Study to Evaluate the Safety/ Efficacy of T-VEC in Japanese Subjects With Unresectable Stage IIIB-IV Malignant Melanoma

Study Overview
=================
Brief Summary
-----------------
There are 2 fold of purposes for this study. 1 is to evaluate safety and tolerability and the other is to study the anti-tumor effects of talimogene laherparepvec in Japanese participants with unresectable stage IIIB-IV malignant melanoma.

Detailed Description
-----------------
This is a phase 1, multicenter, open-label study of talimogene laherparepvec in Japanese participants with unresectable stage IIIB-IVM1c malignant melanoma that are candidates for intralesional therapy. The Screening period is 28 days prior to study enrollment. There will be a Treatment period, Safety Follow-up period and a Long Term Follow-up period. The Screening Period: Informed consent will be obtained prior to screening procedures. Screening procedures to determine eligibility include: medical history (including concomitant medications, prior therapy for melanoma and BRAF status (if known)), physical exam, vital signs, assessment of Eastern Cooperative Oncology Group (ECOG) performance level status, electrocardiogram (ECG), laboratory assessments (including hepatitis serology), baseline tumor assessments, and adverse events assessment. Treatment Period: Initially, 6 Dose Limiting Toxicity (DLT)-evaluable participants will be enrolled and treated at 100% dose regimen of talimogene laherparepvec (Up to 4.0 mL of 10_6 PFU/mL followed by a dose of up to 4.0 mL of 10_8 PFU/mL). Upon demonstration of safety based on DLT incidence in the first 6 participants, an additional 12 participants will be enrolled and treated at Dose 1 to obtain additional safety data. If dose de-escalation is needed based on the DLT evaluation of first 6 participants, then additional 6 participants will be treated at lower dose (up to 4.0 mL of 10_6 PFU/mL followed by a dose of up to 4.0 mL of 10_7PFU/mL). The duration of treatment will vary for each participants. Participants will be treated until the participant has a DLT during the DLT evaluation period, participant has achieved a Complete Response, no injectable lesions, clinically relevant (resulting in clinical deterioration or requiring change in therapy) disease progression beyond 24-weeks of treatment, or safety concern, whichever occurs first. Maximum treatment duration will be 48 months. The total study duration for an individual participant can be up to 4 years. Drug Administration: If the participants are found to be eligible to take part in this study, they will receive talimogene laherparepvec by intralesional injection only into injectable cutaneous, subcutaneous, and nodal tumors, with or without image ultrasound guidance. The first injection of talimogene laherparepvec will take place on day 1 (week 0). The second injection should be administered 3 weeks (+ 5 days) after the initial injection. Subsequent injections should be given every 2 weeks (± 3 days). Study Visits: The participant will have a physical exam along with vital signs and ECOG. At any study visit blood may be collected to monitor health and safety, and effects of talimogene laherparepvec. Adverse events and medications taken will be reviewed at each study visit. The tumor assessment, physical exams, and ECOG performance status will be completed after 12 (± 1) weeks on treatment (ie, day 1 of week 11), and then every 12 (± 1) weeks (eg, weeks 23, 35, 47 etc.), or more frequently if clinically indicated, until Progressive disease beyond 6 months of treatment or until the start of a new anticancer therapy. Central Lab tests: Blood for herpes simplex virus type-1 (HSV-1) Antibody Serostatus will collected within 3 days prior to dose at day 1 (week 0) and at week 5. Throughout the trial any participant developing a lesion of suspected herpetic origin will have a swab of the lesion for presence of talimogene laherparepvec DNA obtained within 3 days of the event. Exposure to talimogene laherparepvec by the healthcare providers of the participant and/or close contacts will be assessed. Safety Follow Visit: A safety follow-up visit will be performed 30 (+7) days after the last dose. The participant will have a physical exam, have vital signs taken, assessment of ECOG status and have weight measured. Adverse events will be assessed as well as the concomitant medications. Routine bloodwork and tumor response assessments will be performed. Long-Term Follow-up Visits: Follow-up for survival status and, if applicable, commencement of any subsequent anticancer melanoma therapy will occur every 12 weeks (± 28 days) by phone or clinic visit for all participants who permanently discontinue talimogene laherparepvec for any reason other than withdrawal of full consent for up to 24 months after the last participant is enrolled in the study. For participants that discontinue talimogene laherparepvec for reason other than disease progression, the following additional procedures will be conducted during the long-term follow-up: radiographic tumor imaging, clinical tumor assessments, ECOG Performance Status assessments, reporting of pregnancy or lactation, assessment of swabs of lesions of suspected herpetic origin for presence of talimogene laherparepvec DNA, and tumor response assessments until documented disease progression beyond 24-weeks of treatment, until the start of a new anticancer therapy, or end of study, whichever is earliest. If a participant discontinues therapy more than 24 months after the last participant was enrolled in the study, when the long-term follow-up period ends, they will not enter long-term follow-up.

