Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Carcinoma, Non-Small-Cell Lung, Tecemotide, Placebo, NSCLC, L-BLP25
Brief summary
This is a multi-center, double-blind, placebo-controlled, randomized, Phase 3 trial in subjects with unresectable stage III non-small cell lung cancer (NSCLC) who have demonstrated either stable disease or objective response following primary concurrent chemo-radiotherapy (CRT), comparing overall survival (OS) time in subjects treated with tecemotide versus subjects treated with tecemotide-matching placebo.
Interventions
DRUGTecemotide
Tecemotide injection will be administered once weekly subcutaneously at a dose of 806 microgram up to Week 8 and from Week 14, every 6 weeks until end-of-trial, or until NSCLC progression.
DRUGPlacebo
Matching placebo injection will be administered once weekly subcutaneously up to Week 8 and from Week 14, every 6 weeks until end-of-trial, or until NSCLC progression.
CPA injection will be administered as a single intravenous infusion at a dose of 300 milligram per square meter (mg/m\^2) (to a maximum of 600 mg) 3 days before the first injection of tecemotide.
DRUGSaline (sodium chloride)
Matching placebo (saline) injection will be administered as a single intravenous (0.9 percent \[%\] sodium chloride) infusion 3 days before the first injection of tecemotide-matching placebo.
Sponsors
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent, before any trial-related activities are carried out * Histologically or cytologically documented unresectable stage III NSCLC, including bronchioalveolar carcinomas. Cancer stage must be confirmed and documented by computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET) scan * Prior concurrent CRT which is defined as follows: * Minimum of 2 cycles of platinum-based chemotherapy * Radiotherapy with a total tumor dose greater than equal to (\>=) 60 Gray and a single fraction dose \>= 1.8 Gray * Overlap of radiotherapy with minimum 2 cycles of platinum-based chemotherapy (one cycle is defined as either 3 or 4 weeks depending on the chemotherapy regimen). A deviation of 2 to 3 days from an exact overlap is acceptable. Purely radiosensitizing doses of chemotherapy are not acceptable (for example \[e.g.\], daily low dose regimens; weekly carbo-platinum + paclitaxel regimens are allowed). * Subjects must have completed the primary thoracic CRT at least 4 weeks (28 days) and no later than 12 weeks (84 days) prior to randomization. Subjects who received prophylactic brain irradiation as part of primary CRT are eligible. * Documented stable disease or objective response, according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, after primary concurrent CRT for unresectable stage III disease, within 4 weeks (28 days) prior to randomization * An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 * A platelet count, white blood cells (WBC) and hemoglobin value as defined in the protocol * Male or female, greater than or equal to 18 years of age * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Undergone lung cancer specific therapy (including surgery) other than initial concurrent CRT * Received chemotherapy during radiotherapy in radiosensitizing doses only (e.g., daily low dose regimens; weekly carbo-platinum + paclitaxel regimens are allowed). * Metastatic disease * Malignant pleural effusion at initial diagnosis, during initial CRT, 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 * A recognized immunodeficiency disease including human immunodeficiency virus (HIV) infection and other cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; subjects who have hereditary, congenital or acquired immunodeficiencies * Splenectomy * Any preexisting medical condition requiring chronic systemic steroid or immunosuppressive therapy (steroids for the treatment of radiation pneumonitis are allowed) * Receipt of immunotherapy (as defined in the protocol) within 4 weeks prior to randomization * Receipt of investigational systemic drugs (including off-label use of approved products) within 4 weeks prior to randomization * Autoimmune disease * Active or chronic infectious hepatitis * Infectious process that, in the opinion of the Investigator, could compromise the subject's ability to mount an immune response * Clinically significant hepatic dysfunction, renal dysfunction and cardiac disease as defined in the protocol * Pregnant or breast-feeding women * Known drug abuse/alcohol abuse * Participation in another interventional clinical trial within the past 28 days (excluding purely observational studies) * 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 * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Time from date of randomization until death, assessed maximum up to 16 months | Overall survival (OS) was defined as the time (in months) from randomization to death. Data has been presented in terms of number subjects who died and number of censored subjects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Symptom