Clinical Trial Results:
A Phase 2, Multicenter, Open-label, Single-arm Trial to Evaluate the Correlation Between Objective Response Rate and Baseline Intratumoral CD8+ Cell Density in Subjects With Unresected Stage IIIB to IVM1c Melanoma Treated With Talimogene Laherparepvec
|
Summary
|
|
EudraCT number |
2013-005552-15 |
Trial protocol |
IT ES DE BE AT HU PL GR NL |
Global end of trial date |
25 Dec 2020
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
14 Oct 2021
|
First version publication date |
14 Oct 2021
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
20120325
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02366195 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Amgen Inc.
|
||
Sponsor organisation address |
One Amgen Center Drive, Thousand Oaks, CA, United States,
|
||
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
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
25 Dec 2020
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
25 Dec 2020
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The main objective of this trial was to explore the correlation between baseline intratumoral CD8+ cell density and objective response rate (ORR) in participants with unresected stage IIIB to IVM1c melanoma treated with talimogene laherparepvec.
|
||
Protection of trial subjects |
This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Apr 2015
|
||
Long term follow-up planned |
Yes
|
||
Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Austria: 4
|
||
Country: Number of subjects enrolled |
Belgium: 3
|
||
Country: Number of subjects enrolled |
France: 17
|
||
Country: Number of subjects enrolled |
Germany: 14
|
||
Country: Number of subjects enrolled |
Greece: 10
|
||
Country: Number of subjects enrolled |
Hungary: 7
|
||
Country: Number of subjects enrolled |
Italy: 7
|
||
Country: Number of subjects enrolled |
Netherlands: 2
|
||
Country: Number of subjects enrolled |
Poland: 6
|
||
Country: Number of subjects enrolled |
Russian Federation: 15
|
||
Country: Number of subjects enrolled |
Spain: 16
|
||
Country: Number of subjects enrolled |
United Kingdom: 11
|
||
Worldwide total number of subjects |
112
|
||
EEA total number of subjects |
86
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
48
|
||
From 65 to 84 years |
54
|
||
85 years and over |
10
|
||
|
|||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||
Recruitment details |
This study was conducted at 36 centers across 12 countries in Europe from 07 April 2015 to 25 December 2020. | ||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||
Screening details |
Participants were screened within 28 days of receiving treatment. | ||||||||||||||||||
|
Period 1
|
|||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
|
||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||
|
Arms
|
|||||||||||||||||||
|
Arm title
|
Talimogene Laherparepvec | ||||||||||||||||||
Arm description |
Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 21 days after the initial dose and every 14 days thereafter. Participants were treated with talimogene laherparepvec until they achieved a complete response, all injectable tumors had disappeared, clinically significant (resulting in clinical deterioration or requiring change of therapy) disease progression beyond 6 months of treatment, per modified World Health Organization (WHO) response criteria, or intolerance of study treatment, whichever occurred first. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Talimogene Laherparepvec
|
||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||
Other name |
|||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||
Routes of administration |
Intralesional use
|
||||||||||||||||||
Dosage and administration details |
Talimogene laherparepvec administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions.
|
||||||||||||||||||
|
|||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall Study
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Talimogene Laherparepvec
|
||
Reporting group description |
Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 21 days after the initial dose and every 14 days thereafter. Participants were treated with talimogene laherparepvec until they achieved a complete response, all injectable tumors had disappeared, clinically significant (resulting in clinical deterioration or requiring change of therapy) disease progression beyond 6 months of treatment, per modified World Health Organization (WHO) response criteria, or intolerance of study treatment, whichever occurred first. | ||
|
|||||||||
End point title |
Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Objective Response Rate [1] | ||||||||
End point description |
A univariate logistic regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of objective response.
Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Objective response rate (ORR) was defined as the percentage of participants with a complete response (CR) or partial response (PR) according to the modified WHO criteria.
The unadjusted odds ratio of log2(baseline intratumoral CD8+ cell density) for objective response rate is reported. P value = 0.435 (method = Regression, Logistic)
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
| 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: Due to the single arm nature of this study, no comparative analysis was performed. |
|||||||||
|
|||||||||
| Notes [2] - Participants who received at least 1 dose of study treatment & baseline CD8+ cell density data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Odds Ratio of Baseline Intratumoral CD8+ Cell Density and Durable Response Rate | ||||||||
End point description |
A univariate logistic regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of durable response.
Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Durable response rate (DRR) was defined as the percentage of participants with an objective response lasting continuously for 6 months and starting any time within 12 months of initiating therapy.
The unadjusted odds ratio of log2(baseline intratumoral CD8+ cell density) for durable response rate is reported. P value = 0.222 (Method = Regression, Logistic).
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| Notes [3] - Participants who received at least 1 dose of study treatment & baseline CD8+ cell density data. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Hazard Ratio of Baseline Intratumoral CD8+ Cell Density and Duration of Response | ||||||||
End point description |
A Cox proportional hazards regression model was performed to evaluate baseline log2(CD8+ cell density) as a predictor of duration of response.
Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Duration of response (DOR) is defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for being in the response (i.e. an overall response of either stable disease [SD] as compared with baseline or progressive disease [PD]).
The unadjusted hazard ratio of log2(baseline intratumoral CD8+ cell density) for duration of response is reported. P value = 0.597 (Method: Cox proportional hazards).
Participants who received at least 1 dose of study treatment and had an objective response and with baseline CD8+ cell density data.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Intratumoral CD8+ cell density: Baseline. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Correlation Between Baseline Intratumoral CD8+ Cell Density and Changes in Tumor Burden | ||||||||
End point description |
Pearson’s correlation coefficient (r) was estimated to assess the relationship between baseline log2(CD8+ cell density) and the maximum decrease in measurable tumor burden.
Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline.
The Pearson’s correlation coefficient (r) of log2(baseline intratumoral CD8+ cell density) and the maximum decrease in tumor burden is reported. P value = 0.90 (Method: Fisher's Z transformation).
Includes all participants who received at least 1 dose of study treatment with available tumor burden data and non-missing baseline CD8+ cell density data.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Intratumoral CD8+ cell density: Baseline; Tumor burden: First dose of study drug until end of follow-up; median time on follow-up:108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Odds Ratio of Change from Baseline Intratumoral CD8+ Cell Density and Objective Response Rate | ||||||||
End point description |
A univariate logistic regression model was performed to evaluate change from baseline to week 6 in log2(CD8+ cell density) in uninjected tumors as a predictor of objective response.
Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Objective response rate (ORR) was defined as the percentage of participants with a complete response or partial response according to the modified WHO criteria. The unadjusted odds ratio of log2(change from baseline intratumoral CD8+ cell density) for objective response rate is reported. P value = 0.881 (Method: Regression, Logistic)
Included all participants who received at least 1 dose of study treatment with non-missing baseline & week 6 CD8+ cell density data for uninjected lesions.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Intratumoral CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Odds Ratio of Change from Baseline in Intratumoral CD8+ Cell Density and Durable Response Rate | ||||||||
End point description |
A univariate logistic regression model was performed to evaluate change from baseline to week 6 in log2(CD8+ cell density) in uninjected lesions as a predictor of durable response.
Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Durable response rate (DRR) was defined as the percentage of participants with an objective response lasting continuously for 6 months and starting any time within 12 months of initiating therapy.
The unadjusted odds ratio of log2(change from baseline in intratumoral CD8+ cell density) for durable response rate is reported. P value = 0.612 (Method: Regression, Logistic)
Includes all participants who received at least 1 dose of study treatment with non-missing baseline and week 6 CD8+ cell density data in uninjected lesions.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Intratumoral CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Hazard Ratio of Change from Baseline in Intratumoral CD8+ Cell Density and Duration of Response | ||||||||
End point description |
A Cox proportional hazards regression model was performed to evaluate change from baseline in log2(CD8+ cell density) as a predictor of duration of response.
Response was assessed according to the modified version of the World Health Organization (WHO) response criteria. Duration of response (DOR) is defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for being in the response (i.e. an overall response of either stable disease [SD] as compared with baseline or progressive disease [PD]).
The unadjusted hazard ratio of log2(change from baseline intratumoral CD8+ cell density) for duration of response is reported. P value = 0.579 (Method: Cox proportional hazards).
