Efficacy and Safety Study of Talimogene Laherparepvec Compared to Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) in Melanoma

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to evaluate the efficacy and safety of treatment with talimogene laherparepvec compared to subcutaneously administered GM-CSF in patients with unresectable Stage IIIb, IIIc and Stage IV melanoma. The efficacy endpoints of the study aim to demonstrate overall clinical benefit for patients treated with talimogene laherparepvec as compared to GM-CSF.

Official Title
-----------------
A Randomized Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of Treatment With OncoVEX^GM-CSF Compared to Subcutaneously Administered GM-CSF in Melanoma Patients With Unresectable Stage IIIb, IIIc and IV Disease

Conditions
-----------------
Melanoma

Intervention / Treatment
-----------------
* Biological: Talimogene laherparepvec
* Biological: GM-CSF


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females age ≥ 18 years Stage IIIb, IIIc or stage IV disease that is not surgically resectable Injectable disease (i.e. suitable for direct injection or through the use of ultrasound guidance) At least 1 injectable cutaneous, subcutaneous or nodal melanoma lesion >= 10 mm in longest diameter or, multiple injectable melanoma lesions which in aggregate have a longest diameter of >= 10 mm Serum lactate dehydrogenase (LDH) levels less than 1.5 x upper limit of normal (ULN) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Prolongation in International Normalized Ratio (INR), Prothrombin Time (PT), and Partial Thromboplastin Time (PTT) when the result is from therapeutic anticoagulation treatment are permitted for patients whose injectable lesions are cutaneous and/or subcutaneous such that direct pressure could be applied in the event of excessive bleeding Exclusion Criteria: Clinically active cerebral or any bone metastases. Patients with up to 3 (neurological performance status of 0) cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, gammaknife therapy, with no evidence of progression, and have not required steroids, for at least two (2) months prior to randomization Greater than 3 visceral metastases (this does not include lung metastases or nodal metastases associated with visceral organs). For patients with < 3 visceral metastases, no lesion > 3 cm, and liver lesions must meet Response Evaluation Criteria In Solid Tumors (RECIST) criteria for stable disease for at least 1 month prior to randomization

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GM-CSF<br>Granulocyte macrophage colony-stimulating factor (GM-CSF) was administered at a dose of 125 μg/m²/day subcutaneously for 14 days, followed by a 14-day rest period for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months. | Biological: GM-CSF<br>* 125 µg/m² subcutaneous injection<br>* Other names: Sargramostim;|
| Experimental: Talimogene Laherparepvec<br>Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose of talimogene laherparepvec was at a concentration of 10⁶ plaque forming units (PFU)/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months. | Biological: Talimogene laherparepvec<br>* Up to 4 mL of 10⁸ pfu/mL/per intratumoral injection<br>* Other names: IMLYGIC™;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durable Response Rate | Durable response rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) maintained continuously for at least 6 months from the time the objective response was first observed and initiating within 12 months of starting therapy as assessed by the Endpoint Assessment Committee (EAC). This reflects all new sites of disease as well as disease sites identified at baseline. Disease assessments were performed at the beginning of each treatment cycle in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline. | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival time was censored at the last date the patient was known to be alive when the confirmation of death was absent or unknown. Participants were censored at the date of randomization if no additional follow-up data were obtained. | From randomization until the first 290 survival events had occurred (data cut-off date of 31 March 2014); median time on follow-up was 44 months. | 
| Objective Response Rate | Objective response rate was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed by the Endpoint Assessment Committee (EAC). Best overall response for a patient is the best overall response observed across all time points. Disease assessments were performed at the beginning of each treatment cycle and assessed in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline. | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | 
| Duration of Response | The duration of response is defined as the longest individual period from entering response (CR or PR as assessed by the EAC) to the first documented evidence of the patient no longer meeting the criteria for being in response or death, whichever is earlier. Responses were censored at the last assessment showing response. | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | 
| Response Onset | Response onset is defined as the time from the date of randomization to the date of the first documented evidence of response (CR or PR) per EAC assessment. | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | 
| Time to Treatment Failure | Time to treatment failure was assessed by the investigator, and calculated from randomization until the first clinically relevant disease progression where there is no response achieved after the progression, or until death if no such progression occurs. Participants who did not have clinically relevant progression or did not die were censored at the time of the their last tumor assessment. Participants who withdrew from treatment due to a clinically unacceptable toxicity were not considered as an event in the analysis. Progressive disease (PD) is defined as a ≥ 25% increase in the sum of the products of the perpendicular diameters of all measurable tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point. Clinically relevant progressive disease is PD that is associated with a decline in performance status and/or in the opinion of the investigator the patient requires alternative therapy. | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | 
| Response Interval | Response interval is defined as the interval between the date of randomization and the date of the last documented evidence of response (CR or PR as assessed by the Investigator) prior to any new anti-cancer therapy. Response Interval post response onset was censored if a patient was still in response at the last observation. | From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Melanoma, OncoVEX^GM-CSF, GM-CSF, Stage IIIb, IIIc and IV Disease, oncolytic, OncoVex, T-Vec, talimogene laherparepvec