Progression (TTSP) | Time from date of randomization until progressive disease (PD), assessed up to 16 months | TTSP was measured from date of randomization to date of disease progression (defined based on RECIST v1.1), using the lung cancer symptom scale (LCSS), a validated questionnaire consisting of an observer scale and a subject scale used to specifically measure symptom changes relevant to quality of life (QoL) for individuals undergoing treatment for lung cancer. Subject scale was used as a tool to determine TTSP. It was a 9-item questionnaire used to document subject-reported outcomes for a variety of lung cancer associated symptoms. The average symptomatic burden index (ASBI) was used to determine differences in the treatment groups. ASBI was the mean of the 6 symptom scores derived from the LCSS questionnaire. Symptom progression was defined as an increase (worsening) of the ASBI score of 10% of the scale breadth (10 mm on a scale of 0-100 mm) from the baseline score on at least 2 consecutive assessments during the period when assessments are performed every 3 weeks and every 6 weeks. |
| Progression Free Survival (PFS) | Time from date of randomization until PD or death, assessed up to 16 months | PFS was defined as the time from date of randomization until date of the first documentation of PD or death due to any cause in the absence of documented PD, whichever occurred first. PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Subjects without event were censored on the date of last tumor assessment. |
| Time to Progression (TTP) | Time from date of randomization until PD, assessed up to 16 months | TTP was measured from the date of randomization to the date of tumor progression. Date of tumor progression was date of radiological diagnosis of PD, performed as per RECIST 1.1. PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. For participants alive without tumor progression at time of analysis, the time between date of randomization and date of last trial treatment was calculated and used as a censored observation in the analysis. Subjects dying from causes other than PD was censored at time of death. |
| Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | Time from first dose up to 42 days after the last dose of the trial treatment: assessed maximum up to 16 months | An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious TEAE 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 occurred between the first dose of study drug and up to 42 days after the last dose that were absent before treatment or that worsened relative to pretreatment state. Number of Subjects With TEAEs, Serious TEAEs, NCI-CTC Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, and ISRs were reported. |
Countries
Germany, United States
Participant flow
Recruitment details
First/last subject(informed consent): 21 Mar 2014/11 Sep 2014. Study completion date: 02 Jul 2015.
Pre-assignment details
50 subjects were screened for eligibility; 15 excluded (mainly due to non-fulfillment of inclusion or exclusion criteria) and 35 subjects were randomized. Three subjects were randomized but were not treated.
Participants by arm
| Arm | Count |
|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide Single dose of cyclophosphamide (300 mg/m\^2 to a maximum of 600 mg) was administered intravenously, 3 days prior to the tecemotide dosing, tecemotide (L-BLP25) (806 mcg) was administered weekly subcutaneously for 8 weeks, followed by a maintenance treatment phase starting at Week 14, in which subcutaneous vaccinations with tecemotide (L-BLP25) (806 mcg) were administered every 6 weeks until disease progression was documented. | 15 |
| Placebo + Saline Single dose of saline (sodium chloride, 9 g/L) was administered intravenously, 3 days prior to the tecemotide dosing, placebo doses matched to tecemotide (L-BLP25) was administered weekly subcutaneously for 8 weeks, followed by a maintenance treatment phase starting at Week 14, in which subcutaneous vaccinations with placebo were administered every 6 weeks until disease progression was documented. | 17 |
| Total Title | 32 |
| Total | 64 |
Baseline characteristics
| Characteristic | Tecemotide (L-BLP25) + Cyclophosphamide | Placebo + Saline | Total Title |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 7 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 10 Participants | 15 Participants |
| Age, Continuous Age Continuous | 66.2 years STANDARD_DEVIATION 5.99 | 63.9 years STANDARD_DEVIATION 10.45 | 65.0 years STANDARD_DEVIATION 8.6 |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Male | 13 Participants | 10 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 15 | 13 / 17 |
| serious Total, serious adverse events | 4 / 15 | 1 / 17 |
Outcome results
Primary
Overall Survival
Overall survival (OS) was defined as the time (in months) from randomization to death. Data has been presented in terms of number subjects who died and number of censored subjects.
