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

• ClinicalTrials.gov Identifier: NCT00796445
• Recruitment Status: Terminated
• First Posted: November 24, 2008
• Results First Posted: March 19, 2019
• Last Update Posted: March 5, 2021
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Tracking Information

• First Submitted Date: November 21, 2008
• First Posted Date: November 24, 2008
• Results First Submitted Date: September 30, 2016
• Results First Posted Date: March 19, 2019
• Last Update Posted Date: March 5, 2021
• Actual Study Start Date: December 1, 2008
• Actual Primary Completion Date: January 27, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 5, 2021)

• Disease Free Survival (DFS) [ Time Frame: At Final analysis (Month 30 = Year 2.5) ]
  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).
• Disease Free Survival (DFS) [ Time Frame: At follow-up analysis (up to Year 5) ]
  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).

• Original Primary Outcome Measures (submitted: November 21, 2008): Disease Free Survival [ Time Frame: Once the pre-defined number of events is reached ]

Current Secondary Outcome Measures (submitted: February 5, 2021)

• Overall Survival (OS) [ Time Frame: At Final analysis (Month 30 = Year 2.5) and at follow-up analysis (up to Year 5) ]
  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.
• Disease-free Specific Survival (DFSS) [ Time Frame: At Final analysis (Month 30 = Year 2.5) ]
  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 (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).
• Distant Metastasis-free Survival (DMFS) [ Time Frame: 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 (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).
• Health-related Quality of Life [ Time Frame: 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 ]
  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.
• Number of Subjects With Anti-MAGE-A3 Antibody Concentrations Above the Cut-off Value [ Time Frame: At Weeks 0, 6, 12, 36, 48 72, 120 (Concluding visit) and at Week 120 + 6 months ]
  The cut-off value was 27 Enzyme-Linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL).
• Anti-MAGE-A3 Antibody Geometric Mean Concentrations [ Time Frame: At Weeks 0, 6, 12, 36, 48 72, 120 (Concluding visit) and at Month 120 + 6 months ]
  Anti-MAGE-A3 antibody concentrations were presented as geometric mean concentrations (GMC) and expressed in EL.U/mL.
• Number of Subjects With Anti-MAGE-A3 Antibody Response [ Time Frame: At Weeks 6, 12, 36, 48 72, 120 (Concluding visit) and at Month 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.
• Number of Subjects With Abnormal Haematological and Biochemical Parameters [ Time Frame: Within the 31-day (Days 0-30) post-treatment period ]
  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.
• Number of Subjects With Any Adverse Events (AEs) [ Time Frame: Within the 31-day (Days 0-30) follow-up period after treatment ]
  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.
• Number of Subjects With Any Serious Adverse Events (SAEs) [ Time Frame: From Day 0 up to study end (up to 5 years) ]
  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.
• Number of Subjects With Potential Immune-mediated Diseases (pIMDs) [ Time Frame: From Day 0 up to study end (up to 5 years) ]
  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.

Original Secondary Outcome Measures (submitted: November 21, 2008)

• Overall Survival [ Time Frame: At the time of analysis ]
• Disease-free specific survival [ Time Frame: At the time of analysis ]
• Distant metastasis-free survival [ Time Frame: At the time of analysis ]
• Anti-MAGE-A3 and anti-protein D seropositivity status. [ Time Frame: Post-treatment and 1 year after concluding visit. ]
• Occurrence of adverse events including abnormal haematological and biochemical parameters. [ Time Frame: Up to 30 days after each study dose. ]
• Occurrence of serious adverse events and autoimmunity events. [ Time Frame: During the whole study duration up to 30 days after the last administration of study treatment. ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: GSK 2132231A
  IM solution, a course of 13 injections administered over 27 months
• Drug: Placebo
  IM solution, a course of 13 injections administered over 27 months

Study Arms

• Experimental: MAGE-A3 Group
  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.
  Intervention: Drug: GSK 2132231A
• Placebo Comparator: Placebo Group
  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.
  Intervention: Drug: Placebo

Publications *

• Dreno B, Thompson JF, Smithers BM, Santinami M, Jouary T, Gutzmer R, Levchenko E, Rutkowski P, Grob JJ, Korovin S, Drucis K, Grange F, Machet L, Hersey P, Krajsova I, Testori A, Conry R, Guillot B, Kruit WHJ, Demidov L, Thompson JA, Bondarenko I, Jaroszek J, Puig S, Cinat G, Hauschild A, Goeman JJ, van Houwelingen HC, Ulloa-Montoya F, Callegaro A, Dizier B, Spiessens B, Debois M, Brichard VG, Louahed J, Therasse P, Debruyne C, Kirkwood JM. MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Jul;19(7):916-929. doi: 10.1016/S1470-2045(18)30254-7. Epub 2018 Jun 13.
• Dizier B, Callegaro A, Debois M, Dreno B, Hersey P, Gogas HJ, Kirkwood JM, Vansteenkiste JF, Sequist LV, Atanackovic D, Goeman J, van Houwelingen H, Salceda S, Wang F, Therasse P, Debruyne C, Spiessens B, Brichard VG, Louahed J, Ulloa-Montoya F. A Th1/IFNgamma Gene Signature Is Prognostic in the Adjuvant Setting of Resectable High-Risk Melanoma but Not in Non-Small Cell Lung Cancer. Clin Cancer Res. 2020 Apr 1;26(7):1725-1735. doi: 10.1158/1078-0432.CCR-18-3717. Epub 2019 Nov 15.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: September 19, 2013): 1351
• Original Estimated Enrollment (submitted: November 21, 2008): 1300
• Actual Study Completion Date: January 27, 2016
• Actual Primary Completion Date: January 27, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Czechia, Estonia, France, Germany, Greece, Ireland, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, New Zealand, Norway, Poland, Romania, Russian Federation, Serbia, Spain, Sweden, Switzerland, Taiwan, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT00796445
• Other Study ID Numbers: 111482; 2008-002447-16 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• URL: https://www.clinicalstudydatarequest.com/Posting.aspx?ID=16038

• Current Responsible Party: GlaxoSmithKline
• Original Responsible Party: Study Director, GSK
• Current Study Sponsor: GlaxoSmithKline
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: GlaxoSmithKline
• Verification Date: February 2021