Clinical Trial Results:
A Phase 2, Multicenter, Randomized, Open-label Trial Assessing the Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma
|
Summary
|
|
EudraCT number |
2014-001146-13 |
Trial protocol |
ES GR |
Global end of trial date |
28 Apr 2022
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
03 Mar 2023
|
First version publication date |
03 Mar 2023
|
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 |
20110266
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
- | ||
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, medinfo@amgen.com
|
||
Scientific contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, medinfo@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 |
16 Aug 2022
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
28 Apr 2022
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery alone in participants with completely resectable stage IIIB, IIIC, or IVM1a melanoma.
|
||
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 |
03 Feb 2015
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Australia: 18
|
||
Country: Number of subjects enrolled |
Brazil: 10
|
||
Country: Number of subjects enrolled |
France: 9
|
||
Country: Number of subjects enrolled |
Greece: 1
|
||
Country: Number of subjects enrolled |
Poland: 8
|
||
Country: Number of subjects enrolled |
Russian Federation: 15
|
||
Country: Number of subjects enrolled |
Spain: 4
|
||
Country: Number of subjects enrolled |
Switzerland: 14
|
||
Country: Number of subjects enrolled |
United States: 71
|
||
Worldwide total number of subjects |
150
|
||
EEA total number of subjects |
22
|
||
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) |
82
|
||
From 65 to 84 years |
66
|
||
85 years and over |
2
|
||
|
|||||||||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||||||||
Recruitment details |
This study was conducted at 35 centers in Australia, Brazil, Europe, Russia, and the United States. Participants were enrolled between 03 February 2015 and 28 April 2022. | ||||||||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||||||||
Screening details |
Participants were randomized 1:1 to receive either talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesions or immediate surgical resection of melanoma tumor lesion(s). Randomization was stratified by disease stage and planned adjuvant therapy. | ||||||||||||||||||||||||
|
Period 1
|
|||||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||
|
Arm title
|
Surgery | ||||||||||||||||||||||||
Arm description |
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6. | ||||||||||||||||||||||||
Arm type |
Surgery alone | ||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
|
||||||||||||||||||||||||
|
Arm title
|
Talimogene Laherparepvec Plus Surgery | ||||||||||||||||||||||||
Arm description |
Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first. Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Talimogene Laherparepvec
|
||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||
Routes of administration |
Subcutaneous use, Cutaneous use
|
||||||||||||||||||||||||
Dosage and administration details |
Talimogene laherparepvec was be administered by intralesional injection into the injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 10^6 plaque forming units (PFU)/mL at Day 1 of Week 1 followed by a dose of 10^8 PFU/mL at Day 1 (±3 days) of Week 4, 6, 8, 10 and 12 or until all injectable tumors disappeared, intolerance of study treatment or in the opinion of the investigator, immediate surgical resection or any other treatment for melanoma was warranted, whichever occurred first.
