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Ipilimumab With or Without Talimogene Laherparepvec in Unresected Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01740297
Recruitment Status : Active, not recruiting
First Posted : December 4, 2012
Results First Posted : October 9, 2017
Last Update Posted : November 6, 2019
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Melanoma
Interventions Drug: Talimogene laherparepvec
Drug: Ipilimumab
Enrollment 217
Recruitment Details

This study was conducted at 33 centers in the United States of America, France, and Germany.

Particiants were enrolled in phase 1b from 07 February 2013 to 08 July 2013 and in phase 2 from 13 August 2013 to 25 February 2016.

Pre-assignment Details In phase 1b all participants received talimogene laherparepvec in combination with ipilimumab. In phase 2 participants were randomized 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab. Participants were stratified by disease stage and either v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation V600E or prior therapy.
Arm/Group Title Phase 1b: Talimogene Laherparepvec + Ipilimumab Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Period Title: Overall Study
Started 19 100 98
Received Talimogene Laherparepvec 19 0 95
Received Ipilimumab 18 95 92
Completed 0 0 0
Not Completed 19 100 98
Reason Not Completed
Continuing Study             10             67             68
Withdrawal by Subject             1             9             11
Death             8             23             19
Sponsor Decision             0             1             0
Arm/Group Title Phase 1b: Talimogene Laherparepvec + Ipilimumab Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab Total
Hide Arm/Group Description Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). Total of all reporting groups
Overall Number of Baseline Participants 19 100 98 217
Hide Baseline Analysis Population Description
All enrolled participants
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 19 participants 100 participants 98 participants 217 participants
61.1  (12.1) 64.2  (13.3) 63.6  (14.0) 63.6  (13.5)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 100 participants 98 participants 217 participants
< 65 years
11
  57.9%
54
  54.0%
46
  46.9%
111
  51.2%
≥ 65 years
8
  42.1%
46
  46.0%
52
  53.1%
106
  48.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 100 participants 98 participants 217 participants
Female
11
  57.9%
45
  45.0%
36
  36.7%
92
  42.4%
Male
8
  42.1%
55
  55.0%
62
  63.3%
125
  57.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 100 participants 98 participants 217 participants
Hispanic or Latino
1
   5.3%
4
   4.0%
0
   0.0%
5
   2.3%
Not Hispanic or Latino
18
  94.7%
96
  96.0%
98
 100.0%
212
  97.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 19 participants 100 participants 98 participants 217 participants
American Indian or Alaska Native 0 1 0 1
Asian 0 1 0 1
Black (or African American) 0 3 0 3
Multiple 0 1 1 2
Native Hawaiian or Other Pacific Islander 0 0 0 0
White 18 92 97 207
Other 1 2 0 3
Eastern Cooperative Oncology Group (ECOG) Performance Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 19 participants 100 participants 98 participants 217 participants
0 (Fully active) 14 73 69 156
1 (Restrictive but ambulatory) 5 27 29 61
[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 19 participants 100 participants 98 participants 217 participants
Stage IIIB - IVM1a 8 57 50 115
Stage IVM1b/c 11 43 48 102
[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.
BRAF V600 Mutation Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 19 participants 100 participants 98 participants 217 participants
Mutation 12 34 35 81
Wild-type 7 60 62 129
Missing/Unknown 0 6 1 7
[1]
Measure Description: Mutation status of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene was based on a gene mutation that results in an amino acid substitution from valine (V) to glutamic acid (E) at codon 600 (V600E) and/or a substitution from valine to lysine (K) (V600K).
1.Primary Outcome
Title Phase 1b: Number of Participants With Dose-limiting Toxicities
Hide Description

A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events version 3.0:

