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Clinical Trial Results:
A Phase 1b/2, Multicenter, Open-label Trial to Evaluate the Safety and Efficacy of Talimogene Laherparepvec and Ipilimumab Compared to Ipilimumab Alone in Subjects With Unresected, Stage IIIB-IV Melanoma

Summary
EudraCT number	2012-000307-32
Trial protocol	DE
Global end of trial date	09 Mar 2021

Results information
Results version number	v1(current)
This version publication date	01 Mar 2022
First version publication date	01 Mar 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

20110264

ISRCTN number

US NCT number

NCT01740297

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Mar 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Mar 2021

Was the trial ended prematurely?

Main objective of the trial

The main objective of the Phase 1b part was to determine the safety and tolerability of talimogene laherparepvec in combination with ipilimumab as assessed by incidence of dose-limiting toxicities (DLT) in subjects with previously untreated, unresected, stages IIIB to IV melanoma. The main objective of the Phase 2 part was to evaluate the efficacy as assessed by confirmed objective response rate (ORR) of treatment with talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in subjects with unresected, stages IIIB to IV melanoma.

Protection of trial subjects

This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The study protocol and all amendments, the informed consent form, and any accompanying materials provided to the subjects were reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) at each study center. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Feb 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

60 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 202

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

Germany: 10

Worldwide total number of subjects

217

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

111

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

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

Screening 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.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1b: Talimogene Laherparepvec + Ipilimumab

Arm 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).

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy®

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab administered intravenously every 3 weeks starting at week 6, for a total of 4 infusions.

Investigational medicinal product name

Talimogene Laherparepvec

Investigational medicinal product code

AMG 678

Other name

IMLYGIC®

Pharmaceutical forms

Solution for injection

Routes of administration

Intratumoral use

Dosage and administration details

Talimogene laherparepvec administered by intratumoral injection on Day 1 of Week 1, Day 1 of Week 4, then every two weeks thereafter.

Phase 2: Ipilimumab

Arm description

Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.

Arm type

Active comparator

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy®

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab administered intravenously every 3 weeks starting at week 1, for a total of 4 infusions.

Phase 2: Talimogene Laherparepvec + Ipilimumab

Arm description

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).

Arm type

Experimental

Investigational medicinal product name

Talimogene Laherparepvec

Investigational medicinal product code

AMG 678

Other name

IMLYGIC®

Pharmaceutical forms

Solution for injection

Routes of administration

Intratumoral use

Dosage and administration details

Talimogene laherparepvec administered by intratumoral injection on Day 1 of Week 1, Day 1 of Week 4, then every two weeks thereafter.

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy®

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab administered intravenously every 3 weeks starting at week 6, for a total of 4 infusions.

Number of subjects in period 1	Phase 1b: Talimogene Laherparepvec + Ipilimumab	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Started	19	100	98
Received Talimogene Laherparepvec	19	0 ^[1]	95
Received Ipilimumab	18	95	92
Completed	6	36	37
Not completed	13	64	61
Consent withdrawn by subject	4	16	17
Death	8	46	40
Lost to follow-up	1	2	4

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants in this group did not receive talimogene laherparepvec.

Baseline characteristics

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Reporting group title

Phase 1b: Talimogene Laherparepvec + Ipilimumab

Reporting group description

Reporting group title

Phase 2: Ipilimumab

Reporting group description

Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.

Reporting group title

Phase 2: Talimogene Laherparepvec + Ipilimumab

Reporting group description

Reporting group values	Phase 1b: Talimogene Laherparepvec + Ipilimumab	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab	Total
Number of subjects	19	100	98	217
Age Categorical
Units: participants
< 65 years	11	54	46	111
≥ 65 years	8	46	52	106
Age Continuous
Units: years
arithmetic mean (standard deviation)	61.1 ( 12.1 )	64.2 ( 13.3 )	63.6 ( 14.0 )	-
Sex: Female, Male
Units: participants
Female	11	45	36	92
Male	8	55	62	125
Race/Ethnicity, Customized
Units: Subjects
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
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	4	0	5
Not Hispanic or Latino	18	96	98	212
Unknown or Not Reported	0	0	0	0
Eastern Cooperative Oncology Group (ECOG) Performance Status
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.
Units: Subjects
0 (Fully active)	14	73	69	156
1 (Restrictive but ambulatory)	5	27	29	61
Tumor, Node, Metastasis (TNM) Disease Stage
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.
Units: Subjects
Stage IIIB - IVM1a	8	57	50	115
Stage IVM1b/c	11	43	48	102
BRAF V600 Mutation Status
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).
Units: Subjects
Mutation	12	34	35	81
Wild-type	7	60	62	129
Missing/Unknown	0	6	1	7

End points

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Reporting group title

Phase 1b: Talimogene Laherparepvec + Ipilimumab

Reporting group description

Reporting group title

Phase 2: Ipilimumab

Reporting group description

Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.