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Surgery
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Talimogene Laherparepvec Plus Surgery
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first. Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Surgery
|
||
Reporting group description |
Immediate surgical resection of melanoma lesion(s) any time during Weeks 1 to 6. | ||
Reporting group title |
Talimogene Laherparepvec Plus Surgery
|
||
Reporting group description |
Talimogene laherparepvec up to 4.0 mL of 10^6 PFU/mL followed by up to 4.0 mL of 10^8 PFU/mL administered 21 (+5) days after the initial dose. Subsequent doses up to 4.0 mL of 10^8 PFU/mL every 14 (± 3) days until Week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever occurs first. Followed by surgical resection of melanoma lesions(s) anytime during Weeks 13 to 18. | ||
|
|||||||||||||
End point title |
Recurrence-Free Survival (RFS) | ||||||||||||
End point description |
Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
5 years after the last subject was randomized (last subject last visit occurred on 28 April 2022)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Log Rank Test | ||||||||||||
Comparison groups |
Surgery v Talimogene Laherparepvec Plus Surgery
|
||||||||||||
Number of subjects included in analysis |
150
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.092 [1] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.76
|
||||||||||||
Confidence interval |
|||||||||||||
level |
80% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.6 | ||||||||||||
upper limit |
0.97 | ||||||||||||
| Notes [1] - Unstratified log-rank test |
|||||||||||||
|
|||||||||||||||||||||||||
End point title |
Kaplan-Meier (K-M) Estimate of RFS Rate at 1 year, 2 years, 3 years, and 5 years | ||||||||||||||||||||||||
End point description |
Kaplan-Meier estimates of the percentage of participants with RFS at 1 year, 2 years, 3 years, and 5 years from randomization. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment. Rate is presented as the percentage of participants with RFS at given time point.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
5 years after the last subject was randomized (last subject last visit occurred on 28 April 2022)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||
End point title |
Histopathology Tumor-Free Margin (R0) Surgical Resection Rate | ||||||||||||
End point description |
Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as absence of ink on the tumor for all disease. Rate is presented as the percentage of participants with histopathology tumor-free margin (R0) surgical resection.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
18 weeks after last participant randomized (data cutoff date of 30 April 2019)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Pathological Complete Response (pCR) Rate | ||||||||||||
End point description |
Pathological Complete Response (pCR) is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standards of care. Rate is presented as the percentage of participants with pCR.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
18 weeks after last participant randomized (data cutoff date of 30 April 2019)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Chi-squared | ||||||||||||
Comparison groups |
Surgery v Talimogene Laherparepvec Plus Surgery
|
||||||||||||
Number of subjects included in analysis |
150
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.003 [2] | ||||||||||||
Method |
Chi-squared | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
14.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
80% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
7.4 | ||||||||||||
upper limit |
21.6 | ||||||||||||
| Notes [2] - The two-sided p-value is based on the Pearson's Chi-square test. |
|||||||||||||
|
|||||||||||||
End point title |
Local Recurrence-Free Survival (LRFS) | ||||||||||||
End point description |
Local recurrence-free survival (LRFS) is defined as the time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Local recurrence is defined as histologically or cytologically confirmed reappearance of melanoma in the area of up to 2 cm from the scar from the surgical excision or at the edge of the skin graft if that was used for closure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
5 years after the last subject was randomized (last subject last visit occurred on 28 April 2022)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Regional Recurrence-Free Survival (RRFS) | ||||||||||||
End point description |
Regional recurrence-free survival (RRFS) is defined as the time from randomization to the date of the first of regional disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Regional recurrence excludes local recurrence and is defined as histologically, cytologically, or radiographically confirmed reappearance of melanoma in the regional lymph node basin.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
5 years after the last subject was randomized (last subject last visit occurred on 28 April 2022)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Distant Metastases-Free Survival (DMFS) | ||||||||||||
End point description |
Distant metastases-free survival (DMFS) is defined as the time from randomization to the date of the first of distant metastases or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Distant metastases exclude local and regional recurrence and will include distant cutaneous/subcutaneous metastases, distant nodal metastases, or visceral, central nervous system, brain, or bone metastases.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
5 years after the last subject was randomized (last subject last visit occurred on 28 April 2022)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Overall Survival (OS) | ||||||||||||
End point description |
Overall survival (OS) is defined as the time from randomization to the date of death due to any cause.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
5 years after the last subject was randomized (last subject last visit occurred on 28 April 2022)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||
End point title |
Kaplan-Meier (K-M) Estimate of OS at 1 year, 2 years, 3 years, and 5 years | ||||||||||||||||||||||||
End point description |
Kaplan-Meier estimates of the percentage of participants with OS at 1 year, 2 years, 3 years, and 5 years from randomization. OS is defined as death due to any cause.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
5 years after the last subject was randomized (last subject last visit occurred on 28 April 2022)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||
End point title |
Best Overall Tumor Response per Investigator Response Rate (Talimogene Laherparepvec Arm Only) [3] | ||||||||
End point description |
Response was assessed based on the response of the index lesions and nonindex lesions as described in protocol-defined World Health Organization (WHO) criteria (for complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), and presence or absence of new lesions. Best response for a participant is the best overall response observed across all time points. Response rate is reported as the percentage of participants with the best overall response (per investigator) of CR or PR. CR: complete disappearance of all index lesions, including any new measurable tumor lesions which might have appeared. PR: ≥ 50% reduction in the sum of the products of the 2 largest perpendicular diameters of all index lesions and new measurable lesions, if applicable, at the time of assessment as compared to the sum of the products of the perpendicular diameters of all index lesions at baseline.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
18 months after last participant randomized (data cutoff date of 30 April 2019).