  • treatment-related non-laboratory adverse events (AE) ≥ grade 4
  • ≥ grade 4 immune-mediated dermatitis
  • ≥ grade 4 immune-mediated endocrinopathy (except autoimmune thyroiditis)
  • ≥ grade 3 immune-mediated enterocolitis
  • ≥ grade 3 immune-mediated hepatitis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset)
  • ≥ grade 3 immune-mediated neuropathy
  • ≥ grade 3 other immune-mediated AEs including hemolytic anemia, angiopathy, myocarditis, pericarditis, temporal arteritis, or vasculitis, autoimmune thyroiditis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset), blepharitis, conjunctivitis, episcleritis, iritis, scleritis, or uveitis, pancreatitis, meningitis, arthritis or polymyalgia rheumatic, nephritis, pneumonitis, psoriasis or leukocytoclastic vasculitis.
Time Frame The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12).
Hide Outcome Measure Data
Hide Analysis Population Description
All phase 1b participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab).
Arm/Group Title Phase 1b: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 19
Measure Type: Number
Unit of Measure: participants
0
2.Primary Outcome
Title Phase 2: Objective Response Rate
Hide Description

Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI).

CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm.

PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.

Time Frame Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized in phase 2
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 100 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
18.0
(11.0 to 26.9)
38.8
(29.1 to 49.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method Chi-squared, Corrected
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.9
Confidence Interval (2-Sided) 95%
1.5 to 5.5
Estimation Comments Obtained from the unstratified logistic regression model.
3.Secondary Outcome
Title Phase 1b: Objective Response Rate
Hide Description

Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI).

CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm.

PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.

Time Frame Tumor response was assesed every 12 weeks until disease progression; median follow-up time was 148.4 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
All phase 1b participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab).
Arm/Group Title Phase 1b: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 19
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
52.6
(28.9 to 75.6)
4.Secondary Outcome
Title Phase 2: Best Overall Response
Hide Description

Best overall response was categorized in descending order as a complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or unevaluable (UE) based on investigator assessment according to the modified irRC.

CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to <10 mm.

PR: Decrease in tumor burden ≥ 50% relative to baseline. PD: Increase in tumor burden ≥ 25% relative to nadir. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization.

CR, PR and PD must have been confirmed at 2 consecutive assessment ≥ 4 weeks apart.

Assessments occurring after the start of the first subsequent anticancer therapy or removal of a lesion were not included.

Time Frame Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized in phase 2
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 100 98
Measure Type: Number
Unit of Measure: participants
Complete Response (CR) 7 13
Partial Response (PR) 11 25
Stable Disease (SD) 24 19
Progressive Disease (PD) 33 31
Unevaluable (UE) 17 4
Not Done (ND) 8 6
5.Secondary Outcome
Title Phase 2: Disease Control Rate
Hide Description

Disease control rate (DCR) was defined as the percentage of participants with a best overall response of CR, PR or SD based on investigator assessment according to the modified irRC.

CR: Complete disappearance of all lesions and no new lesions; any pathological lymph nodes reduced in short axis to <10 mm.

PR: Decrease in tumor burden ≥ 50% relative to baseline. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization.

CR and PR must have been confirmed at 2 consecutive assessments ≥ 4 weeks apart.

