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Efficacy and Safety Study of Talimogene Laherparepvec Compared to Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) in Melanoma

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ClinicalTrials.gov Identifier: NCT00769704
Recruitment Status : Completed
First Posted : October 9, 2008
Results First Posted : December 17, 2015
Last Update Posted : July 13, 2016
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
BioVex Limited

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Melanoma
Interventions Biological: Talimogene laherparepvec
Biological: GM-CSF
Enrollment 437
Recruitment Details

Eligible patients were adults with histologically confirmed, not surgically resectable, stage IIIB - IV melanoma suitable for direct or ultrasound-guided injection.

Among those randomized, the first patient enrolled 29 April 2009 and last patient enrolled 8 June 2011.

1 patient randomized 3 times is counted once under talimogene laherparepvec.

Pre-assignment Details Patients were assigned at a 2:1 ratio using central random assignment to receive intralesional talimogene laherparepvec or subcutaneous granulocyte macrophage colony-stimulating factor (GM-CSF). Randomization was stratified by site of first recurrence, presence of liver metastases, disease stage, and prior nonadjuvant systemic treatment.
Arm/Group Title GM-CSF Talimogene Laherparepvec
Hide Arm/Group Description Granulocyte macrophage colony-stimulating factor (GM-CSF) was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months. Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose of talimogene laherparepvec was at a concentration of 10⁶ plaque forming units (PFU)/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
Period Title: Overall Study
Started 141 296
Intent-to-treat Population 141 [1] 295 [2]
Received Treatment 127 292
Completed 30 97
Not Completed 111 199
Reason Not Completed
Lost to Follow-up             3             2
Death             95             190
Withdrawal by Subject             12             5
Other             1             2
[1]
All participants who were randomized once to study treatment
[2]
Participants who were randomized once to study treatment; excludes 1 participant randomized 3 times
Arm/Group Title GM-CSF Talimogene Laherparepvec Total
Hide Arm/Group Description GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months. Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months. Total of all reporting groups
Overall Number of Baseline Participants 141 296 437
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 141 participants 296 participants 437 participants
62.92  (14.13) 63.07  (13.68) 63.03  (13.81)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 141 participants 296 participants 437 participants
Female
64
  45.4%
123
  41.6%
187
  42.8%
Male
77
  54.6%
173
  58.4%
250
  57.2%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 141 participants 296 participants 437 participants
White 138 290 428
Black 2 1 3
Asian 0 1 1
Native Hawaiian or Other Pacific Islander 0 1 1
Other 1 3 4
Eastern Cooperative Oncology Group (ECOG) Performance Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 141 participants 296 participants 437 participants
0 97 210 307
1 32 82 114
Missing 12 4 16
[1]
Measure Description: Scale used to assess how a patient's disease is progressing, how the disease affects the daily living abilities of the patient: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory, able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self care, confined to a bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
Tumor, Node, Metastasis (TNM) Disease Stage   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 141 participants 296 participants 437 participants
Stage IIIB 12 22 34
Stage IIIC 31 66 97
Stage IV M1a 43 76 119
Stage IV M1b 26 64 90
Stage IV M1c 29 67 96
Missing 0 1 1
[1]
Measure Description: Stage IIIB: Ulcerated lesion and 1 lymph node or 2-3 nodes with micrometastasis, or any-depth lesion with no ulceration, and 1 lymph node or 2-3 nodes with macrometastasis; Stage IIIC: Ulcerated lesion and 1 lymph node with macrometastasis; 2-3 nodes with macrometastasis or ≥4 metastatic lymph nodes, matted lymph nodes, or in-transit met(s)/satellite(s); Stage IV: M1a: Spread to skin, subcutaneous tissue, or lymph nodes; normal lactate dehydrogenase (LDH) level; M1b: Spread to lungs, normal LDH; M1c: Spread to all other visceral organs, normal LDH or any distant disease with elevated LDH.
Line of Therapy  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 141 participants 296 participants 437 participants
First Line 65 138 203
Second Line or Greater 76 158 234
1.Primary Outcome
Title Durable Response Rate
Hide Description

Durable response rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) maintained continuously for at least 6 months from the time the objective response was first observed and initiating within 12 months of starting therapy as assessed by the Endpoint Assessment Committee (EAC). This reflects all new sites of disease as well as disease sites identified at baseline.

