Non-small Cell Lung Cancer
Conditions
Keywords
Non-Small Cell Lung Carcinoma;, stage III;, unresectable;, vaccine; Tecemotide; L-BLP25;, Cyclophosphamide;, placebo controlled;, randomized;, double blind;, immunotherapy;
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)
Interventions
BIOLOGICALTecemotide (L-BLP25)
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.
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.
DRUGPlacebo
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.
Sponsors
Merck KGaA, Darmstadt, Germany
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 66 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time To Symptom Progression (TTSP) as Measured by the Lung Cancer Symptom Scale (LCSS) | Up to 66 months | 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. |
| Time To Progression (TTP) | Up to 66 months | 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. |
| One-, Two- and Three-year Survival Rate | Years 1, 2, and 3 | 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. |
| Number of Participants With Treatment Emergent Adverse Events and Injection Site Reactions | From first dose up to 42 days after the last dose of the trial treatment | 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. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, Denmark, France, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Mexico, Netherlands, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
First/last participant (informed consent): 25 January 2007/31 October 2011. Data cut-off for primary endpoint analysis: 08 August 2012. Participants randomized at 264 centers in 33 countries worldwide.
Pre-assignment details
A total of 1908 participants were screened for eligibility and 1513 participants were enrolled and randomized.
Participants by arm
| Arm | Count |
|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide A single intravenous infusion of 300 milligram per square meter (mg/m\^2) (to a maximum 600 mg) of cyclophosphamide was given 3 days before first tecemotide (L-BLP25) vaccination. After receiving cyclophosphamide, participants received 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 was documented. | 1,006 |
| Saline + Placebo A single intravenous infusion of 0.9 percent (%) saline solution in the same calculated dose as cyclophosphamide was given 3 days before first placebo vaccination. After receiving saline, participants received 8 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 was documented. | 507 |
| Total | 1,513 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ongoing at data cut-off | 383 | 175 |
Baseline characteristics
| Characteristic | Tecemotide (L-BLP25) + Cyclophosphamide | Saline + Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 9.1 | 60.9 years STANDARD_DEVIATION 9 | 60.8 years STANDARD_DEVIATION 9.1 |
| Sex: Female, Male Female | 315 Participants | 162 Participants | 477 Participants |
| Sex: Female, Male Male | 691 Participants | 345 Participants | 1036 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 918 / 1,024 | 417 / 477 |
| serious Total, serious adverse events | 303 / 1,024 | 151 / 477 |
Outcome results
Primary
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.
Time frame: Up to 66 months
Population: Primary analysis set (modified intention-to-treat \[ITT\] population) was based on the ITT population but prospectively excluded all participants (274 participants) that were randomized during the 6 months (22 Sep 2009 to 22 Mar 2010) prior to the effective date of clinical hold.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Overall Survival | 25.6 months |
| Saline + Placebo | Overall Survival | 22.3 months |
p-value: 0.156695% CI: [0.763, 1.044]Regression, Cox
Secondary
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.
Time frame: From first dose up to 42 days after the last dose of the trial treatment
Population: Safety analysis set included all participants who received at least 1 dose of trial treatment (cyclophosphamide, tecemotide, saline, or placebo). Participants were reported based on the actual treatment received (as-treated).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Number of Participants With Treatment Emergent Adverse Events and Injection Site Reactions | Treatment Emergent Adverse events | 938 participants |
| Tecemotide (L-BLP25) + Cyclophosphamide | Number of Participants With Treatment Emergent Adverse Events and Injection Site Reactions | Injection site reaction | 176 participants |
| Saline + Placebo | Number of Participants With Treatment Emergent Adverse Events and Injection Site Reactions | Treatment Emergent Adverse events | 432 participants |
| Saline + Placebo | Number of Participants With Treatment Emergent Adverse Events and Injection Site Reactions | Injection site reaction | 56 participants |
Secondary
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.
Time frame: Years 1, 2, and 3
Population: Primary analysis set (modified ITT population) was based on the ITT population but prospectively excluded all participants (274 participants) that were randomized during the 6 months (22 Sep 2009 to 22 Mar 2010) prior to the effective date of clinical hold.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | One-, Two- and Three-year Survival Rate | Year 1 | 77.0 percentage of participants |
| Tecemotide (L-BLP25) + Cyclophosphamide | One-, Two- and Three-year Survival Rate | Year 2 | 50.8 percentage of participants |
| Tecemotide (L-BLP25) + Cyclophosphamide | One-, Two- and Three-year Survival Rate | Year 3 | 40.2 percentage of participants |
| Saline + Placebo | One-, Two- and Three-year Survival Rate | Year 3 | 37.0 percentage of participants |
| Saline + Placebo | One-, Two- and Three-year Survival Rate | Year 1 | 74.7 percentage of participants |
| Saline + Placebo | One-, Two- and Three-year Survival Rate | Year 2 | 45.9 percentage of participants |
Secondary
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.
Time frame: Up to 66 months
Population: Primary analysis set (modified ITT population) was based on the ITT population but prospectively excluded all participants (274 participants) that were randomized during the 6 months (22 Sep 2009 to 22 Mar 2010) prior to the effective date of clinical hold.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Time To Progression (TTP) | 10.0 months |
| Saline + Placebo | Time To Progression (TTP) | 8.4 months |
p-value: 0.052895% CI: [0.752, 1.002]Regression, Cox
Secondary
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.
Time frame: Up to 66 months
Population: Primary analysis set (modified ITT population) was based on the ITT population but prospectively excluded all participants (274 participants) that were randomized during the 6 months (22 Sep 2009 to 22 Mar 2010) prior to the effective date of clinical hold. N signifies the number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Time To Symptom Progression (TTSP) as Measured by the Lung Cancer Symptom Scale (LCSS) | 14.2 months |
| Saline + Placebo | Time To Symptom Progression (TTSP) as Measured by the Lung Cancer Symptom Scale (LCSS) | 11.4 months |
p-value: 0.022695% CI: [0.732, 0.977]Regression, Cox