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

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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

Participant Flow

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
Arm/Group Description	Granulocyte macrophage colony-stimu...	Participants received talimogene la...
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

Baseline Characteristics

Arm/Group Title		GM-CSF	Talimogene Laherparepvec	Total
Arm/Group Description		GM-CSF was administered at a dose o...	Participants received talimogene la...	Total of all reporting groups
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
Baseline Analysis Population Description		[Not Specified]
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

Outcome Measures

1.Primary Outcome


Title	Durable Response Rate
Description	Durable response rate was defined as the percentage of participants wi...
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.

Outcome Measure Data

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
Arm/Group Description:	GM-CSF was administered at a dose o...	Participants received talimogene la...
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)

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
Description	Overall survival was defined as the time from the date of randomizatio...
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.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population


Arm/Group Title	GM-CSF	Talimogene Laherparepvec
Arm/Group Description:	GM-CSF was administered at a dose o...	Participants received talimogene la...
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)

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
Description	Objective response rate was defined as the percentage of participants ...
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.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population


Arm/Group Title	GM-CSF	Talimogene Laherparepvec
Arm/Group Description:	GM-CSF was administered at a dose o...	Participants received talimogene la...
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)

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
Description	The duration of response is defined as the longest individual period f...
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.

Outcome Measure Data

Analysis Population Description

Participants with an objective response (CR or PR) per EAC assessment.


Arm/Group Title	GM-CSF	Talimogene Laherparepvec
Arm/Group Description:	GM-CSF was administered at a dose o...	Participants received talimogene la...
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

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
Description	Response onset is defined as the time from the date of randomization t...
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.

Outcome Measure Data

Analysis Population Description

Participants with an objective response (CR or PR) per EAC assessment.


Arm/Group Title	GM-CSF	Talimogene Laherparepvec
Arm/Group Description:	GM-CSF was administered at a dose o...	Participants received talimogene la...
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)

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
Description	Time to treatment failure was assessed by the investigator, and calcul...
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.

Outcome Measure Data

Analysis Population Description

Intent to treat population


Arm/Group Title	GM-CSF	Talimogene Laherparepvec
Arm/Group Description:	GM-CSF was administered at a dose o...	Participants received talimogene la...
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)

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
Description	Response interval is defined as the interval between the date of rando...
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.

Outcome Measure Data

Analysis Population Description

Participants with an objective response (CR or PR) per Investigator assessment.


Arm/Group Title	GM-CSF	Talimogene Laherparepvec
Arm/Group Description:	GM-CSF was administered at a dose o...	Participants received talimogene la...
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

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.

Adverse Events

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
Arm/Group Description	GM-CSF was administered at a dose o...	Participants received talimogene la...
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	--/--	--/--
Serious Adverse Events 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
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

Limitations and Caveats

[Not Specified]

More Information

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

Layout table for Results Point of Contact information

Name/Title:	Study Director
Organization:	Amgen, Inc.
Phone:	866-572-6436

Publications of Results:

Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. doi: 10.1200/JCO.2014.58.3377. Epub 2015 May 26.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. doi: 10.1186/s40425-019-0623-z.

Kaufman HL, Andtbacka RHI, Collichio FA, Wolf M, Zhao Z, Shilkrut M, Puzanov I, Ross M. Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials. J Immunother Cancer. 2017 Sep 19;5(1):72. doi: 10.1186/s40425-017-0276-8.

Layout table for additonal information

Responsible Party:	BioVex Limited
ClinicalTrials.gov Identifier:	NCT00769704
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

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