Official Title
-----------------
A Phase 1, Multi-center, Open-Label, Dose De-escalation Study to Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Japanese Subjects With Unresectable Stage IIIB-IV Malignant Melanoma

Conditions
-----------------
Unresectable Stage IIIB-IV Malignant Melanoma

Intervention / Treatment
-----------------
* Drug: Talimogene laherparepvec


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed diagnosis of melanoma Participants with stage IIIB to IVM1c melanoma that is not surgically resectable Participant who is treatment naive and is determined by the physician to be not suitable or eligible for the approved systemic anticancer drug therapy in Japan. Participant may also have received prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy. Treatment for melanoma must have been completed at least 28 days prior to enrollment. Candidate for intralesional therapy (ie, disease is appropriate for direct injection or through the use of ultrasound guidance, where appropriate) defined as one or more of the following: at least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion greater or equal to 10 mm in longest diameter, OR multiple injectable melanoma lesions that in aggregate have a longest diameter of greater or equal to 10 mm Measurable disease defined as one or more of the following: at least 1 melanoma lesion that can be accurately and serially measured in at least 2 dimensions and for which the greatest diameter is greater or equal to 10 mm as measured by contrast-enhanced or spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or ultrasound for nodal/soft tissue disease (including lymph nodes) at least 1 greater or equal to 10 mm longest diameter superficial cutaneous or subcutaneous melanoma lesion as measured by calipers multiple superficial melanoma lesions which in aggregate have a total diameter of greater or equal to 10 mm Serum lactate dehydrogenase (LDH) levels less than or equal to 1.5 X upper limit of normal (ULN) within 28 days prior to enrollment Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Other Inclusion Criteria May Apply. Exclusion Criteria: Clinically active cerebral metastases. Participants with up to 3 cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy (including Gamma Knife) or craniotomy, with no evidence of progression and have not required steroids for at least 2 months prior to enrollment. Greater than 3 visceral metastases (this does not include lung metastases or nodal metastases associated with visceral organs). For participants with less than or equal to 3 visceral metastases, no lesion greater than 3 cm in longest dimension and liver lesions must be stable for at least 1 month prior to enrollment. Bone metastases Primary ocular or mucosal melanoma History or evidence of symptomatic autoimmune disease (eg, pneumonitis, glomerulonephritis, vasculitis, or other), or history of autoimmune disease that required systemic treatment (ie, use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) in past 2 months prior to enrollment. Active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis). Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use. Previous treatment with talimogene laherparepvec Other investigational procedures while participating in this study are excluded. Known to have acute or chronic active hepatitis B infection, acute or chronic active hepatitis C infection or human immunodeficiency virus (HIV) infection Participant has known sensitivity to bovine- or porcine derived components or to any of the products or components to be administered during dosing. History of other malignancy within the past 3 years Other Exclusion Criteria May Apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Talimogene laherparepvec<br>Participants will receive talimogene laherparepvec administered by intralesional injection only into injectable cutaneous, subcutaneous, and nodal tumors, with or without image ultrasound guidance. On Day 1 (Week 0), the initial dose of talimogene laherparepvec will be up to 4.0 mL of 10^6 Plaque forming units per millilitre (PFU/mL). Subsequent doses of talimogene laherparepvec will be up to 4.0 mL of 10^8 or 10^7 PFU/mL. The second dose is to be administered 3 weeks (+ 5 days) after the initial dose, and subsequent doses were to be given every 2 weeks (+ 3 days). | Drug: Talimogene laherparepvec<br>* Talimogene laherparepvec will be administered as an intralesional injection.