Disease assessments were performed at the beginning of each treatment cycle in accordance with modified World Health Organization criteria.

CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline.

Time Frame From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population (all participants randomized to receive study treatment), excluding one participant who was randomized three times.
Arm/Group Title GM-CSF Talimogene Laherparepvec
Hide Arm/Group Description:
GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.
Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
Overall Number of Participants Analyzed 141 295
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
2.1
(0.0 to 4.5)
16.3
(12.1 to 20.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GM-CSF, Talimogene Laherparepvec
Comments The null hypothesis was that there was no difference in the durable response rate between the talimogene laherparepvec and control arms. Study success was defined as the rejection of this hypothesis such that talimogene laherparepvec was found to be superior to GM-CSF using the 2-sided Fisher’s exact test, with a p-value of ≤ 0.0488.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 14.1
Confidence Interval (2-Sided) 95%
9.3 to 19.0
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Overall Survival
Hide Description Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival time was censored at the last date the patient was known to be alive when the confirmation of death was absent or unknown. Participants were censored at the date of randomization if no additional follow-up data were obtained.
Time Frame From randomization until the first 290 survival events had occurred (data cut-off date of 31 March 2014); median time on follow-up was 44 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title GM-CSF Talimogene Laherparepvec
Hide Arm/Group Description:
GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.
Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
Overall Number of Participants Analyzed 141 295
Median (95% Confidence Interval)
Unit of Measure: months
18.9
(16.0 to 23.7)
23.3
(19.5 to 29.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GM-CSF, Talimogene Laherparepvec
Comments The primary method for analysis of overall survival was an unadjusted log-rank test. Testing of overall survival was conditional on a statistically significance difference in the primary endpoint of durable response. Success was defined as a p-value ≤ 0.05.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0511
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.62 to 1.00
Estimation Comments The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average death rate and a longer overall survival for talimogene laherparepvec relative to GM-CSF.
3.Secondary Outcome
Title Objective Response Rate
Hide Description

Objective response rate was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed by the Endpoint Assessment Committee (EAC). Best overall response for a patient is the best overall response observed across all time points.

Disease assessments were performed at the beginning of each treatment cycle and assessed in accordance with modified World Health Organization criteria.

CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline.

Time Frame From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title GM-CSF Talimogene Laherparepvec
Hide Arm/Group Description:
GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.
Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
Overall Number of Participants Analyzed 141 295
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
5.7
(1.9 to 9.5)
26.4
(21.4 to 31.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GM-CSF, Talimogene Laherparepvec
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Descriptive
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 20.8
Confidence Interval (2-Sided) 95%
14.4 to 27.1
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Duration of Response
Hide Description The duration of response is defined as the longest individual period from entering response (CR or PR as assessed by the EAC) to the first documented evidence of the patient no longer meeting the criteria for being in response or death, whichever is earlier. Responses were censored at the last assessment showing response.
Time Frame From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with an objective response (CR or PR) per EAC assessment.
Arm/Group Title GM-CSF Talimogene Laherparepvec
Hide Arm/Group Description:
GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.
Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
Overall Number of Participants Analyzed 8 78
Median (95% Confidence Interval)
Unit of Measure: months
2.8 [1] 
(1.2 to NA)
NA [1] 
(NA to NA)
[1]
Could not be estimated due to the low number of events
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GM-CSF, Talimogene Laherparepvec
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0868
Comments Descriptive
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.40
Confidence Interval (2-Sided) 95%
0.14 to 1.18
Estimation Comments The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a longer average duration of response for talimogene laherparepvec relative to GM-CSF.
5.Secondary Outcome
Title Response Onset
Hide Description Response onset is defined as the time from the date of randomization to the date of the first documented evidence of response (CR or PR) per EAC assessment.
Time Frame From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with an objective response (CR or PR) per EAC assessment.
Arm/Group Title GM-CSF Talimogene Laherparepvec
Hide Arm/Group Description:
GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.
Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
Overall Number of Participants Analyzed 8 78
Median (95% Confidence Interval)
Unit of Measure: months
3.7
(1.9 to 5.6)
4.1
(3.8 to 5.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GM-CSF, Talimogene Laherparepvec
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2020
Comments Descriptive
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.30 to 1.30
Estimation Comments The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio > 1.0 indicates a a higher average response onset rate for talimogene laherparepvec relative to GM-CSF.
6.Secondary Outcome
Title Time to Treatment Failure
Hide Description