Reporting group title

Phase 2: Talimogene Laherparepvec + Ipilimumab

Reporting group description

Primary: Phase 1b: Number of Participants with Dose-limiting Toxicities

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End point title

Phase 1b: Number of Participants with Dose-limiting Toxicities ^[1] ^[2]

End point 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.

End point type

Primary

End point timeframe

The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12).

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Phase 1b was a single-arm study with no statistical comparisons conducted.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 1b: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	19
Units: participants	0

No statistical analyses for this end point

Primary: Phase 2: Objective Response Rate

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End point title

Phase 2: Objective Response Rate ^[3]

End point 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.

End point type

Primary

End point timeframe

Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: percentage of participants
number (confidence interval 95%)	18.0 (11.0 to 26.9)	38.8 (29.1 to 49.2)

Primary Analysis of ORR

Comparison groups

Phase 2: Ipilimumab v Phase 2: Talimogene Laherparepvec + Ipilimumab

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Chi-squared corrected

Parameter type

Odds ratio (OR)

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.5

upper limit

5.5

Secondary: Phase 1b: Objective Response Rate

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End point title

Phase 1b: Objective Response Rate ^[4]

End point description

End point type

Secondary

End point timeframe

Tumor response was assesed every 12 weeks until disease progression; median follow-up time at the primary analysis was 148.4 weeks.

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 1b: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	19
Units: percentage of participants
number (confidence interval 95%)	52.6 (28.9 to 75.6)

No statistical analyses for this end point

Secondary: Phase 2: Best Overall Response

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End point title

Phase 2: Best Overall Response ^[5]

End point 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.

End point type

Secondary

End point timeframe

Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: 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

No statistical analyses for this end point

Secondary: Phase 2: Disease Control Rate

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End point title

Phase 2: Disease Control Rate ^[6]

End point 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.

End point type

Secondary

End point timeframe

Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: percentage of participants
number (confidence interval 95%)	42.0 (32.2 to 52.3)	58.2 (47.8 to 68.1)

Primary Analysis of DCR

Comparison groups

Phase 2: Ipilimumab v Phase 2: Talimogene Laherparepvec + Ipilimumab

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.033 ^[7]

Method

Chi-squared corrected

Parameter type

Odds ratio (OR)

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

3.4

Notes
[7] - P-value is descriptive

Secondary: Phase 2: Durable Response Rate

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End point title

Phase 2: Durable Response Rate ^[8]

End point 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.

End point type

Secondary

End point timeframe

Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: percentage of participants
number (confidence interval 95%)	13.0 (7.1 to 21.2)	29.6 (20.8 to 39.7)

Primary Analysis of DRR

Comparison groups

Phase 2: Ipilimumab v Phase 2: Talimogene Laherparepvec + Ipilimumab

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.007 ^[9]

Method

Chi-squared corrected

Parameter type

Odds ratio (OR)

Point estimate

2.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.4

upper limit

5.8

Notes
[9] - P-value is descriptive.

Secondary: Phase 2: Time to Response

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End point title

Phase 2: Time to Response ^[10]

End point 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. "99999" indicates values that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	5.8 (5.4 to 10.9)

Priamry Analysis of TTR

Comparison groups

Phase 2: Ipilimumab v Phase 2: Talimogene Laherparepvec + Ipilimumab

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.228 ^[11]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

2.49

Notes
[11] - P-value is descriptive

Secondary: Phase 2: Duration of Response

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End point title

Phase 2: Duration of Response ^[12]

End point 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. "99999" indicates values that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	18 ^[13]	38 ^[14]
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[13] - Participants with a confirmed CR or PR.
[14] - Participants with a confirmed CR or PR.

