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Talimogene Laherparepvec With Pembrolizumab for Recurrent Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY232 / KEYNOTE-137) (MASTERKEY232)

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ClinicalTrials.gov Identifier: NCT02626000
Recruitment Status : Completed
First Posted : December 10, 2015
Results First Posted : June 10, 2019
Last Update Posted : September 24, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Amgen

Brief Summary:
The primary objective of this study was to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in adults with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)

Condition or disease Intervention/treatment Phase
Carcinoma of the Head and Neck Drug: Talimogene Laherparepvec Biological: Pembrolizumab Phase 1

Detailed Description:
This is a phase 1b/3, multicenter, clinical trial conducted in 2 parts (phase 1b and phase 3). In phase 1b talimogene laherparepvec is to be administered in combination with pembrolizumab to adults with recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). Dose limiting toxicity (DLT) is to be evaluated based on the first 18 DLT-evaluable participants. An expansion cohort of up to an additional 22 treated patients could be enrolled to further evaluate the safety and to estimate the efficacy of the combination of talimogene laherparepvec with pembrolizumab and to support a decision to initiate the phase 3 part of the study. The phase 3 part of the study is designed as a multicenter, randomized, doubleblind, placebo-controlled study to evaluate the efficacy, as assessed by overall survival, of treatment with talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab in adults with recurrent or metastatic SCCHN.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description: For Phase 1b there are no 'maskings' as it's open-label.
Primary Purpose: Treatment
Official Title: A Phase 1b/3 Multicenter, Randomized, Trial of Talimogene Laherparepvec in Combination With Pembrolizumab for the Treatment of Subjects With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Actual Study Start Date : April 6, 2016
Actual Primary Completion Date : November 2, 2017
Actual Study Completion Date : August 28, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Talimogene Laherparepvec + Pembrolizumab
Talimogene laherparepvec is administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 3 weeks after the initial dose and every 3 weeks (Q3W) thereafter. Pembrolizumab is administered by intravenous infusion at a dose of 200 mg Q3W after the initial dose. Participants are treated until complete response, no injectable lesions, confirmed disease progression, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first.
Drug: Talimogene Laherparepvec
The initial dose of talimogene laherparepvec is up to 8.0 mL of 10⁶ PFU/mL. Subsequent doses of talimogene laherparepvec are up to 8.0 mL of 10⁸ PFU/mL.
Other Name: IMLYGIC®

Biological: Pembrolizumab
Administered as a 30-minute intravenous infusion at a dose of 200 mg Q3W
Other Name: KEYTRUDA®




Primary Outcome Measures :
  1. Number of Participants With a Dose Limiting Toxicity (DLT) [ Time Frame: First 6 weeks after the initial administration of talimogene laherparepvec and pembrolizumab in combination ]

    The following toxicities (graded per the Common Terminology Criteria for Adverse Events v 4.0) were considered DLTs if judged by the investigator to be related to either study drug:

    • grade 4 non-hematologic (non-laboratory) toxicity
    • ≥ grade 3 pneumonitis
    • grade 3 non-hematologic toxicity for > 3 days with optimal supportive care
    • grade 3 fatigue was not classified as DLT, regardless of duration
    • any ≥ grade 3 non-hematologic laboratory value if:

      • medical intervention was required,
      • the abnormality led to hospitalization, or
      • the abnormality persisted at ≥ grade 3 for > 1 week unless deemed not clinically important by investigator and sponsor
    • grade 3 or 4 febrile neutropenia
    • thrombocytopenia < 25 x 10⁹/L associated with bleeding event requiring intervention
    • serious herpetic event: herpetic encephalitis, encephalomyelitis, or disseminated herpetic infection
    • grade 5 toxicity
    • other intolerable toxicity leading to permanent discontinuation of either study drug.


Secondary Outcome Measures :
  1. Objective Response Rate [ Time Frame: Up to the data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks. ]

    Objective response rate was defined as the percentage of participants with a best overall response of complete response or partial response assessed by the investigator using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Response was based on the size of tumors assessed by computed tomography (CT) or magnetic resonance imaging (MRI).

    Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

    Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Confirmation by a consecutive assessment at least 4 weeks after first documentation required.

    Analyses are presented below for both the unconfirmed and confirmed results.


  2. Complete Response Rate [ Time Frame: Up to the data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks. ]

    Complete response rate (iCRR) was defined as the percentage of participants with a best overall response of complete response assessed by the investigator using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Response was based on the size of tumors assessed by computed tomography (CT) or magnetic resonance imaging (MRI).

    Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

    Analyses are presented below for both the unconfirmed and confirmed results.


  3. Best Overall Confirmed Response [ Time Frame: Up to the data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks. ]

    Best overall visit response of iCR, iPR, stable disease (iSD), progressive disease (iPD) or unevaluable (iUE) based on investigator assessment using irRECIST.

    iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (target or non-target) must have reduction in short axis to <10 mm.

    iPR: Decrease in tumor size ≥ 30% relative to baseline. iPD: Increase in tumor size ≥ 20% and at least 5 mm absolute increase compared to nadir or qualitative worsening of non-target lesions or a new lesion.

    iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD.

    iUE: Any baseline lesion which was not assessed or was unable to be evaluated leading to an inability to determine the status of that particular tumor.

    Not Done: Radiographic imaging was not performed to evaluate the response. iCR, iPR, and iPD required confirmation by a consecutive assessment at least 4 weeks after first documentation.


  4. Duration of Confirmed Response [ Time Frame: Up to the data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks. ]
    Duration of response (iDOR) per irRECIST was defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of a participant overall response of iPD or death. Participants who did not end their response at the time of analysis were censored at their last evaluable tumor assessment.

  5. Disease Control Rate [ Time Frame: Up to the data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks. ]

    Disease control rate (iDCR) was defined as the percentage of participants with a best overall response of iCR or iPR or iSD assessed by the investigator using irRECIST.

    Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

    Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Confirmation by a consecutive assessment at least 4 weeks after first documentation required.

    Stable disease (iSD): Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD.

    Analyses are presented below for both the unconfirmed and confirmed results.


  6. Progression Free Survival [ Time Frame: Up to the data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks. ]
    Progression-free survival (iPFS) per irRECIST was defined as the interval from first dose to the earlier of a participant overall response of iPD or death from any cause; otherwise, iPFS was censored at the last evaluable tumor assessment. The initial date of an iPD that was consecutively confirmed was used.

  7. Overall Survival [ Time Frame: Up to the data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks. ]
    Overall survival (OS) was defined as the interval from first dose to the event of death from any cause; otherwise, OS was censored at the date the participant was last known to be alive.

  8. Number of Participants With Adverse Events [ Time Frame: From first dose of study drug to 30 days after last dose; As of 02 November 2017, the median (range) duration of treatment was 5.6 (0.1 to 57.1) weeks for talimogene laherparepvec and 6.1 (0.1, 63.1) weeks for pembrolizumab. ]

    The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and based on the following scale:

    Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Male or female age ≥ 18 years at the time of informed consent
  • Histologically confirmed diagnosis of metastatic or recurrent SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx. Disease must be unsuitable for curative surgical resection and must not be amenable to curative radiotherapy.
  • Disease must have progressed after treatment with a platinum-containing regimen and should be defined as one of the following:

    i. disease progression or recurrence between 3 to 6 months of prior curatively intended multimodal therapy (which includes platinum therapy) for locoregionally advanced SCCHN.

ii. disease progression or recurrence after prior platinum therapy in the recurrent or metastatic setting Note: This criterion is only applicable for subjects who have not had treatment in the recurrent/metastatic setting

  • Subject must be candidate for intralesional therapy administration defined as one or more of the following:

    i. at least 1 injectable cutaneous, subcutaneous, or nodal SCCHN tumor ≥ 10 mm in longest diameter ii. multiple injectable cutaneous, subcutaneous, or nodal SCCHN tumors that in aggregate have a longest diameter of ≥ 10 mm Note: Mucosal surfaces of tumor lesions and visceral metastases should not be injected.

  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Adequate organ function determined within 14 days prior to enrollment
  • Female subject of childbearing potential must have a negative pregnancy test within 72 hours prior to enrollment.
  • Other Inclusion Criteria May Apply