<br>* Other names: T-VEC;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced One or More Dose Limiting Toxicities (DLTs) | DLTs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4 Events were considered DLTs, if judged by the investigator to be related to study treatment: Grade 4 non-hematologic toxicity Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care (grade 3 fatigue not a DLT) Grade 3 or higher non-hematologic laboratory value reported as an adverse event if: medical intervention is required, or abnormality leads to hospitalization, or abnormality persists for > 1 week (Laboratory values that persist for > 1 week but are deemed not clinically important per both investigator and sponsor were not considered DLTs) Febrile neutropenia grade 3 or 4 Thrombocytopenia < 25 x 10^9/L associated with bleeding event requiring intervention Serious herpetic event (eg, herpetic encephalitis, encephalomyelitis, or disseminated herpetic infection) Grade 5 toxicity Any other intolerable toxicity leading to permanent discontinuation of study treatment | Day 1 to Day 35 | 
| Durable Response Rate (DRR) Using Modified World Health Organization (WHO) Response Criteria | DRR using WHO response criteria was defined as the percentage of participants who experienced objective response (complete response [CR] or partial response [PR]) lasting continuously for ≥ 6 months that starting any time within 12 months of initiating treatment. CR: Complete disappearance of all index lesions, including any new tumors which might have appeared. PR: Achieving a 50% or greater reduction in the SPD of the perpendicular diameters of all index lesions at the time of assessment as compared to the sum of the products of the perpendicular diameters of all index lesions at baseline (Day 1). | Day 1 up to the maximum time on treatment or follow-up at primary data cutoff date (03 August 2020): 89.1 weeks of treatment and 37 months of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) Using Modified World Health Organization (WHO) Response Criteria | ORR was defined as the percentage of participants who experienced an objective response of CR or PR per modified WHO response criteria among the set of participants analyzed. | Day 1 to end of study, maximum time to end of study was 212.6 weeks | 
| Time to Response (TTR) Using Modified World Health Organization (WHO) Response Criteria | TTR was defined as the time from the first treatment administration to the first incidence of a confirmed CR or PR according to modified WHO response criteria among the set of participants analyzed. TTR was estimated using Kaplan-Meier (KM) method. | Day 1 to end of study, maximum time to end of study was 212.6 weeks | 
| Duration of Response (DOR) Using Using Modified World Health Organization (WHO) Response Criteria | DOR was defined as the time from the date of an initial response (CR or PR) to the earlier of progressive disease (PD) or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment. PD: A > 25% increase in the sum of the products of the perpendicular diameters of all index tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point. DOR was estimated using Kaplan-Meier (KM) method. | Day 1 to end of study, maximum time to end of study was 212.6 weeks | 
| Progression Free Survival (PFS) Using Using Modified World Health Organization (WHO) Response Criteria | PFS was defined as the interval from the first dose to the earlier of PD per modified WHO response criteria or death from any cause; otherwise, PFS was censored at the last evaluable tumor assessment. PFS was estimated using Kaplan-Meier (KM) method. | Day 1 to end of study, maximum time to end of study was 212.6 weeks | 
| Overall Survival (OS) | OS was defined as the interval from first dose to the event of death from any cause; otherwise, OS was censored at the date the participant was last known to be alive. OS was estimated using Kaplan-Meier (KM) method. | Day 1 to end of study, maximum time to end of study was 212.6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Unresectable Stage IIIB-IV Malignant Melanoma