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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02263508
Registration number
NCT02263508
Ethics application status
Date submitted
26/09/2014
Date registered
13/10/2014
Date last updated
14/11/2022
Titles & IDs
Public title
Pembrolizumab With Talimogene Laherparepvec or Placebo in Unresected Melanoma
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Scientific title
A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable Stage IIIB to IVM1c Melanoma (MASTERKEY-265)
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Secondary ID [1]
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2014-000185-22
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Secondary ID [2]
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20110265
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Universal Trial Number (UTN)
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Trial acronym
MASTERKEY-265
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Melanoma
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Condition category
Condition code
Cancer
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Malignant melanoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Talimogene Laherparepvec
Treatment: Drugs - Pembrolizumab
Treatment: Drugs - Placebo
Experimental: Phase 1b: Talimogene Laherparepvec + Pembrolizumab - Participants received talimogene laherparepvec at an initial dose of up to 4 mL 106 plaque-forming units (PFU)/mL by intralesional injection. Subsequent doses of talimogene laherparepvec at up to 4 mL of 108 PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
Placebo Comparator: Phase 3 : Placebo + Pembrolizumab - Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
Experimental: Phase 3: Talimogene Laherparepvec + Pembrolizumab - Participants received talimogene laherparepvec at an initial dose of up to 4 mL 106 PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 108 PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
Treatment: Drugs: Talimogene Laherparepvec
Talimogene laherparepvec administered by intratumoral injection
Treatment: Drugs: Pembrolizumab
Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.
Treatment: Drugs: Placebo
Administered by intratumoral injection
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)
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Assessment method [1]
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A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0:
Grade 4 non-hematologic toxicity.
Grade 3 or higher pneumonitis.
Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care, excluding grade 3 fatigue.
Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for > 1 week.
Febrile neutropenia grade 3 or grade 4.
Thrombocytopenia < 25 x 10^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit.
Grade 5 toxicity (ie, death).
Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.
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Timepoint [1]
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The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).
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Primary outcome [2]
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Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1
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Assessment method [2]
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PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause.
PD: Increase in size of target lesions from nadir by = 20% and = 5 mm absolute increase above nadir, or the appearance of a new lesion.
Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.
The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).
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Timepoint [2]
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From randomization until the data-cut-off date of 02 March 2020; median (range) time on follow-up was 25.5 (0.6, 44.7) months in the Placebo + Pembrolizumab arm and 25.6 (0.3, 45.8) months in the Talimogene Laherparepvec + Pembrolizumab arm.
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Primary outcome [3]
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Phase 3: Overall Survival
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Assessment method [3]
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Overall survival (OS) is defined as the interval from randomization to death from any cause.
Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
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Timepoint [3]
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From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.
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Secondary outcome [1]
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Phase 1b: Objective Response Rate (ORR)
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Assessment method [1]
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ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area = 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.
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Timepoint [1]
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Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
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Secondary outcome [2]
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Phase 1b: Best Overall Response (BOR)
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Assessment method [2]
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Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area = 50% relative to baseline; PD was defined as an increase in tumor area = 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with = 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
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Timepoint [2]
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Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
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Secondary outcome [3]
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Phase 1b: Durable Response Rate (DRR)
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Assessment method [3]
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DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area = 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
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Timepoint [3]
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Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
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Secondary outcome [4]
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Phase 1b: Duration of Response (DOR)
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Assessment method [4]
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Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area = 50% relative to baseline; PD was defined as an increase in tumor area = 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
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Timepoint [4]
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Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
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Secondary outcome [5]
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Phase 1b: Disease Control Rate (DCR)
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Assessment method [5]
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DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area = 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with = 84 days elapsed after enrollment.
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Timepoint [5]
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Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
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Secondary outcome [6]
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Phase 1b: Progression-free Survival (PFS)
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Assessment method [6]
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Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment.
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Timepoint [6]
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From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
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Secondary outcome [7]
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Phase 1b: Overall Survival (OS)
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Assessment method [7]
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Overall survival is defined as the interval from first dose to death from any cause.
OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
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Timepoint [7]
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From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
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Secondary outcome [8]
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Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR)
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Assessment method [8]
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Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.
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Timepoint [8]
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Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
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Secondary outcome [9]
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Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS)
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Assessment method [9]
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PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause.
iPD: Increase in tumor burden = 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection.
Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.
The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).
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Timepoint [9]
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From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
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Secondary outcome [10]
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Phase 3: Overall Survival Excluding Stage IVM1c Participants
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Assessment method [10]
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Overall survival is defined as the interval from randomization to death from any cause.
Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date.
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Timepoint [10]
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From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.
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Secondary outcome [11]
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Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1
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Assessment method [11]
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ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review.
CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a = 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.
Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.
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Timepoint [11]
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Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
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Secondary outcome [12]
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Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1
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Assessment method [12]
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BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR.
CR: Disappearance of all lesions except lymph node short axis < 10 mm; PR: = 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of = 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and = 84 days from randomization; PD: Increase from nadir by = 20% or = 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
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Timepoint [12]
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Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
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Secondary outcome [13]
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Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1
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Assessment method [13]
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DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of = 6 months.
CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a = 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.
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Timepoint [13]
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Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
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Secondary outcome [14]
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Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1
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Assessment method [14]
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Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or 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 the first subsequent anticancer therapy.
CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a = 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by = 20% or = 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.
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Timepoint [14]
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From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
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Secondary outcome [15]
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Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1
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Assessment method [15]
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Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review.
CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a = 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with = 84 days elapsed after randomization.
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Timepoint [15]
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Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
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Secondary outcome [16]
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Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR)
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Assessment method [16]
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Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
iPR: Decrease in tumor burden = 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.
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Timepoint [16]
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Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
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Secondary outcome [17]
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Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST
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Assessment method [17]
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BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR.
iCR: Disappearance of all lesions confirmed by consecutive assessment = 4 weeks from the date first documented. Reduction of any pathological lymph node to <10 mm.
iPR: Decrease in tumor burden = 30% relative to baseline confirmed = 4 weeks after first documentation.
iPD: Increase in tumor burden = 20 % and at least 5 mm absolute increase relative to nadir confirmed = 4 weeks from initial detection.
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and = 84 days from randomization.
Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
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Timepoint [17]
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Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
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Secondary outcome [18]
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Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR)
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Assessment method [18]
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Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response = 6 months.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
iPR: Decrease in tumor burden = 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
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Timepoint [18]
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Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
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Secondary outcome [19]
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Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR)
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Assessment method [19]
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Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
iPR: Decrease in tumor burden = 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
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Timepoint [19]
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From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
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Secondary outcome [20]
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Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR)
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Assessment method [20]
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Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
iPR: Decrease in tumor burden = 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with = 84 days elapsed after randomization.
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Timepoint [20]
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Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
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Secondary outcome [21]
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Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score
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Assessment method [21]
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The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items.
The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement.
The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).
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Timepoint [21]
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Baseline and day 1 of weeks 3, 6, 9, 12, then every 6 weeks until end of study treatment; median (range) duration of treatment was 39.0 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 54.1 (0.1, 109.6) weeks in Talimogene Laherparepvec + Pembrolizumab.
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Secondary outcome [22]
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Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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Assessment method [22]
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An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose.
A serious adverse event (SAE) is an AE that met at least 1 of the following criteria:
fatal
life threatening
required in-patient hospitalization or prolongation of existing hospitalization
resulted in persistent or significant disability/incapacity
congenital anomaly/birth defect
other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier.
AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.
Query!
Timepoint [22]
0
0
From first dose to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110.1) weeks in Phase 1b, 39 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 56 (0.1, 109.6) weeks in Phase 3 Talimogene Laherparepvec + Pembrolizumab.
Query!
Eligibility
Key inclusion criteria
Key
- Age = 18 years with histologically confirmed diagnosis of melanoma and stage IIIB to
IVM1c for whom surgery is not recommended.
- Subjects must have measurable disease and be a candidate for intralesional therapy
administration into cutaneous, subcutaneous, or nodal lesions.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Adequate hematologic, hepatic, renal, and coagulation function.
- Subjects with serine/threonine protein kinase B-Raf V600 (BRAFV600) wild-type tumors
must not have received any prior systemic anticancer treatment consisting of
chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting for
unresectable stage IIIB to IVM1c melanoma.
- Subjects with B-Raf V600 (BRAFV600) mutated tumors who have received prior BRAF
inhibitor therapy either alone or in combination with mitogen-activated protein kinase
kinase (MEK) inhibitor as their only prior systemic therapy are eligible.
- Subjects who received prior adjuvant therapy for melanoma will not be excluded
(including, but not limited to, interferon, ipilimumab, limb infusion/perfusion, or
use of investigational agents in the adjuvant setting) with the exception that prior
adjuvant therapy with inhibitors of programmed cell death-1 (PD-1) or programmed cell
death ligand 1 (PD-L1) is not allowed. However, if the subject received adjuvant
therapy, the subject must have completed therapy at least 28 days prior to enrollment.