Included all participants who received at least 1 dose of study treatment, who had an objective response, and with non-missing baseline & week 6 CD8+ cell density data for uninjected lesions.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Intratumoral CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Correlation Between Change from Baseline in Intratumoral CD8+ Cell Density and Changes in Tumor Burden | ||||||||
End point description |
Pearson’s correlation coefficient (r) was estimated to assess the relationship between change from baseline in log2(CD8+ cell density) in uninjected lesions and the maximum decrease in measurable tumor burden.
Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline. The Pearson’s correlation coefficient (r) of log2(change from baseline intratumoral CD8+ cell density) and the maximum decrease in tumor burden is reported. P value = 0.14 (Method: Fisher's Z transformation).
Includes all participants who received at least 1 dose of study treatment with available tumor burden data and non-missing baseline and week 6 CD8+ cell density data for uninjected lesions.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Intratumoral CD8+ cell density: Baseline & Week 6. Response: every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Objective Response Rate | ||||||||
End point description |
Objective Response rate is defined as the percentage of participants with either a CR or PR based on Modified WHO Response Criteria.
CR: Complete disappearance of all index lesions, all non-index lesions, and any new tumors which might have appeared. Any residual cutaneous or subcutaneous index lesions must be documented by representative biopsy to not contain viable tumor.
PR: Disappearance of all index lesions with persistence of one or more non-index tumor(s), or, 50% or greater reduction in the 2 largest perpendicular diameters (SPD) of all index lesions as compared to baseline, and disappearance or persistence of non-index lesions.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| Notes [4] - All participants who received at least one dose of study treatment |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Duration of Response | ||||||||
End point description |
Duration of response (DOR) was defined as the longest individual period from entering an objective response (CR/PR) to the first documented evidence of the participant no longer meeting the criteria for objective response (i.e. an overall response of either stable disease [SD] as compared with baseline or progressive disease [PD]).
SD: Neither sufficient tumor shrinkage of index lesion to qualify for response (PR or CR) nor sufficient tumor increase of index lesion to qualify for PD, with no increase in size of non index lesions.
PD: A > 25% increase in the sum of the SPD of all index tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point, or unequivocal progression of one or more non-index lesions.
Participants last reported to be either a CR or PR were censored at that time point.
99999 = Not calculated: Median duration of response was not reached as most participants were still in response.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| Notes [5] - Participants who received at least 1 dose of study treatment and had an objective response |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Durable Response Rate | ||||||||
End point description |
Durable response rate (DRR) was defined as the percentage of participants with an objective response (CR or PR) based on modified WHO response criteria lasting continuously for 6 months and starting any time within 12 months of initiating therapy.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed every 12 weeks until PD beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| Notes [6] - All participants who received at least 1 dose of study treatment |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Time to Treatment Failure | ||||||||
End point description |
Time to treatment failure (TTF) was calculated from first dosing until one or more of the following: (1) clinically relevant disease progression (PDr); (2) death from any cause; (3) non clinically relevant disease progression (PDn) associated with a requirement for alternative therapy as the reason for ending treatment or start of new anti-cancer therapy.
Participants with no event were censored at their last evaluable tumor assessment
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From first dose of study drug until end of follow-up; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| Notes [7] - All participants who received at least 1 dose of study treatment |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Overall Survival | ||||||||
End point description |
Overall survival (OS) was defined as the time from the date of first dose to the date of death from any cause. OS time was censored at the last date the participant was known to be alive when the confirmation of death is absent or unknown.
99999 = Not calculated: Median overall survival was not reached due to the low number of deaths.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From first dose of study drug until end of follow-up; median time on follow-up: 108 weeks (2.7 to 245.6 weeks)
|
||||||||
|
|||||||||
| Notes [8] - All participants who received at least 1 dose of study treatment |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline in Tumor Burden | ||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Tumor burden is the sum of the products of the 2 largest perpendicular diameters (SPD) for all index lesions selected at baseline. Change from baseline in tumor burden was assessed in participants with an objective response.
