Pembrolizumab With Talimogene Laherparepvec or Placebo in Unresected Melanoma
MASTERKEY-265
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)
3 other identifiers
interventional
713
20 countries
150
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).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Dec 2014
Longer than P75 for phase_3
150 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 26, 2014
CompletedFirst Posted
Study publicly available on registry
October 13, 2014
CompletedStudy Start
First participant enrolled
December 8, 2014
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 11, 2021
CompletedStudy Completion
Last participant's last visit for all outcomes
March 11, 2021
CompletedResults Posted
Study results publicly available
May 16, 2022
CompletedNovember 14, 2022
November 1, 2022
6.3 years
September 26, 2014
March 8, 2022
November 10, 2022
Conditions
Keywords
Outcome Measures
Primary Outcomes (3)
Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)
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.
The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).
Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1
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).
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.
Phase 3: Overall Survival
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.
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 (22)
Phase 1b: Objective Response Rate (ORR)
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.
Phase 1b: Best Overall Response (BOR)
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.
Phase 1b: Durable Response Rate (DRR)
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.
Phase 1b: Duration of Response (DOR)
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.
Phase 1b: Disease Control Rate (DCR)
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.
- +17 more secondary outcomes
Study Arms (3)
Phase 1b: Talimogene Laherparepvec + Pembrolizumab
EXPERIMENTALParticipants 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.
Phase 3 : Placebo + Pembrolizumab
PLACEBO COMPARATORParticipants 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.
Phase 3: Talimogene Laherparepvec + Pembrolizumab
EXPERIMENTALParticipants 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.
Interventions
Talimogene laherparepvec administered by intratumoral injection
Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Amgenlead
- Merck Sharp & Dohme LLCcollaborator
Study Sites (161)
Research Site
Birmingham, Alabama, 35243, United States
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Mobile, Alabama, 36608, United States
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Beverly Hills, California, 90211, United States
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Duarte, California, 91010, United States
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Encinitas, California, 92024, United States
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La Jolla, California, 92037, United States
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Los Angeles, California, 90024, United States
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Los Angeles, California, 90025, United States
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Riverside, California, 92505, United States
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San Francisco, California, 94115, United States
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San Francisco, California, 94117, United States
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Santa Monica, California, 90404, United States
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Miami, Florida, 33136, United States
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Miami Beach, Florida, 33140, United States
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Orlando, Florida, 32806, United States
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Atlanta, Georgia, 30322, United States
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Chicago, Illinois, 60611, United States
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Chicago, Illinois, 60637, United States
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Louisville, Kentucky, 40202, United States
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Baltimore, Maryland, 21237, United States
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Boston, Massachusetts, 02215, United States
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Detroit, Michigan, 48201, United States
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Fridley, Minnesota, 55432, United States
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St Louis, Missouri, 63110-1093, United States
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Hackensack, New Jersey, 07601, United States
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Buffalo, New York, 14263, United States
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New York, New York, 10016, United States
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New York, New York, 10032, United States
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New York, New York, 10065, United States
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Cincinnati, Ohio, 45209, United States
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Cleveland, Ohio, 44195, United States
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Philadelphia, Pennsylvania, 19107, United States
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Philadelphia, Pennsylvania, 19111, United States
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Pittsburgh, Pennsylvania, 15232, United States
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Germantown, Tennessee, 38138, United States
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Knoxville, Tennessee, 37920, United States
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Nashville, Tennessee, 37232, United States
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Dallas, Texas, 75246, United States
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Murray, Utah, 84107, United States
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Salt Lake City, Utah, 84112, United States
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Seattle, Washington, 98109-1023, United States
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North Sydney, New South Wales, 2060, Australia
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Waratah, New South Wales, 2298, Australia
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Wollongong, New South Wales, 2500, Australia
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Southport, Queensland, 4215, Australia
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Woolloongabba, Queensland, 4102, Australia
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Woodville South, South Australia, 5011, Australia
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Geelong, Victoria, 3220, Australia
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Heidelberg, Victoria, 3084, Australia
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Melbourne, Victoria, 3000, Australia
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Prahran, Victoria, 3181, Australia
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Murdoch, Western Australia, 6150, Australia
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Graz, 8036, Austria
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Innsbruck, 6020, Austria
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Salzburg, 5020, Austria
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Vienna, 1090, Austria
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Brussels, 1200, Belgium
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Liège, 4000, Belgium
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Edmonton, Alberta, T6G 1Z2, Canada
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Kingston, Ontario, K7L 2V7, Canada
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London, Ontario, N6A 4L6, Canada
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Ottawa, Ontario, K1H 8L6, Canada
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Toronto, Ontario, M5G 2M9, Canada
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Montreal, Quebec, H3T 1E2, Canada
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Québec, Quebec, G1R 2J6, Canada
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Brno, 656 53, Czechia
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Olomouc, 775 20, Czechia