No statistical analyses for this end point

Secondary: Phase 2: Progression-free Survival

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End point title

Phase 2: Progression-free Survival ^[15]

End point 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.

End point type

Secondary

End point timeframe

From randomization until the primary analysis 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.

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: months
median (confidence interval 95%)	6.4 (3.2 to 16.5)	8.2 (4.2 to 21.5)

Primary Analysis of PFS

Comparison groups

Phase 2: Ipilimumab v Phase 2: Talimogene Laherparepvec + Ipilimumab

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.348

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.23

Secondary: Phase 2: Resection Rate

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End point title

Phase 2: Resection Rate ^[16]

End point 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.

End point type

Secondary

End point timeframe

From randomization until the primary analysis 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.

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: percentage of participants
number (confidence interval 95%)	3.0 (0.6 to 8.5)	5.1 (1.7 to 11.5)

Primary Analysis of Resection Rate

Comparison groups

Phase 2: Ipilimumab v Phase 2: Talimogene Laherparepvec + Ipilimumab

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.696

Method

Chi-squared corrected

Confidence interval

Secondary: Phase 2: Overall Survival

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End point title

Phase 2: Overall Survival ^[17]

End point 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. "99999" indicates values that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

From randomization until the primary analysis 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.

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Primary Analysis of OS

Comparison groups

Phase 2: Ipilimumab v Phase 2: Talimogene Laherparepvec + Ipilimumab

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.474

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

1.46

Secondary: Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24

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End point title

Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 ^[18]

End point 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.

End point type

Secondary

End point timeframe

Months 12 and 24; The median (Q1, Q3) follow-up time from randomization to the primary analysis data cutoff date was 80.6 (58.3, 106.3) weeks.

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: percentage of participants
number (confidence interval 95%)
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)

No statistical analyses for this end point

Secondary: Phase 2: Progression-free Survival - Final Analysis

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End point title

Phase 2: Progression-free Survival - Final Analysis ^[19]

End point description

Progression-free survival was measured from the date of randomization to the date of disease progression (as measured by modified irRC) or death, whichever occurred first. Participants who had no disease progression and did not die while on study were censored at the last disease assessment date.

End point type

Secondary

End point timeframe

From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group.

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: months
median (confidence interval 95%)	6.4 (3.8 to 17.1)	13.5 (5.2 to 25.0)

Final Analysis of PFS

Comparison groups

Phase 2: Ipilimumab v Phase 2: Talimogene Laherparepvec + Ipilimumab

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.14

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

1.09

Secondary: Phase 2: Overall Survival - Final Analysis

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End point title

Phase 2: Overall Survival - Final Analysis ^[20]

End point 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. "99999" indicates values that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group.

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: months
median (confidence interval 95%)	50.1 (32.0 to 99999)	84.9 (41.0 to 99999)

Final Analysis of OS

Comparison groups

Phase 2: Ipilimumab v Phase 2: Talimogene Laherparepvec + Ipilimumab

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.37

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.24

Secondary: Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis

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End point title

Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis ^[21]

End point description

End point type

Secondary

End point timeframe

Months 12 and 24

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported separately for Phase 1b and Phase 2

End point values	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	100	98
Units: percentage of participants
number (confidence interval 95%)
Month 12	79.9 (70.4 to 86.7)	83.3 (74.2 to 89.4)
Month 24	69.3 (58.9 to 77.5)	72.7 (62.5 to 80.5)

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events

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End point title

Number of Participants with Adverse Events

End point 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).

End point type

Secondary

End point timeframe

From first dose of study drug until 30 days after last dose of talimogene laherparepvec or 60 days after last dose of ipilimumab, whichever was later; median duration of treatment was 14.7, 9.1, and 21.1 weeks in each treatment group respectively.