Time Frame Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized in phase 2
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 100 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
42.0
(32.2 to 52.3)
58.2
(47.8 to 68.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.033
Comments P-value is descriptive
Method Chi-squared, Corrected
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.9
Confidence Interval (2-Sided) 95%
1.1 to 3.4
Estimation Comments Obtained from the unstratified logistic regression model.
6.Secondary Outcome
Title Phase 2: Durable Response Rate
Hide Description Durable response rate (DRR) was defined as the percentage of participants with a duration of response (best response of CR or PR) per modified irRC of at least 6 months. Duration of response is the time from the first confirmed CR or PR to confirmed disease progression per the modified irRC or death, whichever occurs earlier.
Time Frame Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized in phase 2
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 100 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
13.0
(7.1 to 21.2)
29.6
(20.8 to 39.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments P-value is descriptive.
Method Chi-squared, Corrected
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.8
Confidence Interval (2-Sided) 95%
1.4 to 5.8
Estimation Comments Obtained from the unstratified logistic regression model.
7.Secondary Outcome
Title Phase 2: Time to Response
Hide Description Time to confirmed response (TTR) was defined as the time from randomization to the date of the first confirmed CR or PR per modified irRC criteria. Participants who did not have a confirmed CR or PR were censored at their last evaluable tumor assessment date.
Time Frame Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized in phase 2
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 100 98
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
5.8
(5.4 to 10.9)
[1]
Could not be estimated due to the low number of events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.228
Comments P-value is descriptive
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.41
Confidence Interval (2-Sided) 95%
0.80 to 2.49
Estimation Comments Obtained from unstratified Cox Proportional Hazard Model.
8.Secondary Outcome
Title Phase 2: Duration of Response
Hide Description Duration of response was calculated only for participants with an objective response per modified irRC and was defined as the time from first confirmed objective response (CR or PR) to confirmed disease progression per the modified irRC or death, whichever was earlier. Responders who did not have an event of death or disease progression were censored at their last evaluable tumor assessment date.
Time Frame Tumor response was assessed every 12 weeks until disease progression; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants randomized in phase 2 with a confirmed CR or PR.
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 18 38
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Could not be estimated due to the low number of events
9.Secondary Outcome
Title Phase 2: Progression-free Survival
Hide Description Progression-free survival was measured from the date of randomization to the date of disease progression (as measured by modified irRC) or death on or before the data cutoff date, whichever occurred first. Participants who had no disease progression and did not die while on study were censored at the last disease assessment date.
Time Frame From randomization until the data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized in phase 2
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 100 98
Median (95% Confidence Interval)
Unit of Measure: months
6.4
(3.2 to 16.5)
8.2
(4.2 to 21.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.348
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.56 to 1.23
Estimation Comments Obtained from unstratified Cox Proportional Hazard Model
10.Secondary Outcome
Title Phase 2: Resection Rate
Hide Description Resection rate was defined as the percentage of participants who had surgical procedures for melanoma that resulted in a partial reduction or complete eradication of all previously unresectable cutaneous or visceral metastatic disease. Surgical procedures for melanoma with palliative intent (eg, for pain control) in the presence of disease progression were not considered resection.
Time Frame From randomization until the data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
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Hide Analysis Population Description
All participants randomized in phase 2
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 100 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
3.0
(0.6 to 8.5)
5.1
(1.7 to 11.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.696
Comments [Not Specified]
Method Chi-squared, Corrected
Comments [Not Specified]
11.Secondary Outcome
Title Phase 2: Overall Survival
Hide Description Overall survival was defined as the time from the date of randomization to the date of death from any cause. Participants without an event were censored at the last date they were known to be alive. Participants with a vital status obtained after the data cut-off were censored at the date cut-off date.
Time Frame From randomization until the data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
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Hide Analysis Population Description
All participants randomized in phase 2
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 100 98
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Could not be estimated due to the low number of events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Ipilimumab, Phase 2: Talimogene Laherparepvec + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.474
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.44 to 1.46
Estimation Comments Obtained from unstratified Cox Proportional Hazard Model
12.Secondary Outcome
Title Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24
Hide Description The overall survival estimates at month 24 data were not mature as most participants had not been followed for 24 months at the time of data cutoff.
Time Frame Months 12 and 24; The median (Q1, Q3) follow-up time from randomization to the data cutoff date for the analysis was 80.6 (58.3, 106.3) weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized in phase 2
Arm/Group Title Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 100 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Month 12
81.4
(71.4 to 88.3)
86.9
(78.1 to 92.4)
Month 24
67.7
(53.3 to 78.5)
76.6
(64.5 to 85.0)
13.Secondary Outcome
Title Number of Participants With Adverse Events
Hide Description

Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, where grade 1 = mild AE, grade 2 = moderate AE, grade 3 = severe AE, grade 4 = life-threatening or disabling AE and grade 5 = death related to AE.

The investigator assessed whether each AE was possibly related to talimogene laherparepvec (T-VEC) and/or ipilimumab (Imab).

Note that one participant in the Phase 2 Ipilimumab Alone group was incorrectly noted as having an AE leading to discontinuation of T-VEC which was discovered and corrected after this analysis was conducted.