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Ostrava-Poruba, 708 52, Czechia
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Prague, 100 34, Czechia
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Prague, 128 08, Czechia
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Prague, 180 81, Czechia
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Helsinki, 00290, Finland
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Bordeaux, 33075, France
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Grenoble, 38043, France
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Lille, 59037, France
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Lyon, 69373, France
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Marseille, 13385, France
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Nantes, 44093, France
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Paris, 75010, France
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Pierre-Bénite, 69495, France
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Toulouse, 31059, France
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Vandœuvre-lès-Nancy, 54511, France
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Berlin, 10117, Germany
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Dresden, 01307, Germany
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Erlangen, 91054, Germany
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Essen, 45147, Germany
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Hanover, 30625, Germany
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Heidelberg, 69120, Germany
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Kiel, 24105, Germany
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Leipzig, 04103, Germany
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Mainz, 55131, Germany
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Mannheim, 68167, Germany
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München, 80337, Germany
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Regensburg, 93053, Germany
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Tübingen, 72076, Germany
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Würzburg, 97080, Germany
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Athens, 11527, Greece
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Athens, 18547, Greece
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Heraklion - Crete, 71110, Greece
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Ioannina, 45500, Greece
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Thessaloniki, 54622, Greece
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Budapest, 1122, Hungary
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Pécs, 7632, Hungary
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Szeged, 6720, Hungary
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Bergamo, 24127, Italy
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Brescia, 25123, Italy
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Meldola FC, 47014, Italy
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Milan, 20133, Italy
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Milan, 20141, Italy
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Siena, 53100, Italy
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Amsterdam, 1066 CX, Netherlands
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Amsterdam, 1081 HV, Netherlands
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Groningen, 9713 GZ, Netherlands
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Nijmegen, 6525 GA, Netherlands
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Bielsko-Biala, 43-300, Poland
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Bydgoszcz, 85-796, Poland
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Gdansk, 80-952, Poland
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Konin, 62-500, Poland
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Krakow, 31-501, Poland
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Poznan, 60-848, Poland
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Poznan, 61-866, Poland
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Szczecin, 71-730, Poland
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Warsaw, 02-781, Poland
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Wroclaw, 50-368, Poland
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Almada, 2801-951, Portugal
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Lisbon, 1099-023, Portugal
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Lisbon, 1649-035, Portugal
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Porto, 4200-072, Portugal
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Moscow, 115478, Russia
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Saint Petersburg, 197758, Russia
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Groenkloof, Gauteng, 0181, South Africa
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Johannesburg, Gauteng, 2196, South Africa
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Parktown, Gauteng, 2193, South Africa
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Kraaifontein, 7570, South Africa
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Pretoria, 0002, South Africa
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Pretoria, 0081, South Africa
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Seoul, 03722, South Korea
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Seoul, 05505, South Korea
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Donostia / San Sebastian, Basque Country, 20014, Spain
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Badalona, Catalonia, 08916, Spain
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Barcelona, Catalonia, 08036, Spain
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Pamplona, Navarre, 31008, Spain
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Valencia, Valencia, 46014, Spain
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Madrid, 28009, Spain
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Madrid, 28046, Spain
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Madrid, 28050, Spain
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Bellinzona, 6500, Switzerland
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Bern, 3010, Switzerland
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Geneva, 1211, Switzerland
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Lausanne, 1011, Switzerland
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Zurich, 8091, Switzerland
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Birmingham, B15 2TH, United Kingdom
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Guildford, GU2 7XX, United Kingdom
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Leeds, LS9 7TF, United Kingdom
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Leicester, LE1 5WW, United Kingdom
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London, SE1 9RT, United Kingdom
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London, SW3 6JJ, United Kingdom
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Manchester, M20 4BX, United Kingdom
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Oxford, OX3 7LJ, United Kingdom
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Preston, PR2 9HT, United Kingdom
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Southampton, SO16 6YD, United Kingdom
Related Publications (4)
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.
PMID: 28886381BACKGROUNDDummer 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.
PMID: 28238174BACKGROUNDChesney 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.
PMID: 35998300BACKGROUNDWatanabe D, Goshima F. Oncolytic Virotherapy by HSV. Adv Exp Med Biol. 2018;1045:63-84. doi: 10.1007/978-981-10-7230-7_4.
PMID: 29896663DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Results Point of Contact
- Title
- Study Director
- Organization
- Amgen Inc.
Study Officials
- STUDY DIRECTOR
MD
Amgen
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
September 26, 2014
First Posted
October 13, 2014
Study Start
December 8, 2014
Primary Completion
March 11, 2021
Study Completion
March 11, 2021
Last Updated
November 14, 2022
Results First Posted
May 16, 2022
Record last verified: 2022-11
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF, CSR
- Time Frame
- Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
- Access Criteria
- Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request