A Phase III Study to Test the Benefit of a New Kind of Anti-cancer Treatment in Patients With Melanoma, After Surgical Removal of Their Tumor

Study Overview
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Brief Summary
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The purpose of this clinical trial is to evaluate the benefit of the immunotherapeutic product GSK 2132231A in preventing disease relapse when given to melanoma patients, after surgical removal of their tumor. This Protocol Posting has been updated following Amendments 1 of the Protocol, March 2010. The impacted sections are outcome measures and entry criteria.

Official Title
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GSK 2132231A Antigen-Specific Cancer Immunotherapeutic as Adjuvant Therapy in Patients With Resected Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: GSK 2132231A
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent signed. Male or female patient with histologically proven stage IIIB or IIIC cutaneous melanoma presenting with macroscopic lymph node involvement suitable for surgery. The patient must have been surgically rendered free of disease before the randomization. Patient is ≥ 18 years old at the time of signing the informed consent form. The patient's lymph node tumor shows expression of the MAGE-A3 gene. The patient has fully recovered from surgery. ECOG performance status of 0 or 1 at the time of randomization. The patient must have adequate organ functions as assessed by standard laboratory criteria. If the patient is female, she must be of non-childbearing potential, or practice adequate contraception. In the opinion of the investigator, the patient can and will comply with all the requirements of the protocol. Exclusion Criteria: The patient suffers from a mucosal or ocular melanoma. The patient has or has had any history of in-transit metastases The patient has been treated or is scheduled to be treated with an adjuvant anticancer therapy after the surgery that qualifies the patient for inclusion in the present trial. The patient requires concomitant chronic treatment with systemic corticosteroids or any other immunosuppressive agents. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment. The patient has a history of autoimmune disease. The patient has a family history of congenital or hereditary immunodeficiency. The patient is known to be positive for Human Immunodeficiency Virus (HIV) or has another confirmed or suspected immunosuppressive or immunodeficient condition. History of allergic disease or reactions likely to be exacerbated by any component of the treatments. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures. The patient has concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk. The patient has previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers or carcinoma in situ of the cervix or effectively treated malignancy that has been in remission for over 5 years and is highly likely to have been cured. The patient has an uncontrolled bleeding disorder. For female patients: the patient is pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MAGE-A3 Group<br>Patients who received up to 13 doses of recMAGE-A3 + AS15 ASCI. Study products were administered as intramuscular (IM) injections in the deltoid or the lateral region of the thigh (not in anatomical regions where lymph nodes had been excised): 5 doses of ASCI product at 3-week intervals, followed by 8 doses of ASCI product at 12-week intervals. | Drug: GSK 2132231A<br>* IM solution, a course of 13 injections administered over 27 months<br>|
| Placebo Comparator: Placebo Group<br>Patients who received up to 13 doses of placebo. Study products were administered as intramuscular (IM) injections in the deltoid or the lateral region of the thigh (not in anatomical regions where lymph nodes had been excised): 5 doses of placebo at 3-week intervals, followed by 8 doses of placebo at 12-week intervals. | Drug: Placebo<br>* IM solution, a course of 13 injections administered over 27 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) | DFS = time to event from randomization to the date of first disease recurrence (as assessed by investigator) or the date of death (whatever cause), whichever occurred first. DFS was expressed as the person-year rate i.e. the number of patients with at least one event (n) over the sum of the follow-up periods in years (T), until the 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 (not censored in the stat. analysis) as this approach was less prone to introduce bias. If no event occurred by the time of analysis, then the time to event was censored at the last assessment date (tumor assessment/visit) 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 (SAE). | At Final analysis (Month 30 = Year 2.5) | 
| Disease Free Survival (DFS) | DFS = time to event from randomization to the date of first disease recurrence (as assessed by investigator) or the date of death (whatever cause), whichever occurred first. DFS was expressed as the person-year rate i.e. the number of patients with at least one event (n) over the sum of the follow-up periods in years (T), until the 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 (not censored in the stat. analysis) as this approach was less prone to introduce bias. If no event occurred by the time of analysis, then the time to event was censored at the last assessment date (tumor assessment/visit) 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 (SAE). | At follow-up analysis (up to Year 5) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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 (n) over the sum of the follow-up periods in years (T). Patients alive at the time of the analysis were censored on the date last known to be alive. | At Final analysis (Month 30 = Year 2.5) and at follow-up analysis (up to Year 5) | 
| Disease-free Specific Survival (DFSS) | 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 (n) over the sum of the follow-up periods in years (T), until the first occurrence of a recurrence/death. 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). | At Final analysis (Month 30 = Year 2.5) | 
| Distant Metastasis-free Survival (DMFS) | 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 (n) over the sum of the follow-up periods in years (T), until the first occurrence of distant metastasis/death. 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). | At Final analysis (Month 30 = Year 2.5) | 
| Health-related Quality of Life | 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. | At Weeks 0, 6, 12 [on the day of and 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 | 
| Number of Subjects With Anti-MAGE-A3 Antibody Concentrations Above the Cut-off Value | The cut-off value was 27 Enzyme-Linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL). | At Weeks 0, 6, 12, 36, 48 72, 120 (Concluding visit) and at Week 120 + 6 months | 
| Anti-MAGE-A3 Antibody Geometric Mean Concentrations | Anti-MAGE-A3 antibody concentrations were presented as geometric mean concentrations (GMC) and expressed in EL.U/mL. | At Weeks 0, 6, 12, 36, 48 72, 120 (Concluding visit) and at Month 120 + 6 months | 
| Number of Subjects With Anti-MAGE-A3 Antibody Response | 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. | At Weeks 6, 12, 36, 48 72, 120 (Concluding visit) and at Month 120 + 6 months | 
| Number of Subjects With Abnormal Haematological and Biochemical Parameters | 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. | Within the 31-day (Days 0-30) post-treatment period | 
| Number of Subjects With Any Adverse Events (AEs) | 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. | Within the 31-day (Days 0-30) follow-up period after treatment | 
| Number of Subjects With Any Serious Adverse Events (SAEs) | 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. | From Day 0 up to study end (up to 5 years) | 
| Number of Subjects With Potential Immune-mediated Diseases (pIMDs) | Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology. | From Day 0 up to study end (up to 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DERMA, Tumor antigen, Immunotherapeutic, Adjuvant cancer therapy, Melanoma, ASCI