Talimogene Laherparepvec With Pembrolizumab in Melanoma Following Progression on Prior Anti-PD-1 Based Therapy (MASTERKEY-115) (Mk-3475-A07/KEYNOTE-A07).

Study Overview
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Brief Summary
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This is a phase 2, open-label, single-arm, multicenter clinical trial designed to evaluate the efficacy and safety of talimogene laherparepvec in combination with pembrolizumab following disease progression on prior anti-programmed cell death protein (anti-PD-1) therapy in unresectable/metastatic melanoma (stage IIIB-IVM1d) or prior anti-PD-1 therapy in the adjuvant setting. Subjects will be treated with talimogene laherparepvec and pembrolizumab until confirmed complete response, disappearance of all injectable lesions, documented confirmed disease progression per modified immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST), intolerance of study treatment, or 102 weeks from the first dose of talimogene laherparepvec and/or pembrolizumab, whichever occurs first.

Official Title
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Phase 2 Study of Talimogene Laherparepvec in Combination With Pembrolizumab in Subjects With Unresectable/Metastatic Stage IIIB-IVM1d Melanoma Who Have Progressed on Prior Anti PD-1 Based Therapy

Conditions
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Melanoma

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


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 years with histologically confirmed diagnosis of stage IIIB to IVM1d melanoma and for whom surgery is not recommended. Subjects with stage IVM1d disease may be enrolled with up to 3 cerebral metastases, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or gamma knife therapy, with no evidence of progression and not requiring steroids for at least 2 months prior to enrollment. Subjects must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions. Subjects must have had prior treatment (for at least 2 to 3 consecutive cycles within an 8 week period) with a PD-1 inhibitor and have confirmed disease progression (as defined by RECIST v1.1 criteria). The anti-PD-1 therapy must be the immediate prior line of therapy before enrollment and subjects with disease progression on more than 1 line of anti-PD-1 therapy are not eligible. ECOG performance status of 0 or 1. Adequate hematologic, renal, hepatic, and coagulation function. Key Exclusion Criteria: Subjects considered by the investigator to have rapid clinical progression due to melanoma Subjects with prior treatment and disease progression on more than 1 line of anti-PD-1 therapy Stage IVM1d subjects must not have greater than 3 cerebral melanoma metastases, or clinically active cerebral melanoma metastases requiring therapy, and/or carcinomatous meningitis regardless of clinical stability. Primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states or history of other malignancy within the past 3 years. Subjects must not have history or evidence of symptomatic autoimmune glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome requiring systemic treatment in the past 2 years (ie, with use of disease modifying agents, steroids or immunosuppressive agents) except vitiligo or resolved childhood asthma/atopy, or evidence of clinically significant immunosuppression. Subjects may not have been previously treated with talimogene laherparepvec or any other oncolytic virus. Subjects must not have active herpetic skin lesions or prior complications of herpetic infection and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Locally Recurrent/Metastatic - Primary Resistance<br>Includes participants who received anti-PD1 therapy in the locally recurrent/metastatic setting and experienced a best overall response of disease progression or stable disease prior to confirmed disease progression. Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles. | Drug: Talimogene laherparepvec<br>* Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.<br>Drug: Pembrolizumab<br>* Intravenous (IV) infusion.<br>|
| Experimental: Cohort 2 - Locally Recurrent/Metastatic - Acquired Resistance<br>Includes participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced confirmed disease progression following a complete or partial response on anti-PD-1 therapy. Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles. | Drug: Talimogene laherparepvec<br>* Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.<br>Drug: Pembrolizumab<br>* Intravenous (IV) infusion.<br>|
| Experimental: Cohort 3 - Adjuvant Setting -Disease Free Interval < 6 months<br>Includes participants who received anti-PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of < 6 months after starting the adjuvant anti-PD-1 therapy. Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles. | Drug: Talimogene laherparepvec<br>* Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.<br>Drug: Pembrolizumab<br>* Intravenous (IV) infusion.<br>|