Time Frame From first dose of study treatment until 30 days after the last dose; median duration of treatment was 14.7, 9.1, and 21.1 weeks in each treatment group respectively.
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Hide Analysis Population Description
All participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab).
Arm/Group Title Phase 1b: Talimogene Laherparepvec + Ipilimumab Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description:
Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.
Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
Overall Number of Participants Analyzed 19 95 95
Measure Type: Number
Unit of Measure: participants
All adverse events 19 90 93
Adverse events ≥ grade 2 17 69 77
Adverse events ≥ grade 3 7 33 43
Adverse events ≥ grade 4 1 3 4
Serious adverse events 6 25 34
AEs leading to discontinuation of T-VEC 0 1 2
AEs leading to discontinuation of ipilimumab 0 16 12
Fatal adverse events 0 0 3
T-VEC-related adverse events 17 NA [1]  82
T-VEC-related adverse events AEs ≥ grade 2 12 NA [1]  43
T-VEC-related adverse events AEs ≥ grade 3 3 NA [1]  14
T-VEC-related adverse events ≥ grade 4 0 NA [1]  1
T-VEC-related serious adverse events 1 NA [1]  10
T-VEC-related AEs leading to T-VEC discontinuation 0 NA [1]  0
Fatal T-VEC-related adverse events 0 NA [1]  0
Ipilimumab-related adverse events 15 75 76
Ipilimumab-related adverse events ≥ grade 2 8 46 46
Ipilimumab-related adverse events ≥ grade 3 4 17 18
Ipilimumab-related adverse events ≥ grade 4 1 1 0
Ipilimumab-related serious adverse events 4 15 14
Imab-related AEs leading to Imab discontinuation 0 11 11
Fatal ipilimumab-related adverse events 0 0 0
[1]
Participants in this group did not receive T-VEC
Time Frame From first dose of study treatment until 30 days after the last dose; median duration of treatment was 14.7, 9.1, and 21.1 weeks in each treatment group respectively.
Adverse Event Reporting Description

Safety analyses include all participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab).

