A Study of Recombinant Vaccinia Virus to Treat Malignant Melanoma
A Phase I/II, Open-Label Study of JX-594 (Thymidine Kinase-deleted Vaccinia Virus Plus GM-CSF) Administered by Intratumoral Injection in Patients With Unresectable Stage 3 or Stage 4 Malignant Melanoma
Study Overview
Detailed Description
Cancer of the skin is the most common of all cancers, probably accounting for more than 50% of all cancers. Melanoma accounts for about 4% of skin cancer cases but causes a large majority of skin cancer deaths. The American Cancer Society estimates that about 62,190 new melanomas will be diagnosed in the United States during 2006.
DTIC is the only chemotherapy drug approved by the FDA for the treatment of metastatic melanoma. The reported response rates are 5-20% without any evidence of prolonged survival in randomized clinical trials versus best supportive care. The median overall survival for melanoma patients treated with DTIC alone is approximately 8 months; PFS and TTP following treatment with DTIC is approximately 7 weeks, and the objective response rate for DTIC alone (CR+PR) is less than 10% (Millward, 2004). Other chemotherapy agents including cisplatin and carboplatin, BCNU, vindesine, paclitaxel, docetaxel, and vinorelbine have also been tested but none have improved upon the very modest activity of DTIC.
Melanoma may be the optimal target for JX-594 immunotherapy because of the relatively high rate of accessible disease for injection, the positive response of melanoma seen with IL-2 immunotherapy, and the lack of effective, tolerable therapy for patient with metastatic melanoma. Furthermore, it is speculated that JX-594 replication targets the EGFR pathway, which is highly expressed in melanocytes.
Results from an initial Phase I/II study suggest that intratumoral injection of JX-594 is safe and effective in treating both injected and distant disease in patients with surgically incurable metastatic melanoma. Response of both injected tumors (in 5 of 7 patients) and response of at least one non-injected tumor (in 4 of 7 patients) was demonstrated, including two patients who achieved a partial response (6 + months) and a complete response (4 + months) to JX-594 treatment. Particularly noteworthy is that efficacy and gene expression occurred despite pre-treatment vaccination (and, therefore, pre-existing anti-vaccinia immunity) in all patients.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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California
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Los Angeles, California, United States, 90024
- University of California, Los Angeles
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Montana
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Billings, Montana, United States, 59101
- Billings Clinic
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South Carolina
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Greenville, South Carolina, United States, 29605
- Cancer Centers of the Carolinas
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Histologically-confirmed, Stage 3 or Stage 4 malignant melanoma
- At least one tumor mass measurable by CT/MRI and/or physical examination that can be injected by direct visualization or by ultrasound-guidance
- Anticipated survival of at least 16 weeks
- Cancer is not surgically resectable for cure
- KPS score of ≥ 70 (refer to APPENDIX E: KARNOFSKY PERFORMANCE STATUS (KPS))
- Age ≥18 years
- Men and women of reproductive potential must be willing to follow accepted birth control methods during treatment and for 3 months after the last treatment with JX-594
- The ability to understand and willingness to sign an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent form
- Able to comply with study procedures and follow-up examinations
- Adequate liver function: Total bilirubin ≤ 2.0 x ULN; AST, ALT ≤ 2.0 x ULN
- Adequate bone marrow function: WBC > 3,500 cells/mm3 and < 50,000 cells/mm3; ANC > 1,500 cells/mm3; Hemoglobin > 10 g/dL; Platelet count > 125,000 plts/mm3
- Acceptable coagulation status: INR < (ULN + 10%)
- Acceptable kidney function: Serum creatinine < 2.0 mg/dL
Exclusion Criteria:
- Target tumor(s) adherent to and/or invading a major vascular structure (e.g. carotid artery)
- Pregnant or nursing an infant
- Known infection with HIV
- Systemic corticosteroid or other immunosuppressive medication use within 4 weeks of first treatment with JX-594
- Clinically significant active infection or uncontrolled medical condition (e.g. pulmonary, neurological, cardiovascular, gastrointestinal, genitourinary) considered high risk for investigational new drug treatment Significant immunodeficiency due to underlying illness and/or medication (e.g. systemic corticosteroids)
- History of eczema that at some stage has required systemic therapy
- Clinically significant and/or rapidly accumulating ascites, peri-cardial and/or pleural effusions (e.g. requiring drainage for symptom control)