End point values	Phase 1b: Talimogene Laherparepvec + Ipilimumab	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Number of subjects analysed	19	95	95
Units: participants
All adverse events	19	90	92
Adverse events ≥ grade 2	17	72	80
Adverse events ≥ grade 3	7	41	44
Adverse events ≥ grade 4	2	4	6
Serious adverse events	6	34	34
AEs leading to discontinuation of T-VEC	0	0	6
AEs leading to discontinuation of ipilimumab	0	17	13
Fatal adverse events	1	1	5
T-VEC-related adverse events	17	0	82
T-VEC-related adverse events AEs ≥ grade 2	12	0	44
T-VEC-related adverse events AEs ≥ grade 3	3	0	15
T-VEC-related adverse events ≥ grade 4	0	0	1
T-VEC-related serious adverse events	1	0	10
T-VEC-related AEs leading to T-VEC discontinuation	0	0	0
Fatal T-VEC-related adverse events	0	0	0
Ipilimumab-related adverse events	15	78	75
Ipilimumab-related adverse events ≥ grade 2	8	50	48
Ipilimumab-related adverse events ≥ grade 3	4	21	19
Ipilimumab-related adverse events ≥ grade 4	1	2	1
Ipilimumab-related serious adverse events	4	19	14
Imab-related AEs leading to Imab discontinuation	0	12	11
Fatal ipilimumab-related adverse events	0	0	1

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Phase 1b: Talimogene Laherparepvec + Ipilimumab

Reporting 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. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL 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).

Reporting group title

Phase 2: Ipilimumab

Reporting group description

Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1.

Reporting group title

Phase 2: Talimogene Laherparepvec + Ipilimumab

Reporting group description

Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL 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).