|
||||||||
| 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: Talimogene Laherparepvec Arm Only |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Lesion Objective Response Rate: Injected Lesions (Talimogene Laherparepvec Arm Only) [4] | ||||||||
End point description |
The investigator-assessed tumor response rate for injected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
18 months after last participant randomized (data cutoff date of 30 April 2019).
|
||||||||
| 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: Talimogene Laherparepvec Arm Only |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Lesion Objective Response Rate: Uninjected Lesions (Talimogene Laherparepvec Arm Only) [5] | ||||||||
End point description |
The investigator-assessed tumor response rate for uninjected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
18 months after last participant randomized (data cutoff date of 30 April 2019).
|
||||||||
| 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: Talimogene Laherparepvec Arm Only |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Fatal Adverse Events (AEs), and TEAEs Leading to Discontinuations or Interruptions | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a subject (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Adverse Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
|
||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
End point title |
Number of Participants With Talimogene Laherparepvec-Related TEAEs, SAEs, Fatal AEs, and TEAEs Leading to Discontinuations or Interruptions [6] | ||||||||||||||||||||||||||||
End point description |
Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the
following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a subject (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Adverse Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
|
||||||||||||||||||||||||||||
| 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: Talimogene Laherparepvec Arm Only |
|||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All-cause mortality is reported for all participants randomized in the study. Serious adverse events and other adverse events are reported for all randomized subjects who received talimogene laherparepvec or surgical resection of melanoma tumor lesion(s).
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.1
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TALIMOGENE LAHERPAREPVEC PLUS SURGERY
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Talimogene Laherparepvec Plus Surgery | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
SURGERY
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Surgery Only | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
||
09 Jun 2014 |
The protocol was amended for the following reasons: • To update the Data Review Team section. |
||
22 Apr 2016 |
The protocol was amended for the following reasons: • Regional recurrence-free survival was added as secondary objective and endpoint. • The DMFS endpoint was clarified. • The randomization stratification was updated to replace adjuvant interferon with adjuvant interferon alpha and ipilimumab. • The number of sites was changed from 40 to 50. • The 30-day safety follow-up was modified to specify that subjects would be followed for local, regional, and distant disease recurrence and adverse events potentially related to talimogene laherparepvec. • Inclusion criteria of measurable disease, serum lactate dehydrogenase, serum albumin were modified. • Exclusion criteria of autoimmune disease, clinically significant immunosuppression, tumor vaccine, and sexually active subjects and partners unwilling to use latex condoms were updated. • Long-term follow-up was updated to include reporting of adverse events potentially related to talimogene laherparepvec. • Physical examination and ECOG performance status were added at weeks 4 and 8. • Oral and genital swabs were removed from the safety follow-up visit as this information is already being collected in another protocol. • Surgical safety evaluation and subsequent anticancer therapy for melanoma were added to safety follow-up procedures. • Statistical considerations were updated to add RRFS analysis, to clarify DRT review of interim analyses, and to specify that ad hoc analyses may be conducted if required for submission to regulatory authorities. • The definition of progressive disease was clarified to include the unequivocal appearance of new measurable lesion since the last response assessment. |
||
23 Mar 2018 |
The protocol was amended for the following reasons: • Add a third interim analysis to the protocol 1 year after the end of randomization in order to help inform Amgen regarding future potential clinical trials and data collection in this setting. • Update the time points for assessment of secondary objectives to start at first year. • Update the exclusion criteria for sexually active subjects and their partners with allergy by providing option for alternative condom type. • Provide guidance to sites on how to report data for fully resected lymph nodes after surgery with specific qualitative and quantitative features. • Make minor corrections and clarifications throughout the document, including administrative, typographical, and formatting errors. |
||
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 | |||
