Cancer Vaccine Study for Stage III, Unresectable, Non-small Cell Lung Cancer (NSCLC) in the Asian Population

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the cancer vaccine tecemotide (L-BLP25) in addition to best supportive care is effective in prolonging the lives of Asian subjects with unresectable stage III non-small cell lung cancer in comparison to a placebo plus best supportive care (a so-called placebo controlled study).

Official Title
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A Multi-national, Double-blind, Placebo-controlled, Randomized, Phase III Clinical Trial of the Cancer Vaccine Stimuvax® (L-BLP25 or BLP25 Liposome Vaccine) in Asian Subjects With Stage III, Unresectable, Non-small Cell Lung Cancer (NSCLC) Who Have Demonstrated Either Stable Disease or Objective Response Following Primary Chemo-radiotherapy

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Biological: Tecemotide
* Drug: Single low dose cyclophosphamide
* Drug: Placebo
* Other: Saline
* Other: Best Supportive Care (BSC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented unresectable stage III non-small cell lung cancer (NSCLC) Documented stable disease or objective response, according to Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST v1.0) after primary concomitant chemo-radiotherapy for unresectable stage III disease, within four weeks (28 days) prior to randomization Receipt of concomitant chemo-radiotherapy. The chemotherapy-part must have been platinum-based, must have been administered with a minimum of two cycles overlap with radiotherapy (one cycle lasts either 3 or 4 weeks depending on the chemotherapy regimen), and a minimum of two platinum-based chemotherapy administrations must have been given during radiotherapy. Purely radio sensitizing doses of chemotherapy are not acceptable. Radiotherapy must have delivered a radiation dose of >= (greater than or equal to) 50 Gray (Gy). Induction or consolidation chemotherapy is allowed and if given, should be accounted as part of primary thoracic chemoradiotherapy. Subjects must have completed the primary thoracic chemo-radiotherapy at least four weeks (28 days) and no later than 12 weeks (84 days) prior to randomization. Subjects who received prophylactic brain irradiation as part of primary chemo-radiotherapy are eligible Geographically accessible for ongoing follow-up, and committed to comply with the designated visits An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 A platelet count >= the lower limit of normal for the site or >= 100 x 10^9 per liter (/Liter) (whichever is greater); white blood cell (WBC) >= 2.5 x 10^9/Liter and haemoglobin >= 90 gram per liter (g/L) >=18 years of age (or minimum age of legal consent consistent with local regulations, if minimum is greater than [>] 18 years of age) Other protocol defined inclusion criteria could apply Exclusion Criteria: Pre-Therapies*: Prior sequential chemo-radiotherapy Lung-cancer-specific therapy (including surgery) other than primary chemoradiotherapy Immunotherapy (e.g., interferons, tumor necrosis factor [TNF], interleukins, or biological response modifiers [granulocyte macrophage colony stimulating factor {GMCSF}, granulocyte colony stimulating factor {G-CSF}, macrophage-colony stimulating factor {M-CSF}], monoclonal antibodies) within four weeks (28 days) prior to randomization Investigational systemic drugs (including off-label use of approved products) within four weeks (28 days) prior to randomization Disease Status: Metastatic disease Malignant pleural effusion at initial diagnosis and/or at trial entry Past or current history of neoplasm other than lung carcinoma, except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years Autoimmune disease A recognized immunodeficiency disease including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; subjects who have hereditary or congenital immunodeficiencies Any preexisting medical condition requiring chronic steroid or immunosuppressive therapy (steroids for the treatment of radiation pneumonitis are allowed) Known active Hepatitis B infection and/or Hepatitis C infection Signs and symptoms suggestive of transmissible spongiform encephalopathy, or of family members who suffer(ed) from such Physiological Functions: Clinically significant hepatic dysfunction Clinically significant renal dysfunction Clinically significant cardiac disease Splenectomy Infectious process that in the opinion of the investigator could compromise the subject's ability to mount an immune response Standard Safety: Pregnant or breastfeeding women, women of childbearing potential, unless using effective contraception as determined by the investigator Known drug abuse or alcohol abuse Participation in another clinical trial (excluding purely observational studies) within the past 28 days Requires concurrent treatment with a non-permitted drug Known hypersensitivity to any of the trial treatment ingredients Legal incapacity or limited legal capacity Any other reason that, in the opinion of the investigator precludes the subject from participating in the trial

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Arm<br>Tecemotide (L-BLP25) + Single low dose cyclophosphamide + Best supportive care (BSC) | Biological: Tecemotide<br>* Subjects will receive 8 consecutive weekly subcutaneous vaccinations with 918 microgram (mcg) of tecemotide (L-BLP25) at Week 1, 2, 3, 4, 5, 6, 7, and 8 (primary treatment phase) and then at 6-Week intervals, beginning at Week 14 (maintenance phase) until disease progression (PD) is documented or the subject discontinues for any other reason.<br>* Other names: Stimuvax;Drug: Single low dose cyclophosphamide<br>* A single intravenous (IV) infusion of 300 milligram per square meter (mg/m^2) (to a maximum 600 mg) of cyclophosphamide will be given 3 days before the first administration of tecemotide.<br>Other: Best Supportive Care (BSC)<br>* The BSC will be provided as per the investigator's discretion, and is not limited to palliative radiation, psychosocial support, analgesics and nutritional support.<br>|
| Placebo Comparator: Control Arm<br>Saline + Placebo + Best supportive care (BSC) | Drug: Placebo<br>* Subjects will receive 8 consecutive weekly subcutaneous vaccinations of tecemotide (L-BLP25) matching placebo at Week 1, 2, 3, 4, 5, 6, 7 and 8 followed by maintenance treatment at 6-Week intervals, beginning at Week 14, until PD is documented or the subject discontinues for any other reason.<br>Other: Saline<br>* A single IV infusion of 0.9 percent (%) sodium chloride (saline) will be given 3 days before first placebo vaccination.<br>Other: Best Supportive Care (BSC)<br>* The BSC will be provided as per the investigator's discretion, and is not limited to palliative radiation, psychosocial support, analgesics and nutritional support.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Time | OS time was measured as the time (in months) between the date of randomization and the date of death. For subjects alive or lost to follow-up at time of analysis, the time between the date of randomization and the date on which the subject was last known alive was calculated and used as a censored observation in the analysis. | From the date of randomization until death, assessed up to 5.6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Symptom Progression (TTSP) | TTSP was measured from randomization to symptomatic progression by lung cancer symptom scale (LCSS) used to measure symptom changes relevant to quality of life (QoL).It consisted of 9 items focused on cancer symptoms (loss of appetite, fatigue, cough, shortness of breath, blood in sputum, pain, symptoms of cancer, illness affecting normal activity, QoL).For each symptom score distance from left boundary to point where subject has marked line was measured in millimeters (mm).Total scale length was 100 mm. Symptomatic progression was defined as increase/worsening of average symptomatic burden index (ASBI) (mean of 6 major lung cancer specific symptom scores);Worsening defined as 10% increase of scale breadth from baseline. Score 0 indicate no/minimum symptoms;100 indicates maximum level of symptoms. Subjects without symptomatic progression/lost to follow-up at time of analysis: time from date of randomization to date of last LCSS assessment was calculated & used as censored observation. | From the date of randomization to the date of symptomatic progression, assessed up to 5.6 years | 
| Time to Progression (TTP) | Time from randomization to radiological confirmation of disease progression (PD) as determined by the investigator. PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions from nadir, or the appearance of one or more new lesions as per RECIST version 1.0. For subjects without radiological confirmed PD who discontinued or died due to PD, the date of trial treatment discontinuation was used as event date. Subjects who missed 2 consecutive scheduled doses without evaluable assessment for the related visits and who were lost to follow-up thereafter were considered as having PD, TTP was calculated from the date of randomization to the date of their first missed treatment. Subjects without PD at time of analysis are censored at either date of last vaccination or death or discontinuation of treatment or lost to follow-up. | From the date of randomization to the date of radiological confirmation of PD, assessed up to 5.6 years | 
| Progression Free Survival (PFS) | Time from randomization to objective disease progression (PD) as determined by the investigator or death. PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions from nadir, or the appearance of one or more new lesions as per RECIST version 1.0. Subjects who missed 2 consecutive scheduled doses without evaluable assessment for the related visits and who were lost to follow-up thereafter were considered as having PD, and the PFS was calculated from the date of randomization to the date of their first missed treatment. PFS time for subjects without an event was censored as of the date of last performed imaging. | From the date of randomization to PD, assessed up to 5.6 years | 
| Time to Treatment Failure (TTF) | TTF was time from randomization to discontinuation of trial treatment for any reason as reported by the investigator. For subjects still receiving treatment at the time of analysis, the time between the date of randomization and the last date of treatment will be used as a censored observation in the analysis. Subjects who missed 2 consecutive scheduled doses without evaluable assessment for the related visits and who were lost to follow-up thereafter were considered treatment failure and the TTF was calculated from the date of randomization to the date of their first missed treatment. | From the date of randomization to the date of first missed treatment, assessed up to 5.6 years | 
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as the AEs that occur between first dose of study drug administration and 42 days after the last dose of study drug administration that were absent before treatment or that worsened relative to pretreatment state. Number of subjects with TEAE leading to death and permanent discontinuation of any trial treatment were presented. | From the first dose of study drug administration until 42 days after the last dose of study drug administration, assessed up to 5.6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Small Cell Lung Carcinoma, Tecemotide, L-BLP25, Cyclophosphamide, placebo controlled, Non-Small Cell Lung Cancer