111482

GlaxoSmithKline Biologicals

Rue de l’Institut 89, Rixensart, Belgium, B-1330

Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com

Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com

No

No

No

Final

15 Mar 2016

Yes

01 Sep 2015

Yes

15 Mar 2016

Yes

To demonstrate the clinical efficacy in terms of disease-free survival (DFS) of recMAGE-A3 + AS15 ASCI compared to placebo in the overall study population of patients with completely resected stage III cutaneous melanoma with macroscopic lymph node involvement; To demonstrate the clinical efficacy in terms of DFS of the recMAGE-A3 + AS15 ASCI compared to placebo in the population presenting the potentially favorable gene expression signature.

All subjects were supervised after vaccination/product administration with appropriate medical treatment readily available. Study products were administered by qualified and trained personnel. Study products were administered only to eligible subjects that had no contraindications to any components of the study products.

01 Dec 2008

No

No

Argentina: 5

Australia: 126

Austria: 29

Belgium: 25

Brazil: 6

Bulgaria: 20

Canada: 4

Czech Republic: 40

Estonia: 10

France: 303

Germany: 184

Greece: 7

Ireland: 15

Israel: 4

Italy: 96

Japan: 7

Mexico: 3

Netherlands: 21

Norway: 14

Poland: 69

Romania: 3

Russian Federation: 63

Serbia: 6

Spain: 13

Sweden: 11

Taiwan: 2

Ukraine: 44

United Kingdom: 12

United States: 209

1351

872

0

0

0

0

0

0

958

384

9

Overall Study (overall period)

Randomised - controlled

Yes

recMAGE-A3 recombinant protein formulated in AS15 adjuvant

recMAGE-A3 + AS15

GSK 2132231A, ASCI

Powder and solvent for suspension for injection

Intramuscular use

The study product was administered intramusculalry in 13 doses over 27 months: 5 doses of placebo at 3-week intervals, followed by 8 doses of placebo at 12-week intervals.

Placebo

Powder and solvent for suspension for injection

Intramuscular use

The study product was administered intramusculalry in 13 doses over 27 months: 5 doses of placebo at 3-week intervals, followed by 8 doses of placebo at 12-week intervals.

MAGE-A3 (as treated) Group

Placebo (as treated) Group

MAGE-A3 (as treated) Group

Placebo (as treated) Group

GS+ MAGE-A3 Sub-Group

Subset of patients with the pre-specified gene signature, receiving the MAGE-A3 ASCI product. Gene-signature sub-grouping was based on patients having a potentially predictive gene signature, as assessed at screening.

GS+ Placebo Sub-Group

Subset of patients with the pre-specified gene signature, receiving placebo. Gene-signature sub-grouping was based on patients having a potentially predictive gene signature, as assessed at screening.

GS- MAGE-A3 Sub-Group

Subset of patients without the pre-specified gene signature, receiving the MAGE-A3 ASCI product. Gene-signature sub-grouping was based on patients having a potentially predictive gene signature, as assessed at screening.

GS- Placebo Sub-Group

Subset of patients without the pre-specified gene signature, receiving placebo. Gene-signature sub-grouping was based on patients having a potentially predictive gene signature, as assessed at screening.

MAGE-A3 (as randomized) Group

Patients who were allocated by the randomization system for receiving up to 13 doses of recMAGE-A3 + AS15 ASCI.

Placebo (as randomized) Group

Patients who were allocated by the randomization system for receiving up to 13 doses of placebo.

DFS = time to event from randomization to the date of first disease recurrence or the date of death (whatever cause), whichever occurred first. DFS expressed as person-year rate i.e number of patients with at least one event over the sum of follow-up periods (in years), until first occurrence of a recurrence/death. Types of recurrence to be considered as an event included loco-regional and distant metastases. Any death occurring without prior documentation of tumor recurrence was considered as an event. If no event occurred by the time of analysis, then time to event was censored at the last assessment date of the patient. Any new primary cancer at another site, including second primary melanoma, was not considered as a recurrence and had to be reported as a Serious Adverse Event. The analysis was performed on the Total Treated population - as randomized, which included patients in the treatment groups as allocated by the randomization system at the start of the study.

Primary

At Final analysis (Month 30 = Year 2.5) and at follow-up analysis (up to Year 5)

At Final analysis (Month 30 = Year 2.5). The aim of this analysis was to demonstrate the clinical efficacy in terms of disease-free survival (DFS) of recMAGE-A3 + AS15 ASCI compared to placebo in the overall study population of patients with completely resected stage III cutaneous melanoma with macroscopic lymph node involvement.

MAGE-A3 (as randomized) Group v Placebo (as randomized) Group

1345

Pre-specified

1.013

2-sided

At Final analysis (Month 30 = Year 2.5). The aim of this analysis was to demonstrate the clinical efficacy in terms of DFS of the recMAGE-A3 + AS15 ASCI compared to placebo in the population presenting the potentially favorable gene expression signature.

GS+ Placebo Sub-Group v GS+ MAGE-A3 Sub-Group

316

Pre-specified

1.111

2-sided

At Final analysis (Month 30 = Year 2.5). The aim of this analysis was to demonstrate the clinical efficacy in terms of DFS of the recMAGE-A3 + AS15 ASCI compared to placebo in the population without the potentially favorable gene expression signature.

GS- Placebo Sub-Group v GS- MAGE-A3 Sub-Group

381

Pre-specified

0.915

2-sided

At Follow-up analysis (Up to Year 5). The aim of this analysis was to demonstrate the clinical efficacy in terms of disease-free survival (DFS) of recMAGE-A3 + AS15 ASCI compared to placebo in the overall study population of patients with completely resected stage III cutaneous melanoma with macroscopic lymph node involvement.