Time frame: Time from date of randomization until death, assessed maximum up to 16 months
Population: Safety Analysis Set included all subjects who had taken at least one dose of trial treatment (tecemotide \[L-BLP25\] or placebo), including cyclophosphamide or saline. Analysis was not performed due to the premature termination of this study and the tecemotide program based on negative results in EMR 63325-009 (NCT00960115).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Overall Survival | Number of deaths | 1 subjects |
| Tecemotide (L-BLP25) + Cyclophosphamide | Overall Survival | Number for censored | 14 subjects |
| Placebo + Saline | Overall Survival | Number of deaths | 2 subjects |
| Placebo + Saline | Overall Survival | Number for censored | 15 subjects |
Secondary
Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs)
An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious TEAE 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 occurred between the first dose of study drug and up to 42 days after the last dose that were absent before treatment or that worsened relative to pretreatment state. Number of Subjects With TEAEs, Serious TEAEs, NCI-CTC Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, and ISRs were reported.
Time frame: Time from first dose up to 42 days after the last dose of the trial treatment: assessed maximum up to 16 months
Population: Safety Analysis Set included all subjects who had taken at least one dose of trial treatment (tecemotide \[L-BLP25\] or placebo), including cyclophosphamide or saline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | TEAEs | 14 subjects |
| Tecemotide (L-BLP25) + Cyclophosphamide | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | Serious TEAEs | 4 subjects |
| Tecemotide (L-BLP25) + Cyclophosphamide | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | Grade 3 or 4 TEAEs | 5 subjects |
| Tecemotide (L-BLP25) + Cyclophosphamide | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | TEAEs Leading to Permanent Discontinuation | 2 subjects |
| Tecemotide (L-BLP25) + Cyclophosphamide | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | TEAEs leading to death | 0 subjects |
| Tecemotide (L-BLP25) + Cyclophosphamide | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | ISRs | 0 subjects |
| Placebo + Saline | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | TEAEs leading to death | 0 subjects |
| Placebo + Saline | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | TEAEs | 13 subjects |
| Placebo + Saline | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | TEAEs Leading to Permanent Discontinuation | 1 subjects |
| Placebo + Saline | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | Serious TEAEs | 1 subjects |
| Placebo + Saline | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | ISRs | 3 subjects |
| Placebo + Saline | Number Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, National Cancer Institute-Common Toxicity Criteria (NCI-CTC)Grade 3/4 TEAEs, TEAEs Leading to Permanent Discontinuation, TEAEs Leading to Death, Injection Site Reactions (ISRs) | Grade 3 or 4 TEAEs | 2 subjects |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from date of randomization until date of the first documentation of PD or death due to any cause in the absence of documented PD, whichever occurred first. PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Subjects without event were censored on the date of last tumor assessment.
Time frame: Time from date of randomization until PD or death, assessed up to 16 months
Population: Analysis was not performed due to the premature termination of this study and the tecemotide program based on negative results in EMR 63325-009 (NCT00960115).
Secondary
Time to Progression (TTP)
TTP was measured from the date of randomization to the date of tumor progression. Date of tumor progression was date of radiological diagnosis of PD, performed as per RECIST 1.1. PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. For participants alive without tumor progression at time of analysis, the time between date of randomization and date of last trial treatment was calculated and used as a censored observation in the analysis. Subjects dying from causes other than PD was censored at time of death.
Time frame: Time from date of randomization until PD, assessed up to 16 months
Population: Analysis was not performed due to the premature termination of this study and the tecemotide program based on negative results in EMR 63325-009 (NCT00960115).
Secondary
Time to Symptom Progression (TTSP)
TTSP was measured from date of randomization to date of disease progression (defined based on RECIST v1.1), using the lung cancer symptom scale (LCSS), a validated questionnaire consisting of an observer scale and a subject scale used to specifically measure symptom changes relevant to quality of life (QoL) for individuals undergoing treatment for lung cancer. Subject scale was used as a tool to determine TTSP. It was a 9-item questionnaire used to document subject-reported outcomes for a variety of lung cancer associated symptoms. The average symptomatic burden index (ASBI) was used to determine differences in the treatment groups. ASBI was the mean of the 6 symptom scores derived from the LCSS questionnaire. Symptom progression was defined as an increase (worsening) of the ASBI score of 10% of the scale breadth (10 mm on a scale of 0-100 mm) from the baseline score on at least 2 consecutive assessments during the period when assessments are performed every 3 weeks and every 6 weeks.
Time frame: Time from date of randomization until progressive disease (PD), assessed up to 16 months
Population: Analysis was not performed due to the premature termination of this study and the tecemotide program based on negative results in EMR 63325-009 (NCT00960115).