A Study of Talimogene Laherparepvec in Stage IIIc and Stage IV Malignant Melanoma

Study Overview
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Brief Summary
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The primary objective of the study was to assess the clinical efficacy of talimogene laherparepvec in terms of tumor response rates.

Official Title
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A Phase II Study of the Efficacy, Safety and Immunogenicity of OncoVEX^GM-CSF in Patients With Stage IIIc and Stage IV Malignant Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Talimogene Laherparepvec


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically proven stage IIIc (including two or more palpable lymph nodes, extracapsular or in-transit metastases) or stage IV melanoma that is not eligible for curative surgery and who have one or more tumors that are accessible for direct injection. Tumors 0.5 to 10 cm in the longest diameter that are suitable for injection (i.e. not bleeding or weeping). Serum lactate dehydrogenase (LDH) levels ≤ 2.0 times the upper limit of normal. Aged 18 years or more. Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1. Clinically immunocompetent. Recovered from prior therapy with at least 4 weeks since the last exposure to chemotherapy or radiotherapy. Total white cell count ≥ 3.0 x 10^9/L, platelet count ≥ 80 x 10^9/L. Serum creatinine ≤ 0.2 mmol/L. Bilirubin ≤ 1.5 times the upper limit of the normal range, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) equal to or less than twice the upper limit of the normal range and alkaline phosphatase equal to or less than twice the upper limit of the normal range. Exclusion Criteria: Participation in any previous melanoma immunotherapy trial within one month prior to entry to this trial or any trial of any other investigational agent within the last month prior to entry to this trial. Tumors to be injected lying in mucosal regions or close to an airway, major blood vessel or spinal cord that, in the opinion of the Investigators, could cause occlusion or compression in the case of tumor swelling or erosion into a major vessel in the case of necrosis. Pregnancy, lactation or lack of effective contraception in women of child-bearing potential; lack of effective contraception in men if the partner is of child-bearing potential; women must have been practising an effective contraceptive method for at least three months prior to entry in to the trial (hormonal contraception or intrauterine device in conjunction with a barrier method OR surgically sterilised). Men must use a condom or be surgically sterilised. Major surgery within the 14 days prior to entry to the trial. Intercurrent serious infections within the 28 days prior to entry to the trial. Life-threatening illness unrelated to cancer. Treatment with antiviral agents within the 14 days prior to entry to the trial. Uncontrolled congestive cardiac failure. Clinically active autoimmune disease. Dermatoses involving or near to the tumors to be injected. Limb tumors may not be injected if active dermatoses are present on the same limb. Trunk and head and neck tumors must not be injected if dermatoses are present within 50 cm of the tumor. Known to test positive for human immunodeficiency virus (HIV), hepatitis B or C or syphilis. Patient only has injectable tumors that are not potentially resectable in the case of tumor necrosis or swelling. Previous history of malignancies of other types that have occurred or recurred within the previous 5 years with the exception of cone biopsied carcinoma of the cervix. Corticosteroid use.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Talimogene Laherparepvec<br>Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque forming units (PFU)/mL injected into 1 or more tumors with maximum total volume of 4 mL (up to 2 mL per tumor). Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks for up to 15 weeks. After the initial 8 doses, if indications of biological activity were observed, treatment could continue for up to 16 additional doses. | Drug: Talimogene Laherparepvec<br>* Up to 4 mL of 10⁸ pfu/mL/per intratumoral injection<br>* Other names: IMLYGIC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response Rate | Objective response rate is defined as the percentage of participants with an overall best response of complete response or partial response. The objective response to treatment was assessed by computed tomography (CT) scanning or other clinical measurement using modified Response Evaluation Criteria In Solid Tumors (RECIST). Responses must have been confirmed on two visits not less than 4 weeks apart. Tumor burden for a visit was calculated as the sum of the longest diameters of all tumors identified and measured up to that visit. Tumor response at each visit was derived from tumor burden, as follows: Complete response (CR): zero tumor burden Partial response (PR): a 30% or greater decrease in tumor burden Progressive disease (PD): a 20% or greater increase in tumor burden Stable disease (SD): none of the above (a < 30% decrease and < 20% increase in tumor burden) | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) was calculated from the date of the first talimogene laherparepvec dose to the date of death. Median OS was estimated using the Kaplan-Meier method. | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days | 
| Time to Progression | Time to progression was calculated from the date of the first talimogene laherparepvec dose to the first date of documented progressive disease (via clinical symptom or tumor burden assessment) that was not followed by a later response of CR, PR, or stable disease. Median time to progression was calculated using the Kaplan-Meier method. | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days. | 
| Time to Longest Continuous Response | Time to response was calculated from the date of the first talimogene laherparepvec dose to the initial date of the participant's last response interval. | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days. | 
| Duration of Response | Duration of response was calculated from the initial date of response (CR or PR) until the date of progressive disease (or until last follow up that was CR or PR). Participants could have multiple response periods; in this situation, the last response interval was used for the calculation of duration of response. | From enrollment until the data cut-off date of 29 November 2008; Median duration of follow-up was 253 days. | 
| Number of Participants With Adverse Events | The severity of an adverse event (AE) was graded according to Common Toxicity Criteria for Adverse Events (CTCAE) Version 3 (1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death). Serious adverse events include death, life-threatening events, events requiring or prolonging hospitalization, result in persistent or significant disability/incapacity, or a congenital anomaly/birth defect, or otherwise important medical events that may jeopardise the patient or require intervention to prevent one of the above outcomes. | From first dose of talimogene laherparepvec until 30 days after the last dose; the median (minimum, maximum) duration of treatment was 82 (1, 346) days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene transfer, gene therapy, oncolytic virus, GM-CSF, melanoma