Serious adverse events	Phase 1b: Talimogene Laherparepvec + Ipilimumab	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 19 (31.58%)	34 / 95 (35.79%)	34 / 95 (35.79%)
number of deaths (all causes)	9	51	43
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma
subjects affected / exposed	0 / 19 (0.00%)	2 / 95 (2.11%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Malignant neoplasm progression
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Malignant pleural effusion
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	2 / 95 (2.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Tumour flare
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	5 / 95 (5.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injection site reaction
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	2 / 95 (2.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	2 / 95 (2.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	2 / 95 (2.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Amylase increased
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intracranial mass
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphopenia
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Exophthalmos
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Autoimmune colitis
subjects affected / exposed	0 / 19 (0.00%)	3 / 95 (3.16%)	3 / 95 (3.16%)
occurrences causally related to treatment / all	0 / 0	5 / 5	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 19 (0.00%)	9 / 95 (9.47%)	6 / 95 (6.32%)
occurrences causally related to treatment / all	0 / 0	12 / 12	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 19 (0.00%)	2 / 95 (2.11%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 19 (10.53%)	0 / 95 (0.00%)	2 / 95 (2.11%)
occurrences causally related to treatment / all	2 / 2	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypophysitis
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphocytic hypophysitis
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	2 / 95 (2.11%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adrenocortical insufficiency acute
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus colitis
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	2 / 95 (2.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 19 (0.00%)	2 / 95 (2.11%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase 1b: Talimogene Laherparepvec + Ipilimumab	Phase 2: Ipilimumab	Phase 2: Talimogene Laherparepvec + Ipilimumab
Total subjects affected by non serious adverse events
subjects affected / exposed	19 / 19 (100.00%)	85 / 95 (89.47%)	91 / 95 (95.79%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	1 / 19 (5.26%)	4 / 95 (4.21%)	4 / 95 (4.21%)
occurrences all number	1	5	4
Vascular disorders
Embolism
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Hot flush
subjects affected / exposed	0 / 19 (0.00%)	1 / 95 (1.05%)	6 / 95 (6.32%)
occurrences all number	0	1	6
Hypertension
subjects affected / exposed	1 / 19 (5.26%)	3 / 95 (3.16%)	4 / 95 (4.21%)
occurrences all number	1	3	9
General disorders and administration site conditions
Application site pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	1
Asthenia
subjects affected / exposed	0 / 19 (0.00%)	10 / 95 (10.53%)	7 / 95 (7.37%)
occurrences all number	0	11	13
Chest pain
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	1 / 95 (1.05%)
occurrences all number	1	1	1
Chills
subjects affected / exposed	11 / 19 (57.89%)	4 / 95 (4.21%)	50 / 95 (52.63%)
occurrences all number	46	4	111
Fatigue
subjects affected / exposed	11 / 19 (57.89%)	40 / 95 (42.11%)	56 / 95 (58.95%)
occurrences all number	18	51	103
Influenza like illness
subjects affected / exposed	3 / 19 (15.79%)	1 / 95 (1.05%)	27 / 95 (28.42%)
occurrences all number	5	1	89
Injection site inflammation
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	1
Injection site pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	27 / 95 (28.42%)
occurrences all number	3	0	42
Injection site reaction
subjects affected / exposed	2 / 19 (10.53%)	0 / 95 (0.00%)	15 / 95 (15.79%)
occurrences all number	3	0	34
Injection site swelling
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	5 / 95 (5.26%)
occurrences all number	0	0	6
Malaise
subjects affected / exposed	1 / 19 (5.26%)	2 / 95 (2.11%)	7 / 95 (7.37%)
occurrences all number	1	2	9
Oedema peripheral
subjects affected / exposed	2 / 19 (10.53%)	5 / 95 (5.26%)	14 / 95 (14.74%)
occurrences all number	2	6	19
Pain
subjects affected / exposed	3 / 19 (15.79%)	4 / 95 (4.21%)	11 / 95 (11.58%)
occurrences all number	7	7	20
Performance status decreased
