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).
11. Thyroid function abnormality ≤ Grade 2
12. Candidate for at least one comparator drug:

    * Subjects must be candidates for at least one of the designated comparator drugs

Exclusion Criteria:

1. Presence or history of visceral melanoma metastasis
2. Presence of active nodal metastases (e.g., radiologic or clinical evidence of current nodal disease)
3. Presence of more than 50 melanoma lesions
4. Radiation therapy to any Study Lesion within 6 weeks of initial study treatment.
5. 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
6. Immunotherapy for cancer within 4 weeks of initial study treatment
7. Local treatment (e.g., surgery, cryotherapy, laser ablation) to any Study Lesion within 4 weeks of initial study treatment
8. Anti-tumor vaccine therapy within 6 weeks of initial study treatment.
9. Investigational agents within 4 weeks of initial study treatment.
10. 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
11. 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
12. Contraindication for all comparators:

    * Subjects with contraindications to all of the designated comparator drugs

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: 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 outcomes:
measure: Complete Response Rate (CRR)
timeFrame: 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.
measure: Duration of Complete Response (DCR)
timeFrame: 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.
measure: Overall Survival (OS)
timeFrame: 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.
measure: Number of Participants With Adverse Events
timeFrame: 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.
Other outcomes:
measure: Change in Domain Scores From Baseline Using the Patient Reported Skindex-16 Instrument
timeFrame: Assessed at baseline (Day 1 at start of study treatment) and at the end of each treatment cycle (every 4 or 6 weeks) until disease progression, withdrawal of consent, or study termination; median follow-up time was 26.6 weeks, maximum was 125.8 weeks.
Locations:
city: San Diego
country: United States
facility: Sharp Memorial Hospital - Clinical Oncology Research
state: California
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center and Research Institute
state: Florida
city: Saint Louis
country: United States
facility: Washington University School of Medicine - Dermatology
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Morristown
country: United States
facility: Atlantic Health System
state: New Jersey
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute
state: Oklahoma
city: Easton
country: United States
facility: St Luke's University Hospital and Health Network
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Hershey Cancer Institute
state: Pennsylvania
city: Houston
country: United States
facility: M.D. Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Nantes
country: France
facility: Unité Cancéro-Dermatologie, Hôtel-Dieu CHU Nantes
city: Toulouse
country: France
facility: Institut Claudius Regaud, IUCT ONCOPOLE
city: Berlin
country: Germany
facility: Klinik für Dermatologie, Venerologie und Allergologie Charite Universitätsmedizin Berlin
city: Essen
country: Germany
facility: Klinik für Dermatologie Universitätsklinikum Essen Studienzentrum
city: Kiel
country: Germany
facility: Klinik für Dermatologie, Venerologie und Allergologie Universitätsklinikum Schleswig-Holstein Hautkrebszentrum
city: Mainz
country: Germany
facility: Hautklinik Klinikum der Johannes Gutenberg Universität Hautkrebszentrum
city: Napoli
country: Italy
facility: IRCCS Instituto Nazionale Tumori "Fondazione Giovanni Pascale"
city: Rome
country: Italy
facility: Istituto Dermopatico dell'Immacolata (IDI IRCCS)
city: Siena
country: Italy
facility: Azienda Sanitaria Azienda Ospedaliera Universitaria Senese
city: Juchitán de Zaragoza
country: Mexico
facility: Centro de Estudios y Prevención del Cancer A.C.
state: Oaxaca
city: Culiacán
country: Mexico
facility: Neurociencias Estudios Clínicos S.C.
state: Sinaloa
Study officials:
affiliation: Provectus Biopharmaceuticals, Inc.
name: Eric Wachter, Ph.D.
role: STUDY_DIRECTOR
affiliation: St Luke's University Hospital and Health Network
name: Sanjiv Agarwala, M.D.
role: PRINCIPAL_INVESTIGATOR
References: