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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02626000
Registration number
NCT02626000
Ethics application status
Date submitted
18/11/2015
Date registered
10/12/2015
Date last updated
8/09/2021
Titles & IDs
Public title
Talimogene Laherparepvec With Pembrolizumab for Recurrent Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY232 / KEYNOTE-137)
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Scientific 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
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Secondary ID [1]
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20130232 / KEYNOTE-137
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Secondary ID [2]
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20130232
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Universal Trial Number (UTN)
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Trial acronym
MASTERKEY232
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Carcinoma of the Head and Neck
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Condition category
Condition code
Cancer
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Non melanoma skin cancer
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Cancer
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Kidney
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Cancer
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Head and neck
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Talimogene Laherparepvec
Other interventions - Pembrolizumab
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.
Treatment: Drugs: 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 interventions: Pembrolizumab
Administered as a 30-minute intravenous infusion at a dose of 200 mg Q3W
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With a Dose Limiting Toxicity (DLT)
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Assessment method [1]
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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 10?/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.
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Timepoint [1]
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First 6 weeks after the initial administration of talimogene laherparepvec and pembrolizumab in combination
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Secondary outcome [1]
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Objective Response Rate
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Assessment method [1]
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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.
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Timepoint [1]
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Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.
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Secondary outcome [2]
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Complete Response Rate
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Assessment method [2]
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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.
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Timepoint [2]
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Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.
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Secondary outcome [3]
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Best Overall Confirmed Response
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Assessment method [3]
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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.
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Timepoint [3]
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Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.
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Secondary outcome [4]
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Duration of Confirmed Response
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Assessment method [4]
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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.
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Timepoint [4]
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Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.
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Secondary outcome [5]
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Disease Control Rate
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Assessment method [5]
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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.
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Timepoint [5]
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Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.
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Secondary outcome [6]
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Progression Free Survival
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Assessment method [6]
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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.
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Timepoint [6]
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Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.
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Secondary outcome [7]
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Overall Survival
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Assessment method [7]
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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.
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Timepoint [7]
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Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.
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Secondary outcome [8]
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Number of Participants With Adverse Events
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Assessment method [8]
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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.
A serious adverse event is an AE that met at least 1 of the following serious criteria:
fatal
life threatening
required in-patient hospitalization or prolongation of existing hospitalization
resulted in persistent or significant disability/incapacity
congenital anomaly/birth defect
other medically important serious event.
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Timepoint [8]
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From first dose of study drug to 30 days after last dose; the median (range) duration of treatment was 5.6 (0.1 to 75.3) weeks for talimogene laherparepvec and 6.1 (0.1, 105.3) weeks for pembrolizumab.
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Eligibility
Key inclusion 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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
6/04/2016
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
28/08/2020
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Sample size
Target
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Accrual to date
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Final
36
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Research Site - Geelong
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Recruitment hospital [2]
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Research Site - Melbourne
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Recruitment postcode(s) [1]
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3220 - Geelong
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Recruitment postcode(s) [2]
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3000 - Melbourne
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Recruitment outside Australia
Country [1]
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United States of America
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Delaware
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United States of America
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Illinois
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United States of America
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Kentucky
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United States of America
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Montana
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United States of America
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New York
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United States of America
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Ohio
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Austria
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Salzburg
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Belgium
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Bruxelles
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Belgium
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Wilrijk
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Canada
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Ontario
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France
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Bordeaux
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France
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Pierre-Benite
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France
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Toulouse cedex 9
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Greece
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Athens
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Greece
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Ioannina
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Italy
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Milano
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Spain
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Andalucía
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Spain
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Cataluña
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Spain
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Madrid
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Switzerland
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Bellinzona
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Switzerland
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Geneva 14
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Switzerland
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Zurich
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United Kingdom
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Birmingham
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United Kingdom
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London
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United Kingdom
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Oxford
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United Kingdom
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Sutton
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United Kingdom
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Wirral
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Amgen
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Address
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Merck Sharp & Dohme LLC
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Address [1]
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Ethics approval
Ethics application status
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Summary
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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02626000
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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MD
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Address
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Amgen
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02626000
Download to PDF