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Peripheral swelling
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	3 / 95 (3.16%)
occurrences all number	1	1	5
Pyrexia
subjects affected / exposed	11 / 19 (57.89%)	9 / 95 (9.47%)	36 / 95 (37.89%)
occurrences all number	34	11	76
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 19 (5.26%)	11 / 95 (11.58%)	21 / 95 (22.11%)
occurrences all number	1	13	24
Dyspnoea
subjects affected / exposed	1 / 19 (5.26%)	10 / 95 (10.53%)	8 / 95 (8.42%)
occurrences all number	1	11	13
Hiccups
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	2 / 95 (2.11%)
occurrences all number	1	1	2
Pleural effusion
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	1 / 95 (1.05%)
occurrences all number	2	1	1
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	7 / 95 (7.37%)
occurrences all number	1	1	7
Depression
subjects affected / exposed	0 / 19 (0.00%)	2 / 95 (2.11%)	5 / 95 (5.26%)
occurrences all number	0	2	7
Insomnia
subjects affected / exposed	0 / 19 (0.00%)	16 / 95 (16.84%)	10 / 95 (10.53%)
occurrences all number	0	16	10
Nightmare
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 19 (15.79%)	6 / 95 (6.32%)	8 / 95 (8.42%)
occurrences all number	4	7	14
Amylase increased
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	1 / 95 (1.05%)
occurrences all number	1	1	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 19 (0.00%)	5 / 95 (5.26%)	8 / 95 (8.42%)
occurrences all number	0	6	17
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 19 (0.00%)	2 / 95 (2.11%)	5 / 95 (5.26%)
occurrences all number	0	3	11
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 19 (0.00%)	3 / 95 (3.16%)	5 / 95 (5.26%)
occurrences all number	0	3	8
Lipase increased
subjects affected / exposed	1 / 19 (5.26%)	2 / 95 (2.11%)	0 / 95 (0.00%)
occurrences all number	1	2	0
Weight decreased
subjects affected / exposed	0 / 19 (0.00%)	6 / 95 (6.32%)	2 / 95 (2.11%)
occurrences all number	0	6	2
Injury, poisoning and procedural complications
Radius fracture
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Nervous system disorders
Brain oedema
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences all number	1	1	0
Cluster headache
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	1
Dizziness
subjects affected / exposed	1 / 19 (5.26%)	4 / 95 (4.21%)	10 / 95 (10.53%)
occurrences all number	1	4	13
Headache
subjects affected / exposed	8 / 19 (42.11%)	22 / 95 (23.16%)	34 / 95 (35.79%)
occurrences all number	17	27	67
Peripheral sensory neuropathy
subjects affected / exposed	1 / 19 (5.26%)	2 / 95 (2.11%)	0 / 95 (0.00%)
occurrences all number	1	3	0
Peripheral motor neuropathy
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Speech disorder
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Tension headache
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	5	0	0
Tremor
subjects affected / exposed	1 / 19 (5.26%)	2 / 95 (2.11%)	0 / 95 (0.00%)
occurrences all number	1	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 19 (0.00%)	5 / 95 (5.26%)	11 / 95 (11.58%)
occurrences all number	0	6	18
Lymphopenia
subjects affected / exposed	0 / 19 (0.00%)	3 / 95 (3.16%)	10 / 95 (10.53%)
occurrences all number	0	7	20
Eye disorders
Eye pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Uveitis
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Vision blurred
subjects affected / exposed	3 / 19 (15.79%)	8 / 95 (8.42%)	6 / 95 (6.32%)
occurrences all number	3	8	7
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 19 (0.00%)	11 / 95 (11.58%)	15 / 95 (15.79%)
occurrences all number	0	12	16
Constipation
subjects affected / exposed	2 / 19 (10.53%)	8 / 95 (8.42%)	14 / 95 (14.74%)
occurrences all number	2	8	21
Diarrhoea
subjects affected / exposed	8 / 19 (42.11%)	33 / 95 (34.74%)	40 / 95 (42.11%)
occurrences all number	13	49	81
Dyspepsia
subjects affected / exposed	1 / 19 (5.26%)	2 / 95 (2.11%)	4 / 95 (4.21%)
occurrences all number	1	3	4
Nausea
subjects affected / exposed	9 / 19 (47.37%)	26 / 95 (27.37%)	36 / 95 (37.89%)
occurrences all number	10	27	71
Vomiting
subjects affected / exposed	5 / 19 (26.32%)	13 / 95 (13.68%)	19 / 95 (20.00%)
occurrences all number	5	13	27
Colitis
subjects affected / exposed	0 / 19 (0.00%)	6 / 95 (6.32%)	2 / 95 (2.11%)
occurrences all number	0	10	2
Haematochezia
subjects affected / exposed	0 / 19 (0.00%)	5 / 95 (5.26%)	0 / 95 (0.00%)
occurrences all number	0	5	0
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	0 / 19 (0.00%)	2 / 95 (2.11%)	6 / 95 (6.32%)
occurrences all number	0	2	7
Erythema
subjects affected / exposed	2 / 19 (10.53%)	2 / 95 (2.11%)	6 / 95 (6.32%)
occurrences all number	3	4	6
Hyperhidrosis
