Cancer Vaccine Study for Unresectable Stage III Non-small Cell Lung Cancer (START)

Study Overview
=================
Brief Summary
-----------------
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 subjects with unresectable stage III non-small cell lung cancer, compared to best supportive care alone. A local ancillary (sub) study in European centers will evaluate the immune response in peripheral blood after tecemotide (L-BLP25) or placebo vaccination.

Detailed Description
-----------------
Ancillary Trial: An exploratory investigation of immune response in peripheral blood after tecemotide (L-BLP25) or placebo vaccination. The ancillary study is a sub-study within START. This is an exploratory investigation of the immune response in peripheral blood after tecemotide (L-BLP25) or placebo vaccination. The main objective is to evaluate whether administration of single-shot, low-dose cyclophosphamide followed by tecemotide (L-BLP25) vaccinations induces specific immune response in peripheral blood to BLP25 (the mucinous glycoprotein 1 [MUC1] antigen) as well as a modulation of cellular and soluble components of the immune response in subjects with unresectable stage III NSCLC. Twenty-five of the European START sites will participate in the ancillary study. Sample size: up to 60 to 80 subjects All inclusion criteria specified in the START clinical trial protocol except for hemoglobin >= 100 gram/Liter (g/L) All exclusion criteria are the same as specified in the START clinical trial protocol Schedule of events: Blood samples will be taken at baseline, visit week 4, 8 13 and 25 (80 milliliter (mL) whole blood each)

Official Title
-----------------
A Multi-center Phase III Randomized, Double-blind Placebo-controlled Study of the Cancer Vaccine Stimuvax® (L-BLP25 or BLP25 Liposome Vaccine) in Non-small Cell Lung Cancer (NSCLC) Subjects With Unresectable Stage III Disease.

Conditions
-----------------
Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Biological: Tecemotide (L-BLP25)
* Drug: Single low dose cyclophosphamide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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 (RECIST), after primary chemoradiotherapy (either sequential or concomitant) for unresectable stage III disease, within 4 weeks (28 days) prior to randomization Receipt of concomitant or sequential chemoradiotherapy, consisting of a minimum of two cycles of platinum-based chemotherapy and a minimum radiation dose of >=50 Gray (Gy). 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 0-1 A platelet count > 140 x 10^9/Liter; white blood cells (WBC) > 2.5 x 10^9/Liter and hemoglobin > 90 gram per liter (g/L) Exclusion Criteria: Pre-Therapies: Undergone lung cancer specific therapy (including surgery) other than primary chemo-radiotherapy Receipt of immunotherapy (e.g. interferons, tumor necrosis factor [TNF], interleukins, or biological response modifiers [granulocyte macrophage colony stimulating factor {GM-CSF}, granulocyte colony stimulating factor {G-CSF}, macrophage-colony stimulating factor {M-CSF}], monoclonal antibodies) within 4 weeks (28 days) prior to randomization Receipt of investigational systemic drugs (including off-label use of approved products) within 4 weeks (28 days) prior to randomization Disease Status: Metastatic disease Malignant pleural effusion at initial diagnosis and/or at study 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 Hepatitis B and/or C 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 breast-feeding women, women of childbearing potential, unless using effective contraception as determined by the investigator Known drug abuse/alcohol abuse Legal incapacity or limited legal capacity

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tecemotide (L-BLP25)<br> | Biological: Tecemotide (L-BLP25)<br>* After receiving cyclophosphamide, participants will receive 8 consecutive weekly subcutaneous vaccinations with 806 microgram (mcg) of tecemotide (L-BLP25) at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance vaccinations with 806 mcg of tecemotide (L-BLP25) at 6-week intervals, commencing at Week 13, until disease progression is documented.<br>Drug: Single low dose cyclophosphamide<br>* A single intravenous infusion of 300 milligram per square meter (mg/m^2) (to a maximum 600 mg) of cyclophosphamide will be given 3 days before first tecemotide (L-BLP25) vaccination.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* A single infusion (IV) of 0.9% Saline solution instead of cyclophosphamide but in the same calculated dose will be given three days before first placebo vaccination. Subjects will then receive eight consecutive weekly subcutaneous vaccinations with placebo at weeks 0; 1; 2; 3; 4; 5; 6 and 7 followed by maintenance placebo vaccinations at 6-week intervals, commencing at week 13, until disease progression is documented.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival time was defined as the time from randomization to death. Participants without events were censored at the last date they were known to be alive or the clinical cut-off date, whatever was earlier. | Up to 66 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Symptom Progression (TTSP) as Measured by the Lung Cancer Symptom Scale (LCSS) | Time to symptom progression (TTSP) was measured by LCSS. Symptomatic progression was defined as an increase (worsening) of the Average Symptomatic Burden Index (ASBI that is, the mean of the six major lung cancer specific symptom scores of the LCSS patient scale - ranging from 0 to 100 where higher score indicates worst outcome). Worsening was defined as a 10% increase in the scale breadth from the baseline score. TTSP is defined as the time from randomization to worsening in ASBI. Participants without event are censored at the date of the last LCSS assessment. | Up to 66 months | 
| Time To Progression (TTP) | Time from randomization to disease progression. Disease progression was defined based on Response Evaluation Criteria in Solid Tumors Version 1.0 [RECIST v1.0]) 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. | Up to 66 months | 
| One-, Two- and Three-year Survival Rate | The percentages of participants who were alive at 1, 2, and 3 years were calculated as a cumulative percentage by Kaplan-Meier survival analysis approach. | Years 1, 2, and 3 | 
| Number of Participants With Treatment Emergent Adverse Events and Injection Site Reactions | Treatment -emergent adverse events were defined as those with onset or worsening occurring at or after the first dosing day of study medication and up to 42 days after the last administration of any study drug or the clinical cut-off date. Injection site reactions were reported as assessed by the Investigator. | From first dose up to 42 days after the last dose of the trial treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-Small Cell Lung Carcinoma;, stage III;, unresectable;, vaccine; Tecemotide; L-BLP25;, Cyclophosphamide;, placebo controlled;, randomized;, double blind;, immunotherapy;