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Pembrolizumab With or Without Talimogene Laherparepvec or Talimogene Laherparepvec Placebo in Unresected Melanoma (KEYNOTE-034)

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ClinicalTrials.gov Identifier: NCT02263508
Recruitment Status : Active, not recruiting
First Posted : October 13, 2014
Last Update Posted : December 19, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Amgen

Tracking Information
First Submitted Date  ICMJE September 26, 2014
First Posted Date  ICMJE October 13, 2014
Last Update Posted Date December 19, 2018
Actual Study Start Date  ICMJE December 8, 2014
Estimated Primary Completion Date July 29, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 26, 2017)
  • Incidence of dose limiting toxicities (DLT) [ Time Frame: Start of treatment until 6 weeks from the initial administration of pembrolizumab (MK-3475) ]
    Phase 1b: To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab (MK-3475)
  • Progression Free Survival (PFS) (response evaluation by blinded central review assessed modified RECIST 1.1) [ Time Frame: up to 44 months ]
    Phase 3: 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 1.1 [RECIST]).
  • Overall Survival [ Time Frame: up to 62 months ]
    Phase 3: To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by overall survival (OS).
Original Primary Outcome Measures  ICMJE
 (submitted: October 9, 2014)
  • Incidence of dose limiting toxicities (DLT) [ Time Frame: Start of treatment until 6 weeks from the initial administration of MK-3475 ]
    Phase 1b: To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with MK-3475
  • Confirmed objective response rate (ORR) (Phase 2) [ Time Frame: Week 24 of treatment ]
    Phase 2 part 1: to evaluate the efficacy, as assessed by confirmed ORR of treatment with talimogene laherparepvec in combination with MK-3475 as compared to MK-3475 alone Phase 2 part 2: to evaluate the efficacy, as assessed by confirmed ORR of treatment with talimogene laherparepvec in combination with MK-3475 following progression on MK-3475 alone in Phase 2 part 1
Change History Complete list of historical versions of study NCT02263508 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2017)
  • Incidence of adverse events (AEs) [ Time Frame: Start of treatment to 30 (+7) days after end of treatment ]
    Incidence of treatment-emergent and treatment-related adverse events and abnormal laboratory tests (all AEs, grade ≥ 3 AEs, serious adverse events, fatal AEs, and AEs defined as events of interest)
  • Objective Response Rate (ORR) [ Time Frame: Start of treatment and every 12 weeks until confirmed disease progression, assessed up to 60 months ]
    To evaluate the efficacy, as assessed by ORR of treatment with talimogene laherparepvec in combination with pembrolizumab in Phase 1b and talimogene laherparepvec in combination with pembrolizumab verses placebo in Phase 3.
  • Best overall response (BOR) [ Time Frame: Start of treatment and every 12 weeks until confirmed disease progression, assessed up to 60 months ]
    To be assessed for Phase 3
  • Durable response rate (DRR) defined as rate of objective responses for a duration of 6 months or longer [ Time Frame: Start of treatment and every 12 weeks until confirmed disease progression, assessed up to 60 months ]
    To be assessed for Phase 1b, Phase 3
  • Duration of response (DOR) [ Time Frame: Start of treatment and every 12 weeks until confirmed disease progression, assessed up to 60 months ]
    To be assessed for Phase 1b, Phase 3
  • Disease Control Rate (DCR) [ Time Frame: Start of treatment and every 12 weeks until confirmed disease progression, assessed up to 60 months ]
    To be assessed for Phase 1b, Phase 3
  • Overall survival (OS) [ Time Frame: Start of treatment and every 12 weeks during long term follow up until 60 months after last subject enrolled. Calculated from date of Randomization to date of death. ]
    To be assessed for Phase 1b, Phase 3
  • As assessed by the QLQ-C30 subject questionnaires [ Time Frame: weeks 0, then every 3, 6, 9, 12 weeks then every 6 weeks until the end of the study and at safety follow up, assessed up to 60 months ]
    Phase 3: To evaluate patient reported outcomes (PRO)
  • Complete response rate (CRR) [ Time Frame: Start of treatment and every 12 weeks until confirmed disease progression, assessed up to 60 months ]
    by blinded independent central assessed modified immune-related response criteria simulating response evaluation criteria in solid tumors for Phase 3
Original Secondary Outcome Measures  ICMJE
 (submitted: October 9, 2014)
  • Incidence of adverse events (AEs) [ Time Frame: Start of treatment to 30 (+7) days after end of treatment ]
    Incidence of treatment-emergent and treatment-related adverse events (all AEs, grade ≥ 3 AEs, serious adverse events, fatal AEs, and AEs defined as events of interest)
  • ORR (Phase 1b) [ Time Frame: Week 24 of treatment ]
    Phase 1b: to evaluate the efficacy, as assessed by ORR of treatment with talimogene laherparepvec in combination with MK-3475
  • Best overall response (BOR) [ Time Frame: Start of treatment until 36 months after the last subject enrolled in Phase 2 ]
    To be assessed for Phase 1b, Phase 2 part 1, and Phase 2 part 2
  • Durable response rate (DRR) defined as rate of objective responses for a duration of 6 months or longer [ Time Frame: Start of treatment until 36 months after the last subject enrolled in Phase 2 ]
    To be assessed for Phase 1b, Phase 2 part 1, and Phase 2 part 2
  • Duration of response (DOR) [ Time Frame: Start of treatment until 36 months after the last subject enrolled in Phase 2 ]