subjects affected / exposed	0 / 19 (0.00%)	3 / 95 (3.16%)	6 / 95 (6.32%)
occurrences all number	0	3	7
Night sweats
subjects affected / exposed	2 / 19 (10.53%)	2 / 95 (2.11%)	2 / 95 (2.11%)
occurrences all number	5	2	2
Pruritus
subjects affected / exposed	8 / 19 (42.11%)	35 / 95 (36.84%)	39 / 95 (41.05%)
occurrences all number	12	44	54
Rash
subjects affected / exposed	9 / 19 (47.37%)	29 / 95 (30.53%)	40 / 95 (42.11%)
occurrences all number	13	40	76
Rash erythematous
subjects affected / exposed	2 / 19 (10.53%)	1 / 95 (1.05%)	3 / 95 (3.16%)
occurrences all number	3	1	3
Rash maculo-papular
subjects affected / exposed	0 / 19 (0.00%)	2 / 95 (2.11%)	6 / 95 (6.32%)
occurrences all number	0	2	8
Skin disorder
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Skin lesion
subjects affected / exposed	1 / 19 (5.26%)	2 / 95 (2.11%)	4 / 95 (4.21%)
occurrences all number	2	2	5
Vitiligo
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	4 / 95 (4.21%)
occurrences all number	1	0	5
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	1
Bladder pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Dysuria
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Pollakiuria
subjects affected / exposed	1 / 19 (5.26%)	3 / 95 (3.16%)	3 / 95 (3.16%)
occurrences all number	1	3	3
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 19 (5.26%)	3 / 95 (3.16%)	2 / 95 (2.11%)
occurrences all number	1	3	2
Hypothyroidism
subjects affected / exposed	2 / 19 (10.53%)	4 / 95 (4.21%)	4 / 95 (4.21%)
occurrences all number	2	4	4
Lymphocytic hypophysitis
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	1 / 95 (1.05%)
occurrences all number	1	1	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 19 (5.26%)	15 / 95 (15.79%)	21 / 95 (22.11%)
occurrences all number	5	19	33
Back pain
subjects affected / exposed	2 / 19 (10.53%)	8 / 95 (8.42%)	10 / 95 (10.53%)
occurrences all number	2	8	12
Muscle spasms
subjects affected / exposed	1 / 19 (5.26%)	2 / 95 (2.11%)	4 / 95 (4.21%)
occurrences all number	1	2	4
Muscle tightness
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	5 / 95 (5.26%)
occurrences all number	0	0	12
Muscular weakness
subjects affected / exposed	1 / 19 (5.26%)	4 / 95 (4.21%)	4 / 95 (4.21%)
occurrences all number	1	5	5
Myalgia
subjects affected / exposed	1 / 19 (5.26%)	4 / 95 (4.21%)	10 / 95 (10.53%)
occurrences all number	8	5	12
Pain in extremity
subjects affected / exposed	2 / 19 (10.53%)	7 / 95 (7.37%)	5 / 95 (5.26%)
occurrences all number	3	8	6
Pubic pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Soft tissue mass
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Infections and infestations
Escherichia infection
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Eye infection
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	1
Influenza
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Nasopharyngitis
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	4 / 95 (4.21%)
occurrences all number	1	0	6
Oral herpes
subjects affected / exposed	0 / 19 (0.00%)	0 / 95 (0.00%)	6 / 95 (6.32%)
occurrences all number	0	0	6
Sinusitis
subjects affected / exposed	2 / 19 (10.53%)	0 / 95 (0.00%)	4 / 95 (4.21%)
occurrences all number	2	0	6
Upper respiratory tract infection
subjects affected / exposed	1 / 19 (5.26%)	5 / 95 (5.26%)	6 / 95 (6.32%)
occurrences all number	1	5	6
Vaginal infection
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	2 / 19 (10.53%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	2	0	0
Wound infection
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	0 / 95 (0.00%)
occurrences all number	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 19 (21.05%)	14 / 95 (14.74%)	12 / 95 (12.63%)
occurrences all number	5	16	14
Dehydration
subjects affected / exposed	2 / 19 (10.53%)	5 / 95 (5.26%)	3 / 95 (3.16%)
occurrences all number	2	5	3
Hypercalcaemia
subjects affected / exposed	1 / 19 (5.26%)	0 / 95 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	1
Hyperglycaemia
subjects affected / exposed	4 / 19 (21.05%)	7 / 95 (7.37%)	7 / 95 (7.37%)
occurrences all number	5	8	9
Hyperuricaemia
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences all number	2	1	0
Hypocalcaemia
subjects affected / exposed	1 / 19 (5.26%)	1 / 95 (1.05%)	0 / 95 (0.00%)
occurrences all number	1	1	0
Hypomagnesaemia
subjects affected / exposed	1 / 19 (5.26%)	2 / 95 (2.11%)	3 / 95 (3.16%)
occurrences all number	1	2	5
Hypokalaemia
subjects affected / exposed	2 / 19 (10.53%)	8 / 95 (8.42%)	6 / 95 (6.32%)
occurrences all number	2	9	7
Hyponatraemia
subjects affected / exposed	0 / 19 (0.00%)	5 / 95 (5.26%)	4 / 95 (4.21%)
occurrences all number	0	8	4