Time to treatment failure was assessed by the investigator, and calculated from randomization until the first clinically relevant disease progression where there is no response achieved after the progression, or until death if no such progression occurs. Participants who did not have clinically relevant progression or did not die were censored at the time of the their last tumor assessment. Participants who withdrew from treatment due to a clinically unacceptable toxicity were not considered as an event in the analysis.

Progressive disease (PD) is defined as a ≥ 25% increase in the sum of the products of the perpendicular diameters of all measurable tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point.

Clinically relevant progressive disease is PD that is associated with a decline in performance status and/or in the opinion of the investigator the patient requires alternative therapy.

Time Frame From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population
Arm/Group Title GM-CSF Talimogene Laherparepvec
Hide Arm/Group Description:
GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.
Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ plaque forming units (PFU)/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
Overall Number of Participants Analyzed 141 295
Median (95% Confidence Interval)
Unit of Measure: months
2.9
(2.8 to 4.0)
8.2
(6.5 to 9.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GM-CSF, Talimogene Laherparepvec
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Descriptive
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.42
Confidence Interval (2-Sided) 95%
0.32 to 0.54
Estimation Comments The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a longer average time to treatment failure for talimogene laherparepvec relative to GM-CSF.
7.Secondary Outcome
Title Response Interval
Hide Description Response interval is defined as the interval between the date of randomization and the date of the last documented evidence of response (CR or PR as assessed by the Investigator) prior to any new anti-cancer therapy. Response Interval post response onset was censored if a patient was still in response at the last observation.
Time Frame From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with an objective response (CR or PR) per Investigator assessment.
Arm/Group Title GM-CSF Talimogene Laherparepvec
Hide Arm/Group Description:
GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.
Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
Overall Number of Participants Analyzed 9 91
Median (95% Confidence Interval)
Unit of Measure: months
7.5 [1] 
(1.9 to NA)
NA [1] 
(NA to NA)
[1]
Could not be estimated due to the low number of events
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection GM-CSF, Talimogene Laherparepvec
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0050
Comments Descriptive
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.30
Confidence Interval (2-Sided) 95%
0.13 to 0.73
Estimation Comments The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a longer response interval for talimogene laherparepvec relative to GM-CSF.
Time Frame From first dose of study drug until 30 days after the last dose; Median duration of treatment was 10 weeks (range 0.6 to 72 weeks) in GM-CSF group and 23 weeks (range 0.1 to 78.9 weeks) in the talimogene laherparepvec group.
Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
 