MAGE-A3 (as randomized) Group v Placebo (as randomized) Group

1345

Pre-specified

1.023

2-sided

At Follow-up analysis (Up to Year 5). The aim of this analysis was to demonstrate the clinical efficacy in terms of DFS of the recMAGE-A3 + AS15 ASCI compared to placebo in the population presenting the potentially favorable gene expression signature.

GS+ Placebo Sub-Group v GS+ MAGE-A3 Sub-Group

316

Pre-specified

1.094

2-sided

At Follow-up analysis (Up to Year 5). The aim of this analysis was to demonstrate the clinical efficacy in terms of DFS of the recMAGE-A3 + AS15 ASCI compared to placebo in the population without the potentially favorable gene expression signature.

GS- Placebo Sub-Group v GS- MAGE-A3 Sub-Group

381

Pre-specified

0.918

2-sided

Overall Survival (OS) was defined as the time to event from randomization to the date of death, irrespective of the cause of death; OS was expressed as the person-year rate i.e. the number of patients with death over the sum of the follow-up periods in years; Patients alive at the time of the analysis were censored on the date last known to be alive. The analysis was performed on the Total Treated population - as randomized, which included patients in the treatment groups as allocated by the randomization system at the start of the study.

Secondary

At final analysis (Month 30 = Year 2.5) and Follow-up analysis (Up to Year 5).

Disease Free Specific Survival (DFSS) was defined as the time to event from randomization to the date of first recurrence of disease or date of death due to melanoma (cause as assessed by investigator), whichever occurred first. DFSS was expressed as the person-year rate i.e. the number of patients with at least one event over the sum of the follow-up periods in years. Patients who died due to a cause other than the disease under study and patients alive at the time of analysis were censored on the date of last assessment (visit or tumor assessment). The analysis was performed on the Total Treated population - as randomized, which included patients in the treatment groups as allocated by the randomization system at the start of the study.

Secondary

At Final analysis (Month 30 = Year 2.5)

Distant Metastasis Free Survival (DMFS) was defined as the time to event from randomization to the date of first distant metastasis or date of death, whichever occurred first. DMFS was expressed as the person-year rate i.e. the number of patients with at least one event over the sum of the follow-up periods in year. Patients alive and without distant metastases were censored at the date of last assessment (visit or tumor assessment, or date of last tumor assessment as documented during the yearly contact follow-up period). The analysis was performed on the Total Treated population - as randomized, which included patients in the treatment groups as allocated by the randomization system at the start of the study.

Secondary

At Final analysis (Month 30 = Year 2.5)

The assessment of health-related quality of life was restricted to patients who consented to study participation after Protocol Amendment 1 became effective at their study site, and for whom a validated version of the Euro Quality of Life-5D (EQ-5D) questionnaire was available in their native language. The EQ-5D comprises a 5-dimensional descriptive system (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), where each item has 3 levels and together they define 243 possible health states. For each health state, a value (utility) was determined by using an additive algorithm. These utility scores were calculated for each patient at each timepoint at which an EQ-5D questionnaire was completed. The score had a maximum value of 1.0 corresponding to full health level, while lower scores, down to a minimum value of 0.0 reflected degradation in the health-related quality of life.

Secondary

At Week 0, 6, 12 [on the day of and on the day after treatment administration (TA)], at Month 6, 9, 12, 24, at the Concluding visit (Month 30) + 6 months and +12 Months and at disease recurrence

The cut-off value was 27 ELISA units per millilitre (EL.U/mL).

Secondary

At Weeks 0, 6, 12, 36, 48, 72, 120 (Concluding visit) and at Week 120 + 6 months

Geometric mean concentration (GMC) was expressed as ELISA units per millilitre (EL.U/mL).

Secondary

At Weeks 0, 6, 12, 36, 48, 72, 120 (Concluding visit) and at Week 120 + 6 months

Treatment response defined as: - For initially seronegative patients: post-treatment antibody concentration ≥ 27 EL.U/mL; - For initially seropositive patients: post-treatment antibody concentration ≥ 2 fold the pre-treatment antibody concentration.

Secondary

At Weeks 6, 12, 36, 48, 72, 120 (Concluding visit) and at Week 120 + 6 months

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.

Secondary

Within the 31-day (Days 0-30) follow-up period after treatment

Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Secondary

From Day 0 up to study end (up to 5 years)

Potential Immune-Mediated Disorders (pIMDs) were to be collected up to 5 years after first treatment administration or study withdrawal.

Secondary

From Day 0 up to study end (up to 5 years)

Laboratory abnormalities belong to hematological and biochemical parameters such as: alanine aminotransferase [ALT], asparatate aminostransferase [AST], alkaline phoshatase [AP], bilirubin [BIL], creatinine [CREA], hemoglobin [HGB], leukocytes [LEU], lymphopenia [LYMPH], neutrophils [NEU], platelets [PLA]. Parameter grades (Grade [G] 0, 1, 2, 3, 4, Unknown) were compared to each baseline parameter grade (G Unknown, 0, 1, 2, 3), as defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 of August 9, 2006.

Secondary

Within the 31-day (Days 0-30) post-treatment period

Adverse events (AEs): Within the 31-day (Days 0-30) follow-up period after treatment. Serious Adverse Events: from Day 0 up to study end (up to 5 years).

18.1

Placebo (as treated) Group

MAGE-A3 (as treated) Group