Single-arm Trial to Evaluate the Biodistribution and Shedding of Talimogene Laherparepvec

Study Overview
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Brief Summary
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The primary objective was to estimate the proportion of participants with detectable talimogene laherparepvec deoxyribonucleic acid (DNA) in the blood and urine at any time after administration of talimogene laherparepvec within the first 3 cycles.

Official Title
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A Phase 2, Multicenter, Single-arm Trial to Evaluate the Biodistribution and Shedding of Talimogene Laherparepvec in Subjects With Unresected, Stage IIIB to IVM1c 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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Key Inclusion Criteria: Male or female age ≥ 18 years with histologically confirmed diagnosis of melanoma and unresected stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c regardless of prior line of therapy. Subject is candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal disease and must also have measurable disease, serum lactate dehydrogenase ≤ 1.5 x upper limit of normal, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate hematologic, hepatic, and renal organ function. Key Exclusion Criteria: Subject must not have clinically active cerebral metastases, greater than 3 visceral metastases (this does not include lung metastases or any nodal metastases associated with visceral organs) or any bone metastases melanoma, primary ocular or mucosal melanoma, history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or symptomatic autoimmune disease, or evidence of immunosuppression for any reason. Subject known to have acute or chronic active hepatitis B or hepatitis C infection, or human immunodeficiency virus infection will also be excluded. Subject who has active herpetic skin lesions or prior complications of herpes simplex virus type 1 ( HSV-1) infection (eg, herpetic keratitis or encephalitis), and/or requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use will also be excuded. Subject must not have received previous treatment with talimogene laherparepvec.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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>Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL followed by a dose of 10⁸ PFU/mL 21 days after the initial dose and every 14 days thereafter. Participants were treated with talimogene laherparepvec until they achieved a complete response (CR), all injectable tumors had disappeared, clinically relevant (resulting in clinical deterioration or requiring change of therapy) disease progression per modified World Health Organization (WHO) response criteria beyond 6 months of therapy, or intolerance of study treatment, whichever occurred first. | Drug: Talimogene laherparepvec<br>* Talimogene laherparepvec will be administered by intralesion injection at an initial dose of up to 4.0 mL of 10^6 PFU/mL. The second and subsequent doses will will be up to 4.0 mL 10^8 PFU/mL. The second dose should be administered 21 days from the initial dose. All subsequent doses should be given every 14 days.<br>* Other names: OncoVEX^GM-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Detectable Talimogene Laherparepvec Deoxyribonucleic Acid (DNA) During the First Three Cycles | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of participants with detectable talimogene laherparepvec DNA in blood or urine at any time during cycles 1 to 3 is reported. The first cycle was 21 days in length, and subsequent cycles were 14 days in length. | Cycles 1 and 2 on days 1 (pre-dose and 1, 4, and 8 hours post-dose), 2, 3, 8, and 15 (cycle 1 only), cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clearance of Talimogene Laherparepvec DNA From Blood | A participant was defined as having cleared talimogene laherparepvec if a negative blood sample was obtained following a prior positive test and if there were no subsequent positive tests. | Cycles 1 and 2 on days 1 (pre-dose and 1, 4, and 8 hours post-dose), 2, 3, 8, and 15 (cycle 1 only), cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Participants With Clearance of Talimogene Laherparepvec DNA From Urine | A participant was defined as having cleared talimogene laherparepvec if a negative urine sample was obtained following a prior positive test and if there were no subsequent positive tests. | Cycles 1 and 2 on days 1 (pre-dose and 1, 4, and 8 hours post-dose), 2, 3, 8, and 15 (cycle 1 only), cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Samples With Detectable Talimogene Laherparepvec DNA on the Exterior of the Occlusive Dressing During the First Three Cycles | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of swab samples from the exterior of the occlusive dressing with detectable talimogene laherparepvec DNA at any time during cycles 1 to 3 is reported. | Cycle 1 on days 2, 3, 8, and 15, cycle 2 on days 1 (pre-dose), 2, 3, and 8, cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Samples With Detectable Talimogene Laherparepvec Virus on the Exterior of the Occlusive Dressing During the First Three Cycles | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. The percentage of swab samples from the exterior of the occlusive dressing with