Arm/Group Title GM-CSF Talimogene Laherparepvec
Hide Arm/Group Description GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months. Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10⁶ PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10⁸ PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
All-Cause Mortality
GM-CSF Talimogene Laherparepvec
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
GM-CSF Talimogene Laherparepvec
Affected / at Risk (%) Affected / at Risk (%)
Total   17/127 (13.39%)   75/292 (25.68%) 
Blood and lymphatic system disorders     
Anaemia  1  1/127 (0.79%)  2/292 (0.68%) 
Lymphadenopathy  1  0/127 (0.00%)  1/292 (0.34%) 
Cardiac disorders     
Angina pectoris  1  1/127 (0.79%)  1/292 (0.34%) 
Arrhythmia  1  1/127 (0.79%)  0/292 (0.00%) 
Atrial fibrillation  1  1/127 (0.79%)  2/292 (0.68%) 
Atrial flutter  1  0/127 (0.00%)  1/292 (0.34%) 
Cardiac failure congestive  1  0/127 (0.00%)  1/292 (0.34%) 
Myocardial infarction  1  1/127 (0.79%)  1/292 (0.34%) 
Gastrointestinal disorders     
Constipation  1  1/127 (0.79%)  2/292 (0.68%) 
Dyspepsia  1  1/127 (0.79%)  0/292 (0.00%) 
Dysphagia  1  0/127 (0.00%)  1/292 (0.34%) 
Gastrointestinal haemorrhage  1  0/127 (0.00%)  3/292 (1.03%) 
Gastrooesophageal reflux disease  1  1/127 (0.79%)  0/292 (0.00%) 
Intestinal obstruction  1  0/127 (0.00%)  2/292 (0.68%) 
Intussusception  1  0/127 (0.00%)  1/292 (0.34%) 
Small intestinal haemorrhage  1  1/127 (0.79%)  0/292 (0.00%) 
Small intestinal obstruction  1  1/127 (0.79%)  0/292 (0.00%) 
Vomiting  1  0/127 (0.00%)  2/292 (0.68%) 
General disorders     
Asthenia  1  0/127 (0.00%)  1/292 (0.34%) 
Chills  1  0/127 (0.00%)  1/292 (0.34%) 
Disease progression  1  2/127 (1.57%)  9/292 (3.08%) 
Influenza like illness  1  0/127 (0.00%)  1/292 (0.34%) 
Non-cardiac chest pain  1  1/127 (0.79%)  0/292 (0.00%) 
Oedema peripheral  1  0/127 (0.00%)  1/292 (0.34%) 
Pyrexia  1  0/127 (0.00%)  5/292 (1.71%) 
Infections and infestations     
Cellulitis  1  1/127 (0.79%)  7/292 (2.40%) 
Gastroenteritis  1  1/127 (0.79%)  1/292 (0.34%) 
Lower respiratory tract infection  1  0/127 (0.00%)  1/292 (0.34%) 
Parotitis  1  0/127 (0.00%)  1/292 (0.34%) 
Pelvic abscess  1  0/127 (0.00%)  1/292 (0.34%) 
Sepsis  1  0/127 (0.00%)  1/292 (0.34%) 
Injury, poisoning and procedural complications     
Anaemia postoperative  1  0/127 (0.00%)  1/292 (0.34%) 
Delayed recovery from anaesthesia  1  0/127 (0.00%)  1/292 (0.34%) 
Foot fracture  1  0/127 (0.00%)  1/292 (0.34%) 
Hip fracture  1  1/127 (0.79%)  0/292 (0.00%) 
Pelvic fracture  1  1/127 (0.79%)  1/292 (0.34%) 
Procedural pain  1  0/127 (0.00%)  1/292 (0.34%) 
Radiation associated pain  1  0/127 (0.00%)  1/292 (0.34%) 
Rib fracture  1  0/127 (0.00%)  2/292 (0.68%) 
Seroma  1  0/127 (0.00%)  1/292 (0.34%) 
Wound decomposition  1  1/127 (0.79%)  0/292 (0.00%) 
Metabolism and nutrition disorders     
Dehydration  1  0/127 (0.00%)  2/292 (0.68%) 
Diabetic ketoacidosis  1  0/127 (0.00%)  1/292 (0.34%) 
Failure to thrive  1  0/127 (0.00%)  1/292 (0.34%) 
Hypercalcaemia  1  0/127 (0.00%)  1/292 (0.34%) 
Hyperglycaemia  1  0/127 (0.00%)  1/292 (0.34%) 