Exclusion Criteria

  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
  • Primary nasopharyngeal carcinoma.
  • Subject at risk of airway compromise in the event of postinjection tumor swelling/inflammation based on investigator judgment.
  • Phase 3: Previous treatment with 3 or more systemic regimens given for recurrent and/or metastatic disease
  • History of other malignancy within the past 3 years
  • History of interstitial lung disease (ILD).
  • Prior therapy with talimogene laherparepvec, pembrolizumab, other anti-PD-1, any other antibody or drug specifically targeting T-cell co-stimulation or immune check point pathway.
  • History or evidence of active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
  • Evidence of clinically significant immunosuppression
  • Active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis).
  • Requires intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
  • Prior chemotherapy, radiotherapy, biological cancer therapy, targeted therapy, or major surgery within 28 days prior to enrollment or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or better from adverse event due to cancer therapy administered more than 28 days prior to enrollment.
  • Expected to require other cancer therapy while on study with the exception of local palliative radiation treatment to the site of bone and other metastasis.
  • Known human immunodeficiency virus (HIV) disease.
  • Has acute or chronic active hepatitis B virus or hepatitis C virus infection or received treatment with nucleotide analogs such as those used in the treatment of hepatitis B virus (eg, lamivudine, adefovir, tenofovir, telbivudine, entecavir), ribavirin, or interferon alpha within 12 weeks of initiation of study treatment.
  • Received live vaccine within 28 days prior to enrollment.
  • Subject is pregnant or breast-feeding, or expecting to conceive or father children within the duration of the trial
  • Female subject of childbearing potential or male subject of reproductive potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 3 months after the last dose of talimogene laherparepvec/placebo or 4 months after the last dose of pembrolizumab, whichever is later.
  • Sexually active subjects or their partners unwilling to use male or female latex condom to avoid potential viral transmission during sexual contact while on treatment and within 30 days after treatment with talimogene laherparepvec/placebo.
  • Subject who is unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for herpes simplex virus type 1 (HSV-1)-induced complications (eg, immunosuppressed individuals, HIV-positive individuals, pregnant women, or children under the age of 1 year) during talimogene laherparepvec treatment and through 30 days after the last dose of talimogene laherparepvec
  • Has history of (non-infectious) pneumonitis that required steriods or current pneumonitis
  • Subjects with tumor that directly contacts or encases a major blood vessel AND there is ulceration and/or fungation onto the skin surface
  • History of re-irradiation to a field which includes the carotid arteries
  • Other Exclusion Criteria May Apply

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02626000


Locations
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United States, Delaware
Research Site
Newark, Delaware, United States, 19713
United States, Illinois
Research Site
Chicago, Illinois, United States, 60611
Research Site
Chicago, Illinois, United States, 60637
United States, Kentucky
Research Site
Louisville, Kentucky, United States, 40202
United States, Montana
Research Site
Billings, Montana, United States, 59101
United States, New York
Research Site
New York, New York, United States, 10003
Research Site
New York, New York, United States, 10021
United States, Ohio
Research Site
Canton, Ohio, United States, 44718
Australia, Victoria
Research Site
Geelong, Victoria, Australia, 3220
Research Site
Melbourne, Victoria, Australia, 3000
Austria
Research Site
Salzburg, Austria, 5020
Belgium
Research Site
Bruxelles, Belgium, 1000
Research Site
Wilrijk, Belgium, 2610
Canada, Ontario
Research Site
Toronto, Ontario, Canada, M5G 2M9
France
Research Site
Bordeaux, France, 33076
Research Site
Pierre-Benite, France, 69495
Research Site
Toulouse cedex 9, France, 31059
Greece
Research Site
Athens, Greece, 12462
Research Site
Ioannina, Greece, 45500
Italy
Research Site
Milano, Italy, 20133
Spain
Research Site
Sevilla, Andalucía, Spain, 41013
Research Site
L'Hospitalet de Llobregat, Cataluña, Spain, 08907
Research Site
Madrid, Spain, 28046
Research Site
Madrid, Spain, 28050
Switzerland
Research Site
Bellinzona, Switzerland, 6500
Research Site
Geneva 14, Switzerland, 1211
Research Site
Zurich, Switzerland, 8091
United Kingdom
Research Site
Birmingham, United Kingdom, B15 2TT
Research Site
London, United Kingdom, SE1 7EH
Research Site
London, United Kingdom, SW3 6JJ
Research Site
Oxford, United Kingdom, OX3 7LE
Research Site
Sutton, United Kingdom, SM2 5PT
Research Site
Wirral, United Kingdom, CH63 4JY
Sponsors and Collaborators
Amgen
Merck Sharp & Dohme Corp.
Investigators
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Study Director: MD Amgen
  Study Documents (Full-Text)

Documents provided by Amgen:
Study Protocol  [PDF] May 11, 2018
Statistical Analysis Plan  [PDF] August 28, 2018

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT02626000    
Other Study ID Numbers: 20130232
20130232 / KEYNOTE-137 ( Other Identifier: Merck / Amgen )
2015-003011-38 ( EudraCT Number )
First Posted: December 10, 2015    Key Record Dates
Results First Posted: June 10, 2019
Last Update Posted: September 24, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Amgen:
Recurrent Metastatic Squamous Cell Carcinoma Head and Neck
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Pembrolizumab
Talimogene laherparepvec
Antineoplastic Agents, Immunological
Antineoplastic Agents