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

 
Arm/Group Title Phase 1b: Talimogene Laherparepvec + Ipilimumab Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Hide Arm/Group Description Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6).
All-Cause Mortality
Phase 1b: Talimogene Laherparepvec + Ipilimumab Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Hide Serious Adverse Events
Phase 1b: Talimogene Laherparepvec + Ipilimumab Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/19 (31.58%)   25/95 (26.32%)   34/95 (35.79%) 
Blood and lymphatic system disorders       
Lymphopenia  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Cardiac disorders       
Angina pectoris  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Arrhythmia  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Atrial fibrillation  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Myocardial infarction  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Endocrine disorders       
Hypophysitis  1  0/19 (0.00%)  1/95 (1.05%)  1/95 (1.05%) 
Lymphocytic hypophysitis  1  0/19 (0.00%)  0/95 (0.00%)  2/95 (2.11%) 
Eye disorders       
Exophthalmos  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Gastrointestinal disorders       
Abdominal distension  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Abdominal pain  1  0/19 (0.00%)  1/95 (1.05%)  1/95 (1.05%) 
Autoimmune colitis  1  0/19 (0.00%)  3/95 (3.16%)  3/95 (3.16%) 
Colitis  1  0/19 (0.00%)  6/95 (6.32%)  6/95 (6.32%) 
Constipation  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Diarrhoea  1  0/19 (0.00%)  3/95 (3.16%)  1/95 (1.05%) 
Nausea  1  2/19 (10.53%)  0/95 (0.00%)  2/95 (2.11%) 
General disorders       
Asthenia  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Chest pain  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Disease progression  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Fatigue  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
General physical health deterioration  1  0/19 (0.00%)  1/95 (1.05%)  1/95 (1.05%) 
Influenza like illness  1  0/19 (0.00%)  0/95 (0.00%)  5/95 (5.26%) 
Injection site reaction  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Non-cardiac chest pain  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Pain  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Pyrexia  1  0/19 (0.00%)  0/95 (0.00%)  2/95 (2.11%) 
Hepatobiliary disorders       
Autoimmune hepatitis  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Infections and infestations       
Appendicitis  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Cellulitis  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Cytomegalovirus colitis  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Meningitis aseptic  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Sepsis  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Urinary tract infection  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Injury, poisoning and procedural complications       
Hip fracture  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Investigations       
Amylase increased  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Blood creatinine increased  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Lipase increased  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Neutrophil count decreased  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
White blood cell count decreased  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Metabolism and nutrition disorders       
Dehydration  1  0/19 (0.00%)  0/95 (0.00%)  2/95 (2.11%) 
Hypercalcaemia  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Hypoglycaemia  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Hyponatraemia  1  0/19 (0.00%)  2/95 (2.11%)  0/95 (0.00%) 
Musculoskeletal and connective tissue disorders       
Arthralgia  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Back pain  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Lumbar spinal stenosis  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Musculoskeletal pain  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Rhabdomyolysis  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Malignant melanoma  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Malignant neoplasm progression  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Malignant pleural effusion  1  0/19 (0.00%)  0/95 (0.00%)  2/95 (2.11%) 
Metastases to central nervous system  1  1/19 (5.26%)  1/95 (1.05%)  1/95 (1.05%) 
Tumour flare  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Tumour pain  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Nervous system disorders       