Hyperuricaemia  1  0/127 (0.00%)  1/292 (0.34%) 
Hypoglycaemia  1  1/127 (0.79%)  0/292 (0.00%) 
Hyponatraemia  1  0/127 (0.00%)  1/292 (0.34%) 
Hypophagia  1  0/127 (0.00%)  1/292 (0.34%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  0/127 (0.00%)  2/292 (0.68%) 
Bone pain  1  0/127 (0.00%)  1/292 (0.34%) 
Bursitis  1  0/127 (0.00%)  1/292 (0.34%) 
Muscular weakness  1  0/127 (0.00%)  1/292 (0.34%) 
Musculoskeletal pain  1  0/127 (0.00%)  1/292 (0.34%) 
Osteoarthritis  1  0/127 (0.00%)  1/292 (0.34%) 
Spinal column stenosis  1  0/127 (0.00%)  1/292 (0.34%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bladder transitional cell carcinoma  1  0/127 (0.00%)  1/292 (0.34%) 
Cancer pain  1  0/127 (0.00%)  1/292 (0.34%) 
Infected neoplasm  1  0/127 (0.00%)  3/292 (1.03%) 
Melanoma recurrent  1  0/127 (0.00%)  1/292 (0.34%) 
Metastases to central nervous system  1  1/127 (0.79%)  3/292 (1.03%) 
Metastatic malignant melanoma  1  0/127 (0.00%)  3/292 (1.03%) 
Plasmacytoma  1  0/127 (0.00%)  1/292 (0.34%) 
Tumour haemorrhage  1  0/127 (0.00%)  1/292 (0.34%) 
Tumour pain  1  0/127 (0.00%)  4/292 (1.37%) 
Nervous system disorders     
Brain oedema  1  0/127 (0.00%)  1/292 (0.34%) 
Central nervous system lesion  1  0/127 (0.00%)  1/292 (0.34%) 
Cerebral haemorrhage  1  0/127 (0.00%)  3/292 (1.03%) 
Convulsion  1  0/127 (0.00%)  2/292 (0.68%) 
Haemorrhage intracranial  1  0/127 (0.00%)  1/292 (0.34%) 
Pneumocephalus  1  0/127 (0.00%)  1/292 (0.34%) 
Somnolence  1  0/127 (0.00%)  1/292 (0.34%) 
Spinal cord compression  1  1/127 (0.79%)  0/292 (0.00%) 
Syncope  1  0/127 (0.00%)  1/292 (0.34%) 
Transient ischaemic attack  1  0/127 (0.00%)  1/292 (0.34%) 
Psychiatric disorders     
Anxiety  1  0/127 (0.00%)  1/292 (0.34%) 
Delirium  1  0/127 (0.00%)  1/292 (0.34%) 
Mental status changes  1  0/127 (0.00%)  2/292 (0.68%) 
Renal and urinary disorders     
Glomerulonephritis  1  0/127 (0.00%)  1/292 (0.34%) 
Haematuria  1  0/127 (0.00%)  1/292 (0.34%) 
Nephrolithiasis  1  1/127 (0.79%)  0/292 (0.00%) 
Renal failure  1  1/127 (0.79%)  1/292 (0.34%) 
Renal failure acute  1  1/127 (0.79%)  0/292 (0.00%) 
Renal papillary necrosis  1  0/127 (0.00%)  1/292 (0.34%) 
Respiratory, thoracic and mediastinal disorders     
Aspiration  1  0/127 (0.00%)  1/292 (0.34%) 
Asthma  1  0/127 (0.00%)  1/292 (0.34%) 
Bronchial hyperreactivity  1  0/127 (0.00%)  1/292 (0.34%) 
Chronic obstructive pulmonary disease  1  0/127 (0.00%)  1/292 (0.34%) 
Dyspnoea  1  1/127 (0.79%)  1/292 (0.34%) 
Epistaxis  1  1/127 (0.79%)  0/292 (0.00%) 
Obstructive airways disorder  1  0/127 (0.00%)  1/292 (0.34%) 
Pleural effusion  1  0/127 (0.00%)  3/292 (1.03%) 
Pleuritic pain  1  0/127 (0.00%)  1/292 (0.34%) 
Pulmonary embolism  1  1/127 (0.79%)  2/292 (0.68%) 
Respiratory failure  1  0/127 (0.00%)  1/292 (0.34%) 
Skin and subcutaneous tissue disorders     
Pain of skin  1  1/127 (0.79%)  0/292 (0.00%) 
Vascular disorders     
Deep vein thrombosis  1  0/127 (0.00%)  3/292 (1.03%) 
Hypotension  1  0/127 (0.00%)  1/292 (0.34%) 
Venous thrombosis limb  1  0/127 (0.00%)  1/292 (0.34%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