- Subjects must have a tumor sample that is adequate for PD-L1 assessment prior to
randomization.
Key
Query!
Minimum age
18
Years
Query!
Query!
Maximum age
95
Years
Query!
Query!
Sex
Both males and females
Query!
Can healthy volunteers participate?
No
Query!
Key exclusion criteria
- Subjects must not have clinically active cerebral metastases.
- Subjects must not have 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 may not have been previously treated with talimogene laherparepvec, any other
oncolytic virus, pembrolizumab, or any other inhibitor of PD-1, PD-L1, or PD-L2.
- Subjects must not have history or evidence of symptomatic autoimmune pneumonitis,
glomerulonephritis, vasculitis, other symptomatic autoimmune disease, documented
history of 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 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.
Query!
Study design
Purpose of the study
Treatment
Query!
Allocation to intervention
Randomised controlled trial
Query!
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Query!
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Query!
Masking / blinding
Blinded (masking used)
Query!
Who is / are masked / blinded?
The people receiving the treatment/s
The people analysing the results/data
Query!
Query!
Query!
Query!
Intervention assignment
Parallel
Query!
Other design features
Query!
Phase
Phase 3
Query!
Type of endpoint/s
Query!
Statistical methods / analysis
Query!
Recruitment
Recruitment status
Terminated
Query!
Data analysis
Query!
Reason for early stopping/withdrawal
Query!
Other reasons
Query!
Date of first participant enrolment
Anticipated
Query!
Actual
8/12/2014
Query!
Date of last participant enrolment
Anticipated
Query!
Actual
Query!
Date of last data collection
Anticipated
Query!
Actual
11/03/2021
Query!
Sample size
Target
Query!
Accrual to date
Query!
Final
713
Query!
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Query!
Recruitment hospital [1]
0
0
Research Site - North Sydney
Query!
Recruitment hospital [2]
0
0
Research Site - Waratah
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Recruitment hospital [3]
0
0
Research Site - Wollongong
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Recruitment hospital [4]
0
0
Research Site - Southport
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Recruitment hospital [5]
0
0
Research Site - Woolloongabba
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Recruitment hospital [6]
0
0
Research Site - Woodville South
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Recruitment hospital [7]
0
0
Research Site - Geelong
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Recruitment hospital [8]
0
0
Research Site - Heidelberg
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Recruitment hospital [9]
0
0
Research Site - Melbourne
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Recruitment hospital [10]
0
0
Research Site - Prahran
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Recruitment hospital [11]
0
0
Research Site - Murdoch
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Recruitment postcode(s) [1]
0
0
2060 - North Sydney
Query!
Recruitment postcode(s) [2]
0
0
2298 - Waratah
Query!
Recruitment postcode(s) [3]
0
0
2500 - Wollongong
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Recruitment postcode(s) [4]
0
0
4215 - Southport
Query!
Recruitment postcode(s) [5]
0
0
4102 - Woolloongabba
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Recruitment postcode(s) [6]
0
0
5011 - Woodville South
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Recruitment postcode(s) [7]
0
0
3220 - Geelong
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Recruitment postcode(s) [8]
0
0
3084 - Heidelberg
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Recruitment postcode(s) [9]
0
0
3000 - Melbourne
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Recruitment postcode(s) [10]
0
0
3181 - Prahran
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Recruitment postcode(s) [11]
0
0
6150 - Murdoch
Query!
Recruitment outside Australia
Country [1]
0
0
United States of America
Query!