Dizziness  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Facial paralysis  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Intracranial mass  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Seizure  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Transient ischaemic attack  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Psychiatric disorders       
Anxiety  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Confusional state  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Renal and urinary disorders       
Haematuria  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Respiratory, thoracic and mediastinal disorders       
Acute respiratory failure  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Dyspnoea  1  0/19 (0.00%)  0/95 (0.00%)  2/95 (2.11%) 
Pleural effusion  1  0/19 (0.00%)  0/95 (0.00%)  2/95 (2.11%) 
Pulmonary embolism  1  0/19 (0.00%)  0/95 (0.00%)  1/95 (1.05%) 
Skin and subcutaneous tissue disorders       
Rash maculo-papular  1  0/19 (0.00%)  1/95 (1.05%)  0/95 (0.00%) 
Vascular disorders       
Hypotension  1  0/19 (0.00%)  1/95 (1.05%)  1/95 (1.05%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase 1b: Talimogene Laherparepvec + Ipilimumab Phase 2: Ipilimumab Phase 2: Talimogene Laherparepvec + Ipilimumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   19/19 (100.00%)   85/95 (89.47%)   90/95 (94.74%) 
Blood and lymphatic system disorders       
Anaemia  1  0/19 (0.00%)  5/95 (5.26%)  9/95 (9.47%) 
Leukopenia  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Lymphopenia  1  0/19 (0.00%)  2/95 (2.11%)  8/95 (8.42%) 
Endocrine disorders       
Adrenal insufficiency  1  1/19 (5.26%)  1/95 (1.05%)  1/95 (1.05%) 
Hypothyroidism  1  2/19 (10.53%)  3/95 (3.16%)  3/95 (3.16%) 
Lymphocytic hypophysitis  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Eye disorders       
Eye pain  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Uveitis  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Vision blurred  1  3/19 (15.79%)  6/95 (6.32%)  6/95 (6.32%) 
Gastrointestinal disorders       
Abdominal pain  1  0/19 (0.00%)  9/95 (9.47%)  16/95 (16.84%) 
Constipation  1  2/19 (10.53%)  5/95 (5.26%)  13/95 (13.68%) 
Diarrhoea  1  8/19 (42.11%)  31/95 (32.63%)  40/95 (42.11%) 
Dyspepsia  1  1/19 (5.26%)  2/95 (2.11%)  4/95 (4.21%) 
Nausea  1  9/19 (47.37%)  23/95 (24.21%)  35/95 (36.84%) 
Vomiting  1  5/19 (26.32%)  13/95 (13.68%)  18/95 (18.95%) 
General disorders       
Application site pain  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Asthenia  1  0/19 (0.00%)  9/95 (9.47%)  7/95 (7.37%) 
Chest pain  1  1/19 (5.26%)  1/95 (1.05%)  1/95 (1.05%) 
Chills  1  11/19 (57.89%)  3/95 (3.16%)  50/95 (52.63%) 
Fatigue  1  11/19 (57.89%)  40/95 (42.11%)  56/95 (58.95%) 
Influenza like illness  1  3/19 (15.79%)  1/95 (1.05%)  26/95 (27.37%) 
Injection site inflammation  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Injection site pain  1  1/19 (5.26%)  0/95 (0.00%)  26/95 (27.37%) 
Injection site reaction  1  2/19 (10.53%)  0/95 (0.00%)  15/95 (15.79%) 
Injection site swelling  1  0/19 (0.00%)  0/95 (0.00%)  5/95 (5.26%) 
Malaise  1  1/19 (5.26%)  2/95 (2.11%)  7/95 (7.37%) 
Oedema peripheral  1  2/19 (10.53%)  4/95 (4.21%)  15/95 (15.79%) 
Pain  1  3/19 (15.79%)  4/95 (4.21%)  11/95 (11.58%) 
Performance status decreased  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Peripheral swelling  1  1/19 (5.26%)  1/95 (1.05%)  2/95 (2.11%) 
Pyrexia  1  11/19 (57.89%)  7/95 (7.37%)  34/95 (35.79%) 
Infections and infestations       
Escherichia infection  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Eye infection  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Influenza  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Nasopharyngitis  1  1/19 (5.26%)  0/95 (0.00%)  4/95 (4.21%) 
Oral herpes  1  0/19 (0.00%)  0/95 (0.00%)  5/95 (5.26%) 
Sinusitis  1  2/19 (10.53%)  0/95 (0.00%)  4/95 (4.21%) 
Upper respiratory tract infection  1  1/19 (5.26%)  4/95 (4.21%)  4/95 (4.21%) 
Vaginal infection  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Vulvovaginal mycotic infection  1  2/19 (10.53%)  0/95 (0.00%)  0/95 (0.00%) 
Wound infection  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Injury, poisoning and procedural complications       
Radius fracture  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Investigations       
Alanine aminotransferase increased  1  3/19 (15.79%)  4/95 (4.21%)  7/95 (7.37%) 
Amylase increased  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Aspartate aminotransferase increased  1  0/19 (0.00%)  5/95 (5.26%)  9/95 (9.47%) 