More information

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Were there any global substantial amendments to the protocol? Yes

07 Aug 2013

- Subjects with a history of complicated herpes infection (eg, herpetic keratitis or meningoencephalitis) were excluded from the study. - Study assessments were modified to include collection and storage of blood and urine samples, and swabs of any lesions suspected of herpetic origin, for detection of talimogene laherparepvec DNA using qPCR testing. - A requirement for reporting potential or known unintended exposure to talimogene laherparepvec in a subject’s household member, caregiver, or healthcare provider was added. - Optional tumor biopsy procedure for biomarker analyses was modified to allow biopsy of lesions that were not injectable. - Subjects who completed the protocol-specified long-term follow-up period for reasons other than death or full withdrawal of consent were to be followed for long-term survival under an ongoing separate registry protocol for subjects treated with talimogene laherparepvec in clinical trials. The registry protocol also monitored for late and long-term adverse events thought to be potentially related to talimogene laherparepvec. - Serious adverse event reporting procedures were updated to instruct investigators to report serious adverse events that occurred outside of the protocol-specified reporting period per the European Union CT-3 guidance. - Response criteria were clarified. - The statistical analysis was updated to include descriptive analyses of the qPCR results of talimogene laherparepvec DNA.

08 Oct 2014

- Requirement added that imaging studies in phase 2 were to be collected and held at an independent centralized radiology vendor for potential retrospective evaluation of tumor response by an independent centralized endpoint assessment committee. - The primary objective/endpoint in phase 2 was changed from assessment of OS to assessment of confirmed ORR. The assessment of OS was made a secondary objective/endpoint. - Eligibility criteria were modified to allow subjects who received prior treatment for melanoma to enroll into phase 2. - Sample size in phase 2 was increased from 140 to 200 subjects to allow formal testing for ORR (rather than estimating OS). - Secondary endpoints (BOR, DCR, and DDR) were added for phase 2. - Exploratory objectives were modified to remove investigation of HLA type and other genetic variations and to add PRO exploratory objectives/endpoints to the phase 2 part of the study. - Measurable disease was further defined. - Stratification factors for phase 2 were updated (stage of disease and prior therapy). - Subjects with central nervous system metastasis who had been treated and were stable were allowed to enroll. - Subjects with type I diabetes mellitus, prior splenectomy or splenic irradiation were allowed to enroll. - Coagulation function requirements at baseline were revised to align with other ongoing talimogene laherparepvec studies. - Permitted medications were updated to allow for therapeutic anticoagulants. - Additional details were added regarding the timing of biopsy procedures. - Details regarding the statistical analyses were updated to align with the changes made to the primary and secondary objectives of the study; planned interim analyses for phase 2 were added.

30 Nov 2015

- Study duration was increased to a maximum of 3 years follow-up from the time the last subject was randomized. - Eligibility criteria were modified: subjects who received nononcology vaccine therapies for the prevention of infectious disease were allowed to enroll; the definition of autoimmune disease was clarified, subjects who were unwilling to follow the procedures to safeguard others against the potential transmission of talimogene laherparepvec were excluded. - Permitted medications were updated to allow nononcology vaccine therapies that were used for the prevention of infectious disease. - More flexibility in the frequency of radiographic imaging was allowed for subjects who achieved CR in long-term follow-up. - The long-term follow-up survival assessment was updated to include collection of talimogene laherparepvec-related adverse events. - Response criteria were clarified. - A second updated interim analysis was added, conducted 24 weeks after the first interim analysis of efficacy and safety. - First-line analysis set was removed; testing of ORR used the ITT analysis set with an overall nominal level of 0.05. - The ability to conduct interim analyses and formal testing of OS was added.

02 Mar 2016

- The instructions regarding how to record responses after a tumor resection were corrected for consistency between protocol sections. - The aggregate unblinded results from the interim analyses were allowed to be shared with investigators and study team members on an as-needed basis.

05 Nov 2018

- Added 4- and 5-year OS analysis.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1b/2, Multicenter, Open-label Trial to Evaluate the Safety and Efficacy of Talimogene Laherparepvec and Ipilimumab Compared to Ipilimumab Alone in Subjects With Unresected, Stage IIIB-IV Melanoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Number of Participants with Dose-limiting Toxicities

Primary: Phase 1b: Number of Participants with Dose-limiting Toxicities

Primary: Phase 2: Objective Response Rate

Primary: Phase 2: Objective Response Rate

Secondary: Phase 1b: Objective Response Rate

Secondary: Phase 1b: Objective Response Rate

Secondary: Phase 2: Best Overall Response

Secondary: Phase 2: Best Overall Response

Secondary: Phase 2: Disease Control Rate

Secondary: Phase 2: Disease Control Rate

Secondary: Phase 2: Durable Response Rate

Secondary: Phase 2: Durable Response Rate

Secondary: Phase 2: Time to Response

Secondary: Phase 2: Time to Response

Secondary: Phase 2: Duration of Response

Secondary: Phase 2: Duration of Response

Secondary: Phase 2: Progression-free Survival

Secondary: Phase 2: Progression-free Survival

Secondary: Phase 2: Resection Rate

Secondary: Phase 2: Resection Rate

Secondary: Phase 2: Overall Survival

Secondary: Phase 2: Overall Survival

Secondary: Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24

Secondary: Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24

Secondary: Phase 2: Progression-free Survival - Final Analysis

Secondary: Phase 2: Progression-free Survival - Final Analysis

Secondary: Phase 2: Overall Survival - Final Analysis

Secondary: Phase 2: Overall Survival - Final Analysis

Secondary: Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis

Secondary: Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis

Secondary: Number of Participants with Adverse Events

Secondary: Number of Participants with Adverse Events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1b/2, Multicenter, Open-label Trial to Evaluate the Safety and Efficacy of Talimogene Laherparepvec and Ipilimumab Compared to Ipilimumab Alone in Subjects With Unresected, Stage IIIB-IV Melanoma