Clinical trial NCT02263508: Pembrolizumab With Talimogene Laherparepvec or Placebo in Unresected Melanoma
Official 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Melanoma
Keywords: Talimogene Laherparepvec
pembrolizumab
KEYNOTE-034
MASTERKEY-265
Lead sponsor: Amgen
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2014-10-13
Enrollment: 713
Sex: ALL
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 1b was an open-label, single-arm study. Phase 3 was a randomized, double-blind, placebo-controlled study design.
Primary purpose: TREATMENT

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).


Eligibility criteria: Key Inclusion Criteria:

* 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 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.

Primary outcomes:
measure: Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).
measure: Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1
timeFrame: 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.
measure: Phase 3: Overall Survival
timeFrame: 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.
Secondary outcomes:
measure: Phase 1b: Objective Response Rate (ORR)
timeFrame: 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.
measure: Phase 1b: Best Overall Response (BOR)
timeFrame: 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.
measure: Phase 1b: Durable Response Rate (DRR)
timeFrame: 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.
measure: Phase 1b: Duration of Response (DOR)
timeFrame: 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.
measure: Phase 1b: Disease Control Rate (DCR)
timeFrame: 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.
measure: Phase 1b: Progression-free Survival (PFS)
timeFrame: From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
measure: Phase 1b: Overall Survival (OS)
timeFrame: From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
measure: Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR)
timeFrame: 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.
measure: Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS)
timeFrame: 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.
measure: Phase 3: Overall Survival Excluding Stage IVM1c Participants
timeFrame: 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.
measure: Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1
timeFrame: 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.
measure: Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1
timeFrame: 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.
measure: Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1
timeFrame: 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.
measure: Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1
timeFrame: 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.
measure: Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1
timeFrame: 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.
measure: Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR)
timeFrame: 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.
measure: Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST
timeFrame: 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.
measure: Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR)
timeFrame: 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.
measure: Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR)
timeFrame: 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.
measure: Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR)
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: 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.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Research Site
state: Alabama
city: Mobile
country: United States
facility: Research Site
state: Alabama
city: Beverly Hills
country: United States
facility: Research Site
state: California
city: Duarte
country: United States
facility: Research Site
state: California
city: Encinitas
country: United States
facility: Research Site
state: California
city: La Jolla
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Riverside
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
facility: Research Site
state: California
city: Santa Monica
country: United States
facility: Research Site
state: California
city: Miami Beach
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Orlando
country: United States
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state: Florida
city: Atlanta
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state: Georgia
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Louisville
country: United States
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state: Kentucky
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Fridley
country: United States
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state: Minnesota
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Hackensack
country: United States
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state: New Jersey
city: Buffalo
country: United States
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state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Cincinnati
country: United States
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state: Ohio
city: Cleveland
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state: Ohio
city: Philadelphia
country: United States
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state: Pennsylvania
city: Philadelphia
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state: Pennsylvania
city: Pittsburgh
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state: Pennsylvania
city: Germantown
country: United States
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state: Tennessee
city: Knoxville
country: United States
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state: Tennessee
city: Nashville
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state: Tennessee
city: Dallas
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state: Texas
city: Murray
country: United States
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state: Utah
city: Salt Lake City
country: United States
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state: Utah
city: Seattle
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state: Washington
city: North Sydney
country: Australia
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state: New South Wales
city: Waratah
country: Australia
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state: New South Wales
city: Wollongong
country: Australia
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state: New South Wales
city: Southport
country: Australia
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state: Queensland
city: Woolloongabba
country: Australia
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state: Queensland
city: Woodville South
country: Australia
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state: South Australia
city: Geelong
country: Australia
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state: Victoria
city: Heidelberg
country: Australia
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state: Victoria
city: Melbourne
country: Australia
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state: Victoria
city: Prahran
country: Australia
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state: Victoria
city: Murdoch
country: Australia
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state: Western Australia
city: Graz
country: Austria
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city: Innsbruck
country: Austria
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city: Salzburg
country: Austria
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city: Wien
country: Austria
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Liege
country: Belgium
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city: Edmonton
country: Canada
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state: Alberta
city: Kingston
country: Canada
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state: Ontario
city: London
country: Canada
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state: Ontario
city: Ottawa
country: Canada
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state: Ontario
city: Toronto
country: Canada
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state: Ontario
city: Montreal
country: Canada
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state: Quebec
city: Quebec
country: Canada
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city: Brno
country: Czechia
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city: Olomouc
country: Czechia
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city: Ostrava-Poruba
country: Czechia
facility: Research Site
city: Praha 10
country: Czechia
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city: Praha 2
country: Czechia
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city: Praha 8
country: Czechia
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city: Helsinki
country: Finland
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city: Bordeaux Cedex
country: France
facility: Research Site
city: Grenoble Cedex 9
country: France
facility: Research Site
city: Lille
country: France
facility: Research Site
city: Lyon cedex 08
country: France
facility: Research Site
city: Marseille cedex 05
country: France
facility: Research Site
city: Nantes Cedex 1
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Pierre Benite Cedex
country: France
facility: Research Site
city: Toulouse cedex 9
country: France
facility: Research Site
city: Vandoeuvre les Nancy
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Dresden
country: Germany
facility: Research Site
city: Erlangen
country: Germany
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Heidelberg
country: Germany
facility: Research Site
city: Kiel
country: Germany
facility: Research Site
city: Leipzig
country: Germany
facility: Research Site
city: Mainz
country: Germany
facility: Research Site
city: Mannheim
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Regensburg
country: Germany
facility: Research Site
city: Tübingen
country: Germany
facility: Research Site
city: Würzburg
country: Germany
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Heraklion - Crete
country: Greece
facility: Research Site
city: Ioannina
country: Greece
facility: Research Site
city: Thessaloniki
country: Greece
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Pecs
country: Hungary
facility: Research Site
city: Szeged
country: Hungary
facility: Research Site
city: Bergamo
country: Italy
facility: Research Site
city: Brescia
country: Italy
facility: Research Site
city: Meldola FC
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Siena
country: Italy
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Groningen
country: Netherlands
facility: Research Site
city: Nijmegen
country: Netherlands
facility: Research Site
city: Bielsko-Biala
country: Poland
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Konin
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Szczecin
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Almada
country: Portugal
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Porto
country: Portugal
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: Groenkloof
country: South Africa
facility: Research Site
state: Gauteng
city: Johannesburg
country: South Africa
facility: Research Site
state: Gauteng
city: Parktown
country: South Africa
facility: Research Site
state: Gauteng
city: Kraaifontein
country: South Africa
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
state: Cataluña
city: Barcelona
country: Spain
facility: Research Site
state: Cataluña
city: Valencia
country: Spain
facility: Research Site
state: Comunidad Valenciana
city: Pamplona
country: Spain
facility: Research Site
state: Navarra
city: San Sebastian
country: Spain
facility: Research Site
state: País Vasco
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Bellinzona
country: Switzerland
facility: Research Site
city: Bern
country: Switzerland
facility: Research Site
city: Geneva 14
country: Switzerland
facility: Research Site
city: Lausanne
country: Switzerland
facility: Research Site
city: Zürich
country: Switzerland
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: Guildford
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Preston
country: United Kingdom
facility: Research Site
city: Southampton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: Watanabe D, Goshima F. Oncolytic Virotherapy by HSV. Adv Exp Med Biol. 2018;1045:63-84. doi: 10.1007/978-981-10-7230-7_4.