    To be assessed for Phase 1b, Phase2 part 1, and Phase 2 part 2
  • Ordinal categorical response score [ Time Frame: Start of treatment until 36 months after the last subject enrolled in Phase 2 ]
    To be assessed for Phase 1b, Phase 2 part 1, and Phase 2 part 2
  • Progression-free survival (PFS) [ Time Frame: Start of treatment until 36 months after the last subject enrolled in Phase 2 ]
    To be assessed for Phase 1b, Phase 2 part 1, and Phase 2 part 2
  • Overall survival (OS) [ Time Frame: Start of treatment until 36 months after the last subject enrolled in phase 2 ]
    To be assessed for Phase 1b, Phase 2 part 1, and Phase 2 part 2
  • Incidence of anti-MK-3475 antibodies [ Time Frame: Before first MK-3475 dose and, 2, 8, 16, 24 and every 12 weeks thereafter, at 30 (+7) days after end of treatment, at 3 and 6 months after study discontinuation or until new anticancer treatment started, whichever is first. ]
    From blood samples obtained prior to MK-3475 dosing in Phase 1b, Phase 2 part 1, and Phase 2 part 2
  • Lowest plasma concentration (Cmin) of MK-3475 [ Time Frame: Before first MK-3475 dose and 0, 2, 8, 16, 24 and every 12 weeks thereafter, at 30 (+7) days after end of treatment, at 3 and 6 months after study discontinuation or until new anticancer treatment started, whichever is first. ]
    From blood samples obtained prior to MK-3475 dosing in Phase 1b, Phase 2 part 1, and Phase 2 part 2
  • Maximum concentration (Cmax) or MK-3475 [ Time Frame: 30 minutes after first dose of MK-3475 ]
    From blood sample obtained after first MK-3475 dose in Phase 1b, Phase 2 part 1, and Phase 2 part 2
  • Area under the curve (AUC) of MK-3475 [ Time Frame: First dose of MK-3475 to second dose ]
    From blood samples obtained during first cycle of MK-3475 in Phase 1b, Phase 2 part 1, and Phase 2 part 2
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pembrolizumab With or Without Talimogene Laherparepvec or Talimogene Laherparepvec Placebo in Unresected Melanoma (KEYNOTE-034)
Official Title  ICMJE 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/KEYNOTE-034)
Brief Summary Phase 1b Subjects will be treated with talimogene laherparepvec until all injectable tumors have disappeared, disease progression per modified Immune-Related Response Criteria (irRC), or intolerance of study treatment, up to a maximum of 24 months of study treatment. Subjects will be treated with MK-3475 (pembrolizumab) until complete response (CR) disease progression per irRC, or intolerance of study treatment, up to a maximum of 24 months of study treatment. In Phase 3, Subjects will be treated with talimogene laherparepvec plus pembrolizumab(arm 1) or placebo plus pembrolizumab (arm 2) until 24 months from the date of the first dose of pembrolizumab or end of treatment due to disappearance of injectable lesions, complete response, disease progression per irRC-RECIST or intolerance of study treatment.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE
  • Drug: talimogene laherparepvec
    Phase 1b: talimogene laherparepvec will be administered by intralesional injection at Day 1, Week -5; then every 2 weeks starting at Day 1, Week -2; Phase 3, Arm 1 talimogene laherparepvec will be administered by intralesional injection at Day 1 Week 0, 3, 5, 7 then every 3 weeks starting at Day 1 Week 9.
  • Drug: pembrolizumab (MK-3475)
    Phase 1b: pembrolizumab will be administered intravenously every 2 weeks starting at Day 1 Week 0; Phase 3, Arm 1 and Arm 2 pembrolizumab will be administered intravenously on Day 1 Week 0, then every 3 weeks starting at Day 1 Week 3.
  • Drug: placebo
    Phase 3, Arm 2 placebo will be administered by intralesional injection at Day 1 Week 0, 3, 5, 7 then every 3 weeks starting at Day 1 Week 9.
Study Arms  ICMJE
  • Experimental: Phase 1b;
    Phase 1b: talimogene laherparepvec and pembrolizumab (MK-3475)
    Interventions:
    • Drug: talimogene laherparepvec
    • Drug: pembrolizumab (MK-3475)
  • Experimental: Phase 3 Arm 1;
    Phase 3 Arm 1: talimogene laherparepvec and pembrolizumab (MK-3475)
    Interventions:
    • Drug: talimogene laherparepvec
    • Drug: pembrolizumab (MK-3475)
  • Experimental: Phase 3 Arm 2;
    Phase 3 Arm 2: placebo and pembrolizumab (MK-3475)
    Interventions:
    • Drug: pembrolizumab (MK-3475)
    • Drug: placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 4, 2018)
713
Original Estimated Enrollment  ICMJE
 (submitted: October 9, 2014)
110
Estimated Study Completion Date  ICMJE April 28, 2023
Estimated Primary Completion Date July 29, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
  • ECOG performance status of 0 or 1.
  • Adequate hematologic, hepatic, renal, and coagulation function.
  • Subjects with 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 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 95 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   Czechia,   Finland,   France,   Germany,   Greece,   Hungary,   Italy,   Korea, Republic of,   Netherlands,   Poland,   Portugal,   Russian Federation,   South Africa,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02263508
Other Study ID Numbers  ICMJE 20110265
2014-000185-22 ( EudraCT Number )
KEYNOTE-034 ( Other Identifier: Merck Sharp & Dohme Corp. )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (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.
URL: https://www.amgen.com/datasharing
Responsible Party Amgen
Study Sponsor  ICMJE Amgen
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Study Director: MD Amgen
PRS Account Amgen
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP