Study to Test the Efficacy of the Vaccine GSK 249553 in Treating Non-small-cell Lung Cancer After Tumour Removal by Surgery

Study Overview
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Brief Summary
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Patients will receive injections of GSK 249553 vaccine . Appropriate tests will be performed to assess the safety of the treatment and its ability to induce an immune response.

Detailed Description
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This Phase IIb study will be conducted at centres in several European countries according to a multicentre, international, randomised, double-blind design. It will provide information about the clinical and immunological efficacy and the tolerability of GSK 249553 when this is administered to patients with stage IB, II NSCLC. The study treatment will be administered by intramuscular injection; first administration will take place 4-6 weeks after surgery. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Official Title
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A Phase IIB Study to Assess the Efficacy of GSK 249553 as Adjuvant Therapy Given to MAGE-3-Positive Patients With Non-Small-Cell Lung Cancer in Stage IB (T2/N0) or II (T1/N1 or T2/N1 or T3/N0), Who Have Had Complete Surgical Resection

Conditions
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Lung Cancer, Non-Small Cell

Intervention / Treatment
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* Biological: GSK 249553 vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent has been obtained prior to surgical tumour resection and prior to the performance of any other protocol-specific procedures. At least 18 years of age at the time of resection. Pathologically proven, surgically staged squamous or non-squamous IB, IIA or IIB NSCLC, and complete surgical resection. The operative technique for resection of the patient's tumour involves at least a lobectomy or a sleeve lobectomy, conforming to all of the following criteria: Removal of all gross disease with negative resection margins, by lobectomy, sleeve resection, bilobectomy or pneumonectomy, based on intra-operative findings. The level of nodal sampling is at least as follows: Levels 4, 7, 10 in both right upper and right middle lobes Levels 4, 7, 9, 10 in right lower lobe Levels 5, 6, 7 in left upper lobe Levels 7, 9, 10 in left lower lobe. or at the maximum defined as systematic radical mediastinal lymphadenectomy: all ipsilateral and easily accessible lymph-node levels must be removed, independently of the location of the primary tumour. The level of nodal sampling is as follows: Levels 2, 4, 7, 8, 9, 10 in right-sided tumours, Levels 5, 6, 7, 8, 9, 10 in left-sided tumours Tumour shows expression of MAGE-3 antigen. Recovered from surgery for at least 4 weeks and not more than 6 weeks. ECOG performance status of ≤ 1 at the time of randomisation. Laboratory criteria (all of the following must be fulfilled): adequate bone marrow reserve, adequate renal function, adequate hepatic function, serum bilirubin within normal range, negative HIV antibody test, negative HBV antigen test, negative HCV antibody test. (For females): EITHER not of child-bearing potential OR sexually abstinent OR all of the following: negative urine/serum β-HCG pregnancy test, use of adequate contraceptive precautions for 30 days before first vaccination. Agree to continue such precautions for 2 months after completion of the course of vaccination. Exclusion Criteria: Received any anti-cancer specific treatment including radiotherapy, prior to surgery, unless the treatment was for previous malignancies allowed by the protocol, i.e., basal and localised squamous-cell skin carcinoma that has been successfully treated, or carcinoma in situ of the cervix (see exclusion criterion no. 10). Candidate for post-surgery radiation therapy or any kind of anti-cancer-specific treatment. Pregnant/lactating. (For female patients of child-bearing potential): not agree to practice an effective method of contraception. Uncontrolled bleeding disorder. Autoimmune disease. History of anaphylaxis or severe allergic reaction. Undergone splenectomy or radiation to the spleen. Received a major organ allograft. Malignancies at other sites (except (i) basal and localised squamous-cell skin carcinoma that has been successfully treated, and (ii) carcinoma in situ of the cervix). Concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk. Uncontrolled congestive heart failure or hypertension. Unstable heart disease or uncontrolled arrhythmia at the time of enrolment. Psychiatric or addictive disorders that may compromise ability to give informed consent, or to comply with the trial procedures. Any evidence of residual tumour after surgery. Require concomitant treatment with systemic corticosteroids, or any other immunosuppressive agents. Received chemotherapy, immunotherapy related to NSCLC. Need home oxygenation. Received any investigational or non-registered drug or vaccine other than the study vaccine within the 30 days preceding the first dose of study vaccine, or plans to receive such a drug during the study period.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK 249553 Group<br>Male and female patients at least 18 years of age, with resectable non-small-cell lung cancer (NSCLC), who received 13 doses of GSK 249553 vaccine, administered intramuscularly in the deltoid or lateral regions of the thighs, alternatively on the right and left sides, according to the following schedule: 5 doses at 3-week intervals, followed by 8 doses at 3-month intervals. | Biological: GSK 249553 vaccine<br>* Intramuscular injection, 13 doses<br>|
| Placebo Comparator: Placebo Group<br>Male and female patients at least 18 years of age, with resectable non-small-cell lung cancer (NSCLC), who received 13 doses of placebo, administered intramuscularly in the deltoid or lateral regions of the thighs, alternatively on the right and left sides, according to the following schedule: 5 doses at 3-week intervals, followed by 8 doses at 3-month intervals. | Biological: Placebo<br>* Intramuscular administration, 13 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Reporting Confirmed Non-small-cell Lung Cancer (NSCLC) Recurrence | Types of recurrence included local, regional and distant metastasis and second primary lung tumours, and comprised: Local recurrence, defined as a tumour within the same lung or at the bronchial stump; Regional recurrence, involving a clinically or radiologically manifest disease in the mediastinum or in supraclavicular nodes; and Distant recurrence, i.e., any tumour arising in the contralateral lung or outside the hemithorax. The time to recurrence was defined as the interval from the date of surgical resection to the date of recurrence. The latter was defined as the date of the first study assessment at which new lesion(s) were found and confirmed by appropriate imaging. | Over a median follow-up time of 28 months post-Dose 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Disease Recurrence | Types of recurrence included local, regional and distant metastasis and second primary lung tumours, and comprised: Local recurrence, defined as a tumour within the same lung or at the bronchial stump; Regional recurrence, involving a clinically or radiologically manifest disease in the mediastinum or in supraclavicular nodes; and Distant recurrence, i.e., any tumour arising in the contralateral lung or outside the hemithorax. The time to recurrence was defined as the interval from the date of surgical resection to the date of recurrence. The latter was defined as the date of the first study assessment at which new lesion(s) were found and confirmed by appropriate imaging. | At 6, 12, 18, 24 and 30 months after enrolment | 
| Number of Patients Reporting Confirmed Non-small-cell Lung Cancer (NSCLC) Recurrence or Death - Disease Free Survival (DFS) | Types of recurrence included local, regional and distant metastasis and second primary lung tumours, and comprised: Local recurrence, defined as a tumour within the same lung or at the bronchial stump; Regional recurrence, involving a clinically or radiologically manifest disease in the mediastinum or in supraclavicular nodes; and Distant recurrence, i.e., any tumour arising in the contralateral lung or outside the hemithorax. The time to recurrence was defined as the interval from the date of surgical resection to the date of recurrence. The latter was defined as the date of the first study assessment at which new lesion(s) were found and confirmed by appropriate imaging. | Over a median follow-up time of 44 months post-Dose 1 | 
| Number of Participants Who Died - Overall Survival (OS) | Overall Survival (OS) was based on total number of deaths, irrespective of cause of death. Non-small-cell Lung Cancer Overall Survival (NSCLC-OS) was based on total number of deaths due to lung cancer; deaths due to other or to unknown causes were censored appropriately. | Over a median follow-up time of 44 months post-Dose 1 | 
| Number of Subjects Seropositive Against MAGE-A3 | A seropositive subject was defined as a subject whose antibody concentration was greater than or equal to (≥) 27.000 enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). | At Day 0, Week 6, Week 12, Month 9, Month 18, Month 24, at Month 30 and at Follow-Up (FU) visit (Post Dose 13 at Month 42 for patients with full treatment course or Post last product dose + 12 months for the other patients) | 
| Anti- MAGE-A3 Antibody Concentrations | Concentrations are presented as geometric mean concentrations (GMCs), expressed in enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). | At Day 0, Week 6, Week 12, Month 9, Month 18, Month 24, at Month 30 and at Follow-Up (FU) visit (Post Dose 13 at Month 42 for patients with full treatment course or Post last product dose + 12 months for the other patients) | 
| Number of Subjects Seropositive Against Protein D (PD) Antigens | A seropositive subject was defined as a subject whose antibody concentration was greater than or equal to (≥) 100.000 enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). | At Day 0, Week 6, Week 12, Month 9, Month 18, Month 24, at Month 30 and at Follow-Up (FU) visit (Post Dose 13 at Month 42 for patients with full treatment course or Post last product dose + 12 months for the other patients) | 