99999 = Not calculated: Only 1 participant with non-missing data at that time point, so standard deviation could not be calculated.
|
||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Day 1 of cycle 6, 12 , 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, and 120. The first cycle was 21 days and all subsequent cycles were 14 days
|
||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [9] - Participants who received at least 1 dose of study treatment with an objective response |
|||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Number of Participants with Adverse Events | ||||||||||||||||||||||||||||||
End point description |
The severity of each adverse event (AE) was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 grading scale, where
Grade 1 = Mild AE
Grade 2 = Moderate AE
Grade 3 = Severe AE
Grade 4 = Life-threatening or disabling AE
Grade 5 = Death related to AE
Treatment-related adverse events (TRAE) were those assessed by the investigator as possibly related to talimogene laherparepvec.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
From first dose through 30 days after last dose of talimogene laherparepvec; median duration of treatment was 25.143 weeks (range 0.14 to 241.43 weeks)
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Deaths: first dose through to end of follow-up; median time on follow up was 108.0 weeks (2.7 to 245.6 weeks). Adverse events: first dose through 30 days after last dose; median duration of treatment was 25.143 weeks (0.14 to 241.43 weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All-cause mortality, serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Talimogene Laherparepvec
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 21 days after the initial dose and every 14 days thereafter. Participants were treated with talimogene laherparepvec until they achieved a complete response, all injectable tumors had disappeared, clinically significant (resulting in clinical deterioration or requiring change of therapy) disease progression beyond 6 months of treatment, per modified World Health Organization (WHO) response criteria, or intolerance of study treatment, whichever occurred first. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
31 Aug 2015 |
The following updates were made:
* Removed Inclusion Criterion 105 to allow participants to join the study after having received first-line therapy.
* Removed exclusion of participants receiving any non oncology vaccine therapies used for the prevention of infectious disease within 28 days prior to enrollment and during treatment period.
* Clarified that if no viable cells were found following surgery, the response definition will be complete response (CR).
* Added testing for herpes simplex virus type 2 (HSV-2) within 3 days prior to dose at day 1 of week 1 [Cycle 1], week 6 [Cycle 3], and week 12 [Cycle 6].
* Increased the window to 5 days for tumor biopsy for biomarker analysis for the Week 1 biopsy, 7 days for the Week 6 biopsy, and to 7 days after documentation of disease progression at PD.
* Added assessment of Eastern Cooperative Oncology Group (ECOG) performance status every 3 months during treatment period.
* Revised photography assessments in the schedule of assessments to remove requirement at screening, update cycles, and removed the word “measurable.”
* In Schedule of Assessments, clarified that the week 1 biopsy should not be collected prior to the participant being enrolled.
* Removed word “uninjected” from the correlation between changes in intratumoral CD8+ cell density during treatment and objective response rate in the study endpoints.
* Revised the number of planned sites to be 50, and removed reference to including sites in the United States.
* Added male contraceptive language to the inclusion criteria.
* Specified how lesions that separate or merging are to be assessed.
* Added an interim analysis.
* Added reporting of treatment related adverse events during the long-term follow-up.
* Added addition of anti-cancer therapy for melanoma during long term period follow-up. |
||
31 Aug 2015 |
31-Aug-2015 amendment continued:
* In Table 5: Definition of Index Lesion Tumor Response Including New Lesions, removed the following text from the definition of partial response, “Any residual cutaneous or subcutaneous index or new lesions that must be tumor free for the participant to meet the criteria for partial response (PR) must be documented as such by representative biopsy”.
* Updated text throughout document to specify cycle number corresponding to study week.
* Implemented minor administrative and formatting changes.
* Added references in Section 2.2 and in the reference list.
* Added ECOG and physical examination during treatment period and follow-up period.
* Added exclusion criteria as specified in the Country-specific protocol supplement for Germany to exclude participants who are unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for HSV-1 induced complications and participants for whom there is any concern of potential harmful effect due to the interaction between talimogene laherparepvec and the residual of prior investigational drug.
* Defined the final analysis after 24 months from LSE rather than keeping it open ended.
* Clarified that unless patients dies or withdraws full consent after they have completed the LTFU portion of the study they will then be transferred to the registry protocol where they will continue to be followed up, until death or full consent withdraw. |
||
21 Sep 2015 |
The following changes were made:
* Added exclusion criterion to avoid potential viral transmission during sexual contact. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