- Severe or unstable cardiac disease which includes, but is not limited to, any of the following within 6 months prior to screening: myocardial infarct, unstable angina, congestive heart failure, myocarditis, arrhythmias diagnosed and requiring medication, or any clinically-significant change in cardiac status
- Treatment of the target tumor(s) with radiotherapy, chemotherapy, surgery, or an investigational drug within 4 weeks of screening (6 weeks in case of mitomycin C or nitrosoureas)
- Experienced a severe reaction or side-effect as a result of a previous smallpox vaccination
- Inability or unwillingness to give informed consent or comply with the procedures required in this protocol
- Patients with household contacts who are pregnant or nursing an infant, children < 5 years old, have history of eczema that at some stage has required systemic therapy, or have a significant immunodeficiency due to underlying illness (e.g. HIV) and/or medication (e.g. systemic corticosteroids) will be excluded unless alternate living arrangements can be made during the patient's active dosing period and for three weeks following the last dose of study medication.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
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Experimental: Single Arm
Intratumoral injection(s) of Recombinant Vaccinia virus JX-594
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Thymidine kinase-inactivated vaccinia virus expressing human GM-CSF
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Number of Participants With Objective Response in Injected Tumor(s)
Time Frame: Initial response assessment after six weeks (Day 43)
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Response was evaluated at the participant level based on the sum of the longest diameters of the injected target tumors.
Tumor assessments were performed using RECIST criteria.
Complete response (CR): all lesions disappear; Partial response (PR): maximum diameter decrease of > 30% of the longest diameter (LD) of target lesions using the baseline LD; Progressive disease (PD): increase of >20% in the sum of LD target lesions using the smallest sum LD recorded since treatment started; Stable disease (SD): unable to categorize as PR or PD using as reference the lobe with the smallest diameter at baseline.
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Initial response assessment after six weeks (Day 43)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Incidence of Treatment-related Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: Up to Day 64
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Safety was determined by the incidence of treatment-related adverse events (AEs), treatment-related serious adverse events (SAEs), and clinically-significant changes from baseline in routine laboratory parameters.
Severity was determined by NCI-CTCAE version 3.0.
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Up to Day 64
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Best Overall Response for Entire Disease Burden (RECIST Criteria)
Time Frame: Initial response assessment after six weeks (Day 43)
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Overall response was defined as the best response recorded from the start of the treatment until disease progression or recurrence across the entire disease burden (both injected and non-injected tumors), evaluated using RECIST criteria (Complete Response [CR], Partial Response [PR], Stable Disease [SD], or Progressive Disease [PD]).
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Initial response assessment after six weeks (Day 43)
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Progression-free Survival
Time Frame: From first study treatment until objective evidence of disease progression or death, up to 20.5 months
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Progression-free survival was defined as the time from the first study treatment until objective evidence of disease progression or death.
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From first study treatment until objective evidence of disease progression or death, up to 20.5 months
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Number of Participants With Objective Response in Non-injected Tumor(s)
Time Frame: Initial response assessment after six weeks (Day 43)
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Response was evaluated at the participant level for non-injected tumors.Response rate was evaluated specifically in non-injected tumors to assess systemic anti-tumoral efficacy, evaluated using RECIST criteria (Complete Response [CR], Partial Response [PR], Stable Disease [SD], or Progressive Disease [PD]).
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Initial response assessment after six weeks (Day 43)
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: James Burke, M.D., Billings Clinic
- Study Director: David H Kirn, M.D., Jennerex Biotherapeutics
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- JX594-IT-MEL005
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