| Anti-protein D (Anti-PD) Antibody Concentrations | Concentrations are presented as geometric mean concentrations (GMCs), expressed in enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). | At Day 0, Week 6, Week 12, Month 9, Month 18, Month 24, at Month 30 and at Follow-Up (FU) visit (Post Dose 13 at Month 42 for patients with full treatment course or Post last product dose + 12 months for the other patients) | 
| Number of Subjects With Cell-mediated Immunity (CMI) Cluster of Differentiation (CD) 4+ Response | Responders were patients with at least 5x10-⁶ increase in minimal CD4 precursor frequency versus baseline. Any = at least one post treatment time point. | At Week 6, Week 12, Month 9, Month 18, Month 24, at Month 30 and at Follow-Up (FU) visit (Post Dose 13 at Month 42 for patients with full treatment course or Post last product dose + 12 months for the other patients) | 
| Number of Subjects With Cell-mediated Immunity (CMI) Cluster of Differentiation (CD) 8+ Response | Responders were patients with at least 5x10-⁶ increase in minimal CD8 precursor frequency versus baseline. Any = at least one post treatment time point. | At Week 6, Week 12, Month 9, Month 18, Month 24, at Month 30 and at Follow-Up (FU) visit (Post Dose 13 at Month 42 for patients with full treatment course or Post last product dose + 12 months for the other patients) | 
| Number of Subjects With Cell-mediated Immunity (CMI) CD4+ or CD8+ Response | Responders are patients with at least 5x10-⁶ increase in minimal CD4 or CD8 precursor frequency versus baseline. Any = at least one post treatment time point. | At Week 6, Week 12, Month 9, Month 18, Month 24, at Month 30 and at Month 60 | 
| Number of Patients Reporting Non-small-cell Lung Cancer (NSCLC) Recurrence by Gene Signature | Types of recurrence included local, regional and distant metastasis and second primary lung tumours, and comprised: Local recurrence, defined as a tumour within the same lung or at the bronchial stump; Regional recurrence, involving a clinically or radiologically manifest disease in the mediastinum or in supraclavicular nodes; and Distant recurrence, i.e., any tumour arising in the contralateral lung or outside the hemithorax. Gene expression profiling was performed by qRT-PCR in primary tumor samples taken at the time of resection of the tumor, and thus before any study treatment. Gene signature positive (GS+) and negative (GS-) profiles were assessed with a 61-set gene signature (GS) and a classifier which were defined in the Phase II melanoma EORTC 16032-18031 study. | Over a median follow up time of 86 months | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm) of injection site. | During the 8-day (Days 0-7) post-vaccination period, across doses | 
| Number of Subjects With Any, Grade 2/3/4 and Related Solicited General Symptoms | Assessed solicited general symptoms were fatigue, headache, myalgia, nasea, rigors/chills, sweating/diaphoresis, temperature [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], vomiting. Any = occurrence of the symptom regardless of intensity grade. Grade 4 Fatigue = Bedridden or disabling. Grade 4 Headache, Myalgia = Disabling. Grade 3 Nausea = No significant intake, requiring i.v. fluids. Grade 3 Rigors/Chills = Not responsive to narcotic medication. Grade 2 Sweating/Diaphoresis = Frequent or drenching. Grade 4 Vomiting = Requiring parenteral nutrition; or physiologic consequences requiring intensive care; haemodynamic collapse. Grade 3 fever = fever higher than (>) 40.0 °C for more than 24 hours. Related = symptom assessed by the investigator as related to the vaccination. | During the 8-day (Days 0-7) post-vaccination period, across doses | 
| Number of Subjects With Any Unsolicited 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) post-vaccination period | 
| Number of Subjects With 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. | Throughout the study (Day 0 - Month 86) | 
| Number of Subjects With Normal and Abnormal Urinalysis Parameters | The parameters analysed were Protein, Red Blood Cells (RBC) and White Blood Cells (WBC), with respect to normal laboratory ranges. The subjects were grouped by status at baseline. | At Month 6, Month 12, Month 18, Month 24 and Month 30 | 
| Number of Subjects With Normal and Abnormal Hematological Parameters | The parameters analysed were Basophils (BAS), Eosinophils (EOS), Haemoglobin (HGB), Lymphocytes (LYM), Monocytes (MON), Neutrophils (NEU), Platelets (PLA), Red Blood Cells (RBC), Sedimentations rate (SED) and White Blood Cells (WBC), with respect to normal laboratory ranges. The subjects were grouped by status at baseline. | At Month 6, Month 12, Month 18, Month 24 and Month 30 | 
| Number of Subjects With Normal and Abnormal Biochemical Parameters | The parameters analysed were Albumin (ALB), Bicarbonate (BIC), Blood urea nitrogen (BUN), Calcium (CAL), Chloride (CHL), Cholesterol (CHO), Creatinine (CREA), Glucose (GLU), Magnesium (MAG), Phosphate (PHO), Potassium (POT), Sodium (SOD), Total protein (TPROT), Total bilirubin (TBIL), Triglycerides (TRIG) and Uric acid (UAC), with respect to normal laboratory ranges. The subjects were grouped by status at baseline. | At Month 6, Month 12, Month 18, Month 24 and Month 30 |