| Experimental: Cohort 4 - Adjuvant Setting -Disease Free Interval ≥ 6 months<br>Includes participants who received anti PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of ≥ 6 months after starting the adjuvant PD-1 inhibitor. Participants will receive talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL will be administered every 3 weeks for up to 35 cycles in total. Participants will also receive pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles. | Drug: Talimogene laherparepvec<br>* Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.<br>Drug: Pembrolizumab<br>* Intravenous (IV) infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Per Modified RECIST v1.1 | ORR was defined as the incidence of a best overall response (BOR) of complete response (CR) or partial response (PR) per modified RECIST v1.1: CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Non-CR/Non-progressive disease (PD): Persistence of 1 or more non-target lesion(s). | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (CRR) Per Modified RECIST v1.1 | CRR was defined as the incidence of a BOR of CR per modified RECIST v1.1: CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis). Confirmation of CR was not required per modified RECIST v1.1. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Complete Response Rate (iCRR) Per Modified Immune-related Response Criteria (irRC) RECIST v1.1 | iCRR was defined as the incidence of a best overall response (iBOR) of a complete response (iCR) per modified irRC-RECIST: iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have had a reduction in short axis to < 10 mm. Confirmation of iCR was required per modified irRC-RECIST. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| BOR Per Modified RECIST v1.1 | BOR was the best overall visit response up to & including the first overall visit response of PD: CR: Disappearance of all target & non-target lesions. Any pathological lymph nodes must have had a reduction in short axis to <10 mm. All lymph nodes must have been non-pathological in size. PR: ≥30% decrease in the sum of diameters of target lesions. Stable disease (SD): Neither sufficient shrinkage to qualify for PR/CR nor sufficient increase to qualify for PD. PD: ≥20% increase in the sum of diameters of target lesions and an increase of ≥5mm. Progression of existing non-target lesions. Unable to evaluate (UE): Any lesion present at baseline which was not assessed or unable to be evaluated leading to an inability to determine the status of that particular tumor. Non-CR/Non-PD: Persistence of 1+ non-target lesion(s). Non-CR/non-PD was relevant to participants who did not have measurable disease at baseline. Confirmation of CR, PR & PD were not required per modified RECIST 1.1. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Best Overall Response (iBOR) Per Modified irRC-RECIST | iBOR was defined as the best overall visit response up to and including the first overall visit response of progressive disease (iPD) per modified irRC-RECIST: iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to < 10 mm. Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Stable disease (iSD): Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD. iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase. Unable to evaluate (iUE): Any lesion present at baseline or a new measurable lesion which was not assessed or was unable to be evaluated leading to an inability to determine the status of that particular tumor for that time point. Confirmation of iCR, iPR and iPD was required per modified irRC-RECIST. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Durable Response Rate (DRR) Per Modified RECIST v1.1 | DRR was defined as the percentage of participants with a CR or PR per modified RECIST v1.1 with a duration of response (DOR) ≥ 6 months. One month was calculated based on 365.25 days per year. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Confirmation of CR and PR were not required per modified RECIST v1.1. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Durable Response Rate (iDRR) Per Modified irRC-RECIST | iDRR was defined as the percentage of participants with an iCR or iPR per modified irRC-RECIST with a duration of response (iDOR) ≥ 6 months. One month was calculated based on 365.25 days per year. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to < 10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline. Confirmation of iCR and iPR were required per modified irRC-RECIST. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| DOR Per Modified RECIST v1.1 | DOR was defined as the time from the date of an initial response of CR or PR to the earlier of PD/death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of first subsequent anticancer therapy. One month was calculated based on 365.25 days per year. CR:Disappearance of all target & non-target lesions. All lymph nodes must have a reduction in short axis to <10 mm. Any pathological lymph nodes must have had a reduction in short axis to <10 mm. All lymph nodes must have been non-pathological in size (<10mm short axis). PR:At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD:At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions. Confirmation of CR, PR and PD were not required per modified RECIST v1.1. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| iDOR Per Modified irRC-RECIST | iDOR was defined as the time from the date of an initial response that is subsequently confirmed to the earlier of iPD per modified irRC-RECIST. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of first subsequent anticancer therapy. One month was calculated based on 365.25 days per year. iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to < 10 mm. iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. iPD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Disease Control Rate (DCR) Per Modified RECIST v1.1 | DCR per modified RECIST v1.1 was defined as the incidence of a BOR of CR, PR or SD. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor sufficient increase to qualify for PD. Confirmation of CR and PR were not required per modified RECIST v1.1. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Disease Control Rate (iDCR) Per Modified irRC-RECIST | iDCR per modified irRC-RECIST was defined as the incidence of an iBOR of iCR, iPR or iSD. iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to < 10 mm. iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. iSD: Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD. Confirmation of iCR and iPR were required per modified irRC-RECIST. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Objective Response Rate (iORR) Per Modified irRC-RECIST | iORR was defined as the incidence of an iBOR of iCR or iPR per modified irRC-RECIST iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to < 10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline. Confirmation of iCR and iPR were required per modified irRC-RECIST. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Progression Free Survival (PFS) Per Modified RECIST v1.1 | PFS per modified RECIST 1.1 was defined as the interval from first dose to the earlier event of PD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. - PD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Progression Free Survival (iPFS) Per Modified irRC-RECIST | iPFS per modified irRC-RECIST was defined as the interval from first dose to the earlier event of iPD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. - iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Overall Survival (OS) | OS was defined as the interval from first dose to death from any cause. Participants without an event were censored at the last date known to be alive. One month was calculated based on 365.25 days per year. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Evaluation of TEAEs included the number of participants with at least 1: TEAE Treatment-related TEAE Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 TEAE Treatment-related CTCAE grade ≥ 3 TEAE Serious TEAE Serious treatment-related TEAE Fatal TEAE Fatal treatment-related TEAE TEAE of interest Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. A CTCAE grade ≥ 3 was determined using the CTCAE grading systems based on CTCAE version 5.0 per the below definitions: Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to TEAE. Abnormal laboratory tests were also recorded as TEAEs. | Day 1 to up to 90 days post-last dose of treatment. The maximum duration of talimogene laherparepvec treatment at data cut off was 74.7 weeks and pembrolizumab treatment at data cut off was 75.9 weeks. | 
| Time to First Subsequent Anti-cancer Therapy | Time to first subsequent anti-cancer therapy was defined as the time from enrollment to the start of subsequent anticancer therapy. Participants who did not start subsequent anticancer therapy were censored as the last known to be alive date. One month was calculated based on 365.25 days per year. | Every 12 weeks. Maximum overall time on-study (treatment + follow up) at data cut off was 17.48 months. | 
| DOR Per Modified RECIST v1.1 | DOR was defined as the time from the date of an initial response of CR or PR to the earlier of PD/death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of first subsequent anticancer therapy. One month was calculated based on 365.25 days per year. CR:Disappearance of all target & non-target lesions. All lymph nodes must have a reduction in short axis to <10 mm. Any pathological lymph nodes must have had a reduction in short axis to <10 mm. All lymph nodes must have been non-pathological in size (<10mm short axis). PR:At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD:At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions. Confirmation of CR, PR and PD were not required per modified RECIST v1.1. | Every 12 weeks up to 4 years | 
| iDOR Per Modified irRC-RECIST | iDOR was defined as the time from the date of an initial response that is subsequently confirmed to the earlier of iPD per modified irRC-RECIST. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of first subsequent anticancer therapy. One month was calculated based on 365.25 days per year. iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to < 10 mm. iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. iPD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions. | Every 12 weeks up to 4 years | 
| Progression Free Survival (PFS) Per Modified RECIST v1.1 | PFS per modified RECIST 1.1 was defined as the interval from first dose to the earlier event of PD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. - PD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions. | Every 12 weeks up to 4 years | 
| Progression Free Survival (iPFS) Per Modified irRC-RECIST | iPFS per modified irRC-RECIST was defined as the interval from first dose to the earlier event of iPD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. - iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase. | Every 12 weeks up to 4 years | 
| Overall Survival (OS) | OS was defined as the interval from first dose to death from any cause. Participants without an event were censored at the last date known to be alive. One month was calculated based on 365.25 days per year. | Every 12 weeks up to 4 years | 
| Time to First Subsequent Anti-cancer Therapy | Time to first subsequent anti-cancer therapy was defined as the time from enrollment to the start of subsequent anticancer therapy. Participants who did not start subsequent anticancer therapy were censored as the last known to be alive date. One month was calculated based on 365.25 days per year. | Every 12 weeks up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Talimogene Laherparepvec, Pembrolizumab, Oncolytic immunotherapy, Anti-PD-1, Checkpoint inhibitor, MASTERKEY-115