detectable talimogene laherparepvec virus at any time during cycles 1 to 3 is reported. | Cycle 1 on days 2, 3, 8, and 15, cycle 2 on days 1 (pre-dose), 2, 3, and 8, cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Participants With Detectable Talimogene Laherparepvec DNA on the Exterior of the Occlusive Dressing During the First Three Cycles | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of participants with detectable talimogene laherparepvec DNA on the exterior of the occlusive dressing at any time during cycles 1 to 3 is reported. | Cycle 1 on days 2, 3, 8, and 15, cycle 2 on days 1 (pre-dose), 2, 3, and 8, cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Participants With Detectable Talimogene Laherparepvec Virus on the Exterior of the Occlusive Dressing During the First Three Cycles | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. The percentage of participants with detectable talimogene laherparepvec virus on the exterior of the occlusive dressing at any time during cycles 1 to 3 is reported. | Cycle 1 on days 2, 3, 8, and 15, cycle 2 on days 1 (pre-dose), 2, 3, and 8, cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Samples From the Surface of Injected Lesions With Detectable Talimogene Laherparepvec DNA During the First Three Cycles | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of swab samples from the surface of injected lesions with detectable talimogene laherparepvec DNA at any time during cycles 1 to 3 is reported. | Cycle 1 on days 2, 3, 8, and 15, cycle 2 on days 1 (pre-dose), 2, 3, and 8, cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Samples From the Surface of Injected Lesions With Detectable Talimogene Laherparepvec Virus During the First Three Cycles | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. The percentage of samples taken from the surface of injected lesions with detectable talimogene laherparepvec virus at any time during cycles 1 to 3 is reported. | Cycle 1 on days 2, 3, 8, and 15, cycle 2 on days 1 (pre-dose), 2, 3, and 8, cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Participants With Detectable Talimogene Laherparepvec DNA on the Surface of Injected Lesions During the First Three Cycles | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of participants with detectable talimogene laherparepvec DNA swabs taken from the surface of injected lesions at any time during cycles 1 to 3 is reported. | Cycle 1 on days 2, 3, 8, and 15, cycle 2 on days 1 (pre-dose), 2, 3, and 8, cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Participants With Detectable Talimogene Laherparepvec Virus on the Surface of Injected Lesions During the First Three Cycles | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. The percentage of participants with detectable talimogene laherparepvec virus on swabs taken from the surface of injected lesions at any time during cycles 1 to 3 is reported. | Cycle 1 on days 2, 3, 8, and 15, cycle 2 on days 1 (pre-dose), 2, 3, and 8, cycle 3 on day 1 (pre-dose) and day 8, and cycle 4 on day 1 (pre-dose). | 
| Percentage of Samples From Oral Mucosa With Detectable Talimogene Laherparepvec DNA During Treatment | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of swab samples from oral mucosa with detectable talimogene laherparepvec DNA at any time during treatment is reported. | Cycle 1 on days 1 (pre-dose), 8, and 15, cycles 2 and 3 on days 1 (pre-dose), and 8, cycle 4 and subsequent cycles (up to 47) on day 1 (pre-dose), cycle 25 on day 1 (pre-dose) and day 8. | 
| Percentage of Samples From Oral Mucosa With Detectable Talimogene Laherparepvec Virus During Treatment | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. The percentage of samples taken from oral mucosa with detectable talimogene laherparepvec virus at any time during treatment is reported. | Cycle 1 on days 1 (pre-dose), 8, and 15, cycles 2 and 3 on days 1 (pre-dose), and 8, cycle 4 and subsequent cycles (up to 47) on day 1 (pre-dose), Cycle 25 on day 1 (pre-dose) and day 8. | 
| Percentage of Participants With Detectable Talimogene Laherparepvec DNA in Oral Mucosa During Treatment | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of participants with detectable talimogene laherparepvec DNA on swabs taken from oral mucosa at any time during treatment is reported. | Cycle 1 on days 1 (pre-dose), 8, and 15, cycles 2 and 3 on days 1 (pre-dose), and 8, cycle 4 and subsequent cycles (up to 47) on day 1 (pre-dose), Cycle 25 on day 1 (pre-dose) and day 8. | 
| Percentage of Participants With Detectable Talimogene Laherparepvec Virus in Oral Mucosa During Treatment | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. The percentage of participants with detectable talimogene laherparepvec virus in swabs taken from oral mucosa at any time during treatment is reported. | Cycle 1 on days 1 (pre-dose), 8, and 15, cycles 2 and 3 on days 1 (pre-dose), and 8, cycle 4 and subsequent cycles (up to 47) on day 1 (pre-dose), Cycle 25 on day 1 (pre-dose) and day 8. | 
| Percentage of Samples From the Anogenital Area With Detectable Talimogene Laherparepvec DNA During Treatment | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of swab samples from the anogenital area with detectable talimogene laherparepvec DNA at any time during treatment is reported. | Cycle 1 on days 1 (pre-dose), 8, and 15, cycles 2 and 3 on days 1 (pre-dose), and 8, cycle 4 and subsequent cycles (up to 50) on day 1 (pre-dose), Cycle 25 on day 1 (pre-dose) and day 8. | 
| Percentage of Samples With Detectable Talimogene Laherparepvec Virus in Swabs From the Anogenital Area During Treatment | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. The percentage of samples with detectable talimogene laherparepvec virus in swabs taken from the anogenital area at any time during treatment is reported. | Cycle 1 on days 1 (pre-dose), 8, and 15, cycles 2 and 3 on days 1 (pre-dose), and 8, cycle 4 and subsequent cycles (up to 50) on day 1 (pre-dose), Cycle 25 on day 1 (pre-dose) and day 8. | 
| Percentage of Participants With Detectable Talimogene Laherparepvec DNA in Swabs From the Anogenital Area During Treatment | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of participants with detectable talimogene laherparepvec DNA in swabs from the anogenital area at any time during treatment is reported. | Cycle 1 on days 1 (pre-dose), 8, and 15, cycles 2 and 3 on days 1 (pre-dose), and 8, cycle 4 and subsequent cycles (up to 50) on day 1 (pre-dose), Cycle 25 on day 1 (pre-dose) and day 8. | 
| Percentage of Participants With Detectable Talimogene Laherparepvec Virus in Swabs From the Anogenital Area During Treatment | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. The percentage of participants with detectable talimogene laherparepvec virus in swabs taken from the anogenital area at any time during treatment is reported. | Cycle 1 on days 1 (pre-dose), 8, and 15, cycles 2 and 3 on days 1 (pre-dose), and 8, cycle 4 and subsequent cycles (up to 50) on day 1 (pre-dose), Cycle 25 on day 1 (pre-dose) and day 8. | 
| Percentage of Samples From Oral Mucosa With Detectable Talimogene Laherparepvec DNA After the End of Treatment | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of swab samples from oral mucosa with detectable talimogene laherparepvec DNA after the end of treatment is reported. | From 30 to 60 days after the last dose of talimogene laherparepvec (the median [minimum, maximum] duration of treatment was 23 [3, 141] weeks). | 
| Percentage of Samples From Oral Mucosa With Detectable Talimogene Laherparepvec Virus After the End of Treatment | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. | From 30 to 60 days after the last dose of talimogene laherparepvec (the median [minimum, maximum] duration of treatment was 23 [3, 141] weeks). | 
| Percentage of Participants With Detectable Talimogene Laherparepvec DNA in Oral Mucosa After the End of Treatment | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of participants with detectable talimogene laherparepvec DNA in swabs taken from oral mucosa after the end of treatment is reported. | From 30 to 60 days after the last dose of talimogene laherparepvec (the median [minimum, maximum] duration of treatment was 23 [3, 141] weeks). | 
| Percentage of Participants With Detectable Talimogene Laherparepvec Virus in Oral Mucosa After the End of Treatment | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. | From 30 to 60 days after the last dose of talimogene laherparepvec (the median [minimum, maximum] duration of treatment was 23 [3, 141] weeks). | 
| Percentage of Samples From the Anogenital Area With Detectable Talimogene Laherparepvec DNA After the End of Treatment | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of swab samples from the anogenital area with detectable talimogene laherparepvec DNA after the end of treatment is reported. | From 30 to 60 days after the last dose of talimogene laherparepvec (the median [minimum, maximum] duration of treatment was 23 [3, 141] weeks). | 
| Percentage of Samples From the Anogenital Area With Detectable Talimogene Laherparepvec Virus After the End of Treatment | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. | 30 toFrom 30 to 60 days after the last dose of talimogene laherparepvec (the median [minimum, maximum] duration of treatment was 23 [3, 141] weeks). 60 days after the last dose of talimogene laherparepvec. | 
| Percentage of Participants With Detectable Talimogene Laherparepvec DNA in Swabs From the Anogenital Area After the End of Treatment | Talimogene laherparepvec DNA was measured using a quantitative polymerase chain reaction (qPCR) method. The percentage of participants with detectable talimogene laherparepvec DNA in swabs from the anogenital area after the end of treatment is reported. | From 30 to 60 days after the last dose of talimogene laherparepvec (the median [minimum, maximum] duration of treatment was 23 [3, 141] weeks). | 
| Percentage of Participants With Detectable Talimogene Laherparepvec Virus in Swabs From the Anogenital Area After the End of Treatment | If the result of the qPCR testing was positive, then a 50% tissue culture infective dose (TCID50) assay was performed on the swab sample to measure viral infectivity. | From 30 to 60 days after the last dose of talimogene laherparepvec (the median [minimum, maximum] duration of treatment was 23 [3, 141] weeks). | 
| Number of Samples With Detectable Talimogene Laherparepvec in Lesions Suspected to be Herpetic in Origin | Any lesion such as a cold sore or vesicle thought to be herpetic in origin was evaluated by the investigator and swabbed if HSV infection was suspected. Quantitative PCR was performed on the swab sample to evaluate whether talimogene laherparepvec DNA was detectable in the sample. | From first dose until 60 days after last dose of talimogene laherparepvec; The median actual follow-up time was 28.9 weeks (range: 4 to 151 weeks). | 