State/province [1]
0
0
Alabama
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Country [2]
0
0
United States of America
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State/province [2]
0
0
California
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0
0
United States of America
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State/province [3]
0
0
Florida
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0
0
United States of America
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State/province [4]
0
0
Georgia
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0
0
United States of America
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0
0
Illinois
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0
0
United States of America
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State/province [6]
0
0
Kentucky
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United States of America
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Maryland
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United States of America
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Massachusetts
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United States of America
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Michigan
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United States of America
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Minnesota
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Missouri
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New Jersey
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New York
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Ohio
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Pennsylvania
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Tennessee
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Texas
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United States of America
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Utah
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Washington
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Austria
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Graz
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Austria
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Innsbruck
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Austria
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Salzburg
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Austria
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Wien
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Belgium
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Bruxelles
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Belgium
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Liege
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Canada
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Alberta
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Canada
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Ontario
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Canada
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Quebec
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Czechia
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Brno
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Czechia
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Olomouc
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Czechia
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Ostrava-Poruba
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Czechia
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Praha 10
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Czechia
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Praha 2
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Czechia
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Praha 8
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Finland
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Helsinki
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France
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Bordeaux Cedex
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France
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Grenoble Cedex 9
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France
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Lille
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France
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Lyon cedex 08
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France
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Marseille cedex 05
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France
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Nantes Cedex 1
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France
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Paris
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France
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Pierre Benite Cedex
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France
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Toulouse cedex 9
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France
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0
0
Vandoeuvre les Nancy
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Germany
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0
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Berlin
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Germany
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Dresden
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Germany
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0
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Erlangen
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Germany
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0
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Essen
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0
0
Germany
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Hannover
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0
0
Germany
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0
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Heidelberg
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0
0
Germany
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0
0
Kiel
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0
0
Germany
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Leipzig
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0
0
Germany
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Mainz
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0
0
Germany
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0
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Mannheim
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0
0
Germany
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München
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0
0
Germany
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Regensburg
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0
0
Germany
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Tübingen
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0
Germany
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Würzburg
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0
Greece
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0
Athens
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0
Greece
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0
Heraklion - Crete
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Greece
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Ioannina
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0
Greece
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Thessaloniki
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Hungary
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Budapest
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Hungary
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Pecs
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Hungary
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Szeged
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Italy
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Bergamo
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Italy
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Brescia
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Italy
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Meldola FC
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Italy
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Milano
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Italy
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Siena
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Korea, Republic of
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Seoul
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Netherlands
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Amsterdam
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Groningen
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Netherlands
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Nijmegen
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Poland
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Bielsko-Biala
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Poland
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Bydgoszcz
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Poland
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Gdansk
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Poland
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Konin
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Poland
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Krakow
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Poland
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Poznan
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Szczecin
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Warszawa
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Wroclaw
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Portugal
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Almada
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Portugal
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Lisboa
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Portugal
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Porto
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Russian Federation
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Moscow
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Russian Federation
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Gauteng
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South Africa
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Kraaifontein
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South Africa
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Pretoria
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Spain
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Cataluña
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Spain
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Comunidad Valenciana
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Spain
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Navarra
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Spain
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País Vasco
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Spain
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Madrid
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Bellinzona
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Switzerland
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Bern
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Switzerland
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Geneva 14
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Switzerland
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Lausanne
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Switzerland
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Zürich
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Birmingham
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Guildford
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Leeds
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Leicester
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London
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United Kingdom
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Manchester
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Oxford
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Preston
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United Kingdom
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Southampton
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Amgen
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Address
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Country
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Other collaborator category [1]
0
0
Commercial sector/Industry
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Name [1]
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0
Merck Sharp & Dohme LLC
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Address [1]
0
0
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Country [1]
0
0
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Ethics approval
Ethics application status
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Summary
Brief summary
The primary objectives of the Phase 1b part of the study are to evaluate the safety, as
assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in
combination with pembrolizumab in adults with previously untreated, unresectable, stage IIIB
to IVM1c melanoma.
The primary objective of Phase 3 are to evaluate the efficacy of talimogene laherparepvec
with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free
survival (PFS) (response evaluation by blinded independent central review using modified
Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and overall survival (OS).
Query!
Trial website
https://clinicaltrials.gov/ct2/show/NCT02263508
Query!
Trial related presentations / publications
Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS, Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long GV. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017 Sep 7;170(6):1109-1119.e10. doi: 10.1016/j.cell.2017.08.027. Erratum In: Cell. 2018 Aug 9;174(4):1031-1032.
Dummer R, Hoeller C, Gruter IP, Michielin O. Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors. Cancer Immunol Immunother. 2017 Jun;66(6):683-695. doi: 10.1007/s00262-017-1967-1. Epub 2017 Feb 25.
Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Gutzmer R, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Guilera JM, Rapoport BL, VanderWalde A, Diede SJ, Anderson JR, Treichel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. J Clin Oncol. 2023 Jan 20;41(3):528-540. doi: 10.1200/JCO.22.00343. Epub 2022 Aug 23.
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Public notes
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Contacts
Principal investigator
Name
0
0
MD
Query!
Address
0
0
Amgen
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0
0
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Phone
0
0
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Fax
0
0
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Email
0
0
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Contact person for public queries
Name
0
0
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Fax
0
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Email
0
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02263508
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