Blood alkaline phosphatase increased  1  0/19 (0.00%)  2/95 (2.11%)  5/95 (5.26%) 
Blood lactate dehydrogenase increased  1  0/19 (0.00%)  1/95 (1.05%)  5/95 (5.26%) 
Lipase increased  1  1/19 (5.26%)  1/95 (1.05%)  0/95 (0.00%) 
Weight decreased  1  0/19 (0.00%)  6/95 (6.32%)  1/95 (1.05%) 
Metabolism and nutrition disorders       
Decreased appetite  1  4/19 (21.05%)  11/95 (11.58%)  12/95 (12.63%) 
Dehydration  1  2/19 (10.53%)  4/95 (4.21%)  3/95 (3.16%) 
Hypercalcaemia  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Hyperglycaemia  1  4/19 (21.05%)  6/95 (6.32%)  6/95 (6.32%) 
Hyperuricaemia  1  1/19 (5.26%)  1/95 (1.05%)  0/95 (0.00%) 
Hypocalcaemia  1  1/19 (5.26%)  1/95 (1.05%)  0/95 (0.00%) 
Hypokalaemia  1  2/19 (10.53%)  5/95 (5.26%)  5/95 (5.26%) 
Hypomagnesaemia  1  1/19 (5.26%)  1/95 (1.05%)  3/95 (3.16%) 
Musculoskeletal and connective tissue disorders       
Arthralgia  1  1/19 (5.26%)  12/95 (12.63%)  20/95 (21.05%) 
Back pain  1  2/19 (10.53%)  7/95 (7.37%)  10/95 (10.53%) 
Muscle spasms  1  1/19 (5.26%)  0/95 (0.00%)  4/95 (4.21%) 
Muscle tightness  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Muscular weakness  1  1/19 (5.26%)  3/95 (3.16%)  3/95 (3.16%) 
Musculoskeletal chest pain  1  0/19 (0.00%)  0/95 (0.00%)  5/95 (5.26%) 
Musculoskeletal pain  1  0/19 (0.00%)  2/95 (2.11%)  7/95 (7.37%) 
Myalgia  1  1/19 (5.26%)  3/95 (3.16%)  10/95 (10.53%) 
Pain in extremity  1  2/19 (10.53%)  5/95 (5.26%)  5/95 (5.26%) 
Pubic pain  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Soft tissue mass  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Tumour pain  1  1/19 (5.26%)  4/95 (4.21%)  4/95 (4.21%) 
Nervous system disorders       
Brain oedema  1  1/19 (5.26%)  1/95 (1.05%)  0/95 (0.00%) 
Cluster headache  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Dizziness  1  1/19 (5.26%)  4/95 (4.21%)  11/95 (11.58%) 
Headache  1  8/19 (42.11%)  18/95 (18.95%)  34/95 (35.79%) 
Peripheral motor neuropathy  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Peripheral sensory neuropathy  1  1/19 (5.26%)  2/95 (2.11%)  0/95 (0.00%) 
Speech disorder  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Tension headache  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Tremor  1  1/19 (5.26%)  1/95 (1.05%)  0/95 (0.00%) 
Psychiatric disorders       
Anxiety  1  1/19 (5.26%)  1/95 (1.05%)  6/95 (6.32%) 
Depression  1  0/19 (0.00%)  2/95 (2.11%)  5/95 (5.26%) 
Insomnia  1  0/19 (0.00%)  13/95 (13.68%)  10/95 (10.53%) 
Nightmare  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Renal and urinary disorders       
Acute kidney injury  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Bladder pain  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Dysuria  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Pollakiuria  1  1/19 (5.26%)  3/95 (3.16%)  3/95 (3.16%) 
Respiratory, thoracic and mediastinal disorders       
Cough  1  1/19 (5.26%)  8/95 (8.42%)  18/95 (18.95%) 
Dyspnoea  1  1/19 (5.26%)  8/95 (8.42%)  8/95 (8.42%) 
Hiccups  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Pleural effusion  1  1/19 (5.26%)  0/95 (0.00%)  1/95 (1.05%) 
Skin and subcutaneous tissue disorders       
Dry skin  1  0/19 (0.00%)  2/95 (2.11%)  6/95 (6.32%) 
Erythema  1  2/19 (10.53%)  2/95 (2.11%)  5/95 (5.26%) 
Hyperhidrosis  1  0/19 (0.00%)  3/95 (3.16%)  5/95 (5.26%) 
Night sweats  1  2/19 (10.53%)  2/95 (2.11%)  1/95 (1.05%) 
Pruritus  1  8/19 (42.11%)  34/95 (35.79%)  38/95 (40.00%) 
Pruritus generalised  1  1/19 (5.26%)  1/95 (1.05%)  3/95 (3.16%) 
Rash  1  9/19 (47.37%)  27/95 (28.42%)  37/95 (38.95%) 
Rash erythematous  1  2/19 (10.53%)  1/95 (1.05%)  3/95 (3.16%) 
Rash maculo-papular  1  0/19 (0.00%)  2/95 (2.11%)  6/95 (6.32%) 
Skin disorder  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Skin lesion  1  1/19 (5.26%)  2/95 (2.11%)  4/95 (4.21%) 
Vitiligo  1  1/19 (5.26%)  0/95 (0.00%)  3/95 (3.16%) 
Vascular disorders       
Embolism  1  1/19 (5.26%)  0/95 (0.00%)  0/95 (0.00%) 
Hot flush  1  0/19 (0.00%)  1/95 (1.05%)  6/95 (6.32%) 
Hypertension  1  2/19 (10.53%)  2/95 (2.11%)  4/95 (4.21%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
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
Layout table for additonal information
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01740297    
Other Study ID Numbers: 20110264
2012-000307-32 ( EudraCT Number )
First Submitted: November 14, 2012
First Posted: December 4, 2012
Results First Submitted: August 23, 2017
Results First Posted: October 9, 2017
Last Update Posted: November 6, 2019