GM-CSF Talimogene Laherparepvec
Affected / at Risk (%) Affected / at Risk (%)
Total   112/127 (88.19%)   282/292 (96.58%) 
Blood and lymphatic system disorders     
Anaemia  1  2/127 (1.57%)  15/292 (5.14%) 
Gastrointestinal disorders     
Abdominal pain  1  3/127 (2.36%)  26/292 (8.90%) 
Constipation  1  8/127 (6.30%)  34/292 (11.64%) 
Diarrhoea  1  14/127 (11.02%)  55/292 (18.84%) 
Dyspepsia  1  8/127 (6.30%)  15/292 (5.14%) 
Nausea  1  25/127 (19.69%)  104/292 (35.62%) 
Vomiting  1  12/127 (9.45%)  61/292 (20.89%) 
General disorders     
Chills  1  11/127 (8.66%)  141/292 (48.29%) 
Fatigue  1  46/127 (36.22%)  147/292 (50.34%) 
Influenza like illness  1  19/127 (14.96%)  88/292 (30.14%) 
Injection site erythema  1  33/127 (25.98%)  15/292 (5.14%) 
Injection site pain  1  8/127 (6.30%)  81/292 (27.74%) 
Injection site pruritus  1  21/127 (16.54%)  5/292 (1.71%) 
Injection site reaction  1  12/127 (9.45%)  9/292 (3.08%) 
Injection site swelling  1  8/127 (6.30%)  10/292 (3.42%) 
Oedema peripheral  1  12/127 (9.45%)  34/292 (11.64%) 
Pain  1  13/127 (10.24%)  47/292 (16.10%) 
Pyrexia  1  11/127 (8.66%)  121/292 (41.44%) 
Infections and infestations     
Upper respiratory tract infection  1  8/127 (6.30%)  29/292 (9.93%) 
Investigations     
Weight decreased  1  1/127 (0.79%)  17/292 (5.82%) 
Metabolism and nutrition disorders     
Decreased appetite  1  14/127 (11.02%)  30/292 (10.27%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  11/127 (8.66%)  50/292 (17.12%) 
Back pain  1  8/127 (6.30%)  27/292 (9.25%) 
Muscle spasms  1  7/127 (5.51%)  13/292 (4.45%) 
Musculoskeletal pain  1  7/127 (5.51%)  14/292 (4.79%) 
Myalgia  1  7/127 (5.51%)  51/292 (17.47%) 
Neck pain  1  7/127 (5.51%)  14/292 (4.79%) 
Pain in extremity  1  12/127 (9.45%)  48/292 (16.44%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Tumour pain  1  7/127 (5.51%)  19/292 (6.51%) 
Nervous system disorders     
Dizziness  1  4/127 (3.15%)  28/292 (9.59%) 
Headache  1  12/127 (9.45%)  55/292 (18.84%) 
Psychiatric disorders     
Anxiety  1  2/127 (1.57%)  19/292 (6.51%) 
Depression  1  3/127 (2.36%)  15/292 (5.14%) 
Insomnia  1  6/127 (4.72%)  21/292 (7.19%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  10/127 (7.87%)  31/292 (10.62%) 
Dyspnoea  1  13/127 (10.24%)  13/292 (4.45%) 
Oropharyngeal pain  1  1/127 (0.79%)  17/292 (5.82%) 
Skin and subcutaneous tissue disorders     
Erythema  1  9/127 (7.09%)  21/292 (7.19%) 
Hyperhidrosis  1  9/127 (7.09%)  23/292 (7.88%) 
Pruritus  1  19/127 (14.96%)  28/292 (9.59%) 
Rash  1  10/127 (7.87%)  26/292 (8.90%) 
Vitiligo  1  1/127 (0.79%)  15/292 (5.14%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
Name/Title: Study Director
Organization: Amgen, Inc.
Phone: 866-572-6436
Responsible Party: BioVex Limited
ClinicalTrials.gov Identifier: NCT00769704     History of Changes
Other Study ID Numbers: 005/05
20110263 ( Other Identifier: Sponsor )
2008-006140-20 ( EudraCT Number )
First Submitted: October 7, 2008
First Posted: October 9, 2008
Results First Submitted: September 22, 2015
Results First Posted: December 17, 2015
Last Update Posted: July 13, 2016