| Best Overall Response | Response was assessed according to modified World Health Organization (WHO) criteria using both clinical (cutaneous, subcutaneous, or nodal tumor measurement by caliper) and radiological imaging (computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound of the chest, abdomen, and pelvis and all other sites of disease). Complete response: disappearance of all index and non-index lesions. Partial Response: ≥ 50% reduction in size of all index lesions and any new measurable lesions. Stable disease: Neither sufficient tumor shrinkage of index lesion to qualify for response nor sufficient tumor increase of index lesion to qualify for progressive disease, assessed a minimum interval of 77 days from the first dose of study drug. Progressive Disease: ≥ 25% increase in size of index lesions or appearance of one or more non-index lesions. | Tumor response was assessed at weeks 12 and 24 and then at least every 3 months up to the end of treatment; median duration of treatment was 23.1 weeks (range: 3 to 141 weeks). | 
| Objective Response Rate | Response was assessed according to modified World Health Organization (WHO) criteria using both clinical (cutaneous, subcutaneous, or nodal tumor measurement by caliper) and radiological imaging (computed tomography, magnetic resonance imaging or ultrasound of the chest, abdomen, and pelvis and all other sites of disease). Objective response rate is defined as the percentage of participants with either a complete response or partial response. Subsequent confirmation was not required. Complete response: disappearance of all index and non-index lesions. Partial Response: ≥ 50% reduction in size of all index lesions and any new measurable lesions. | Tumor response was assessed at weeks 12 and 24 and then at least every 3 months up to the end of treatment; median duration of treatment was 23.1 weeks (range: 3 to 141 weeks). | 
| Time to Response | Time to response was defined as the interval from the first dose of talimogene laherparepvec to the first event of complete response or partial response per modified WHO criteria; participants who did not respond were censored at the last evaluable tumor assessment. | Tumor response was assessed at weeks 12 and 24 and then at least every 3 months up to the end of treatment; median duration of treatment was 23.1 weeks (range: 3 to 141 weeks). | 
| Duration of Response | Duration of response (DOR) was calculated only for those participants with an objective response and defined as the longest interval from an initial objective response (complete response or partial response) to disease progression per the modified WHO criteria or death, whichever occurred earlier; otherwise, DOR was censored at the last evaluable tumor assessment for participants who did not die or progress. | Tumor response was assessed at weeks 12 and 24 and then at least every 3 months up to the end of treatment; median duration of treatment was 23.1 weeks (range: 3 to 141 weeks). | 
| Durable Response Rate | Response was assessed according to modified World Health Organization (WHO) criteria using both clinical (cutaneous, subcutaneous, or nodal tumor measurement by caliper) and radiological imaging (computed tomography, magnetic resonance imaging or ultrasound of the chest, abdomen, and pelvis and all other sites of disease). Durable response rate is defined as the percentage of participants with a complete response or partial response maintained continuously for at least 6 months (183 days). Complete response: disappearance of all index and non-index lesions. Partial Response:≥ 50% reduction in size of all index lesions and any new measurable lesions. | Tumor response was assessed at weeks 12 and 24 and then at least every 3 months up to the end of treatment; median duration of treatment was 23.1 weeks (range: 3 to 141 weeks). | 
| Overall Survival | Overall Survival (OS) was defined as the interval from first dose of talimogene laherparepvec to death from any cause; participants still alive were censored at the last known alive date. | From first dose until 60 days after last dose of talimogene laherparepvec; The median actual follow-up time was 28.9 weeks (range: 4 to 151 weeks). | 
| Number of Participants With Adverse Events (AEs) | The Common Terminology Criteria for Adverse Events version 3.0 was used to grade severity of adverse events, based on the following general guideline: Grade 1 = Mild AE Grade 2 = Moderate AE Grade 3 = Severe AE Grade 4 = Life-threatening or disabling AE Grade 5 = Death related to AE. A serious adverse event was defined as an adverse event that meets at least 1 of the following serious criteria: fatal life threatening requires in-patient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event Treatment-related adverse events (TRAEs) are defined as adverse events possibly caused by talimogene laherparepvec, as assessed by the investigator. | From the first administration of talimogene laherparepvec up to 30 days after the last administration of talimogene laherparepvec; median duration of treatment was 23.1 weeks (range: 3 to 141 weeks). |