Non-small Cell Lung Cancer
Conditions
Keywords
NSCLC, Stage III, EMD531444, L-BLP25, Cyclophosphamide, Immunotherapy, Tecemotide
Brief summary
This is a phase I/II study in Japan to evaluate the safety of EMD531444 and its effects on survival time in patients with stage III unresectable non-small cell lung cancer.
Detailed description
Phase I part is designed to evaluate the safety of EMD531444 930 microgram (mcg) dose to be used in phase II. Phase II part is designed to be conducted as randomized, double blind, placebo controlled study to compare overall survival time in all randomized subjects.
Interventions
BIOLOGICALTecemotide (L-BLP25)
After receiving a single low-dose cyclophosphamide, participants will receive weekly subcutaneous vaccinations with tecemotide (L-BLP25) (930 microgram \[mcg\]) for 8 weeks, followed by a maintenance treatment phase starting at Week 14, in which subcutaneous vaccinations with tecemotide (L-BLP25) (930 mcg) will be administered every 6 weeks until progressive disease (PD).
A single intravenous (IV) infusion of 300 milligram per square meter (mg/m\^2) (to a maximum 600 mg/m\^2) of cyclophosphamide will be administered 3 days prior to tecemotide (L-BLP25), the first vaccine treatment.
BIOLOGICALPlacebo
After receiving single dose of saline, participants will receive weekly subcutaneous vaccinations with placebo that matches with tecemotide (L-BLP25) for 8 weeks, followed by a maintenance treatment phase starting at Week 14, in which subcutaneous vaccinations with placebo will be administered every 6 weeks until PD.
OTHERSaline
A single dose of saline (sodium chloride, 9 grams per liter \[g/L\]) will be administered intravenously, 3 days prior to the start of placebo.
Sponsors
Merck Serono Co., Ltd., Japan
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Receipt of concomitant or sequential chemoradiotherapy, consisting of a minimum of two cycles of platinum-based chemotherapy and a minimum radiation dose of greater than or equal to (\>=) 50 Gray (Gy). Participant must have completed the primary thoracic chemoradiotherapy at least 4 weeks and no later than 12 weeks prior to randomization * Written informed consent given before any study-related activities are carried out. * Histologically or cytologically documented unresectable stage III NSCLC. Cancer stage must be confirmed and documented by Computed Tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scan * Documented stable disease or objective response, according to RECIST, after primary chemoradiotherapy for unresectable stage III disease, within four weeks 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 Gy * Eastern cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate bone marrow function * Greater than or equal to 20 years of age
Exclusion criteria
* Lung cancer-specific therapy (including surgery), other than primary chemoradiotherapy. Note: exploratory surgery before study entry is allowed * 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) received within four weeks prior to randomization * Malignant pleural/pericardial effusion or pleural dissemination or separate tumor nodules in the same lobe at initial diagnosis and/or at study entry * Past or current history of neoplasm other than lung carcinoma, except for adequately 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 five years * Autoimmune disease * A recognized immunodeficiency disease including cellular immunodeficiencies, hypogamma-globulinemia, or dysgammaglobulinemia; participants who have hereditary or congenital/acquired immunodeficiencies * Any preexisting medical condition requiring chronic steroid or immunosuppressive therapy, including presence of diffuse radiation pneumonitis spreading out of the involved field * Known Hepatitis B and/or C * 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 * Pregnant or breast-feeding women. Participants whom the investigator considers may be at risk of pregnancy will have a pregnancy test performed per institutional standard. Male and female subjects who have a reproductive ability, unless using effective contraception as determined by the investigator throughout the study until at least 6 months after the last study treatment * Known drug abuse or alcohol abuse * Legal incapacity or limited legal capacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Time | Time from randomization to death or last day known to be alive reported between day of first subject randomized in Step 2 (i.e. 03 Feb 2010), until clinical cut-off date (i.e. 01 May 2014). | OS time was defined as the time from randomization to death. Participants without event were censored at the last date known to be alive or at the clinical cut-off date (01 May 2014), whichever was earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time To Progression (TTP) - Investigator Read | Time from randomization to PD, reported between day of first subject randomized in Step 2 (i.e. 03 Feb 2010), until clinical cut-off date (i.e. 01 May 2014). | TTP was defined as the time from date of randomization to date of radiological diagnosis of PD (based on Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.0). In the event that radiological confirmation could not be obtained but participant was withdrawn from trial treatment or died due to disease progression, TTP was measured from date of randomization to the date of discontinuation of trial treatment. Participants without event who died from causes other than disease progression were censored at date of death. Participants without event who were lost to follow-up were censored at the date of lost to follow-up, except if they missed 2 consecutive scheduled doses, in which case they were considered as having disease progression at time of first missed administration. Participants without event with ongoing treatment at time of analysis, or who had stopped treatment for reasons other than PD, were censored on the date of last treatment administration. |
| Progression Free Survival (PFS) Time - Investigator Read | Time from randomization to disease progression, death or last tumor assessment, reported between day of first subject randomized in Step 2 (i.e. 03 Feb 2010), until clinical cut-off date (i.e. 01 May 2014). | PFS time was defined as the duration from randomization to either first observation of objective PD (based on RECIST v1.0) or occurrence of death due to any cause. Participants without event still on treatment at time of analysis, or who stopped treatment for reasons other than PD or PD without radiological confirmed progression, were censored at the last imaging date. Participants without event who were lost to follow-up were censored at the date of lost to follow-up, except if they missed 2 consecutive scheduled doses, in which case they were considered as having disease progression at time of first missed administration. |
| Time to Treatment Failure (TTF) | Time from randomization to discontinuation of trial treatment, reported between day of first subject randomized in Step 2 (i.e. 03 Feb 2010), until clinical cut-off date (i.e. 01 May 2014). | TTF was defined as the duration from date of randomization to the date of discontinuation of any trial treatment (cyclophosphamide or saline, tecemotide \[L-BLP25\] or placebo vaccine) for any reason as reported by the Investigator. Participants who had missed 2 consecutive scheduled doses and were subsequently lost to follow-up were considered as treatment failures with event date as date of first missed administration. Participants without event still on treatment at time of analysis were censored on the date of last treatment administration. |
Countries
Germany
Participant flow
Recruitment details
First/last subject (informed consent, Step 2 \[randomized part\]): 03 Feb 2010/15 Feb 2012. Clinical data cut-off: 01 May 2014. Study completion date: 15 June 2015
Pre-assignment details
Enrolled: 197 screened for eligibility; 25 excluded (mainly due to non-fulfillment of inclusion or exclusion criteria) and 172 subjects randomized.
Participants by arm
| Arm | Count |
|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide Single dose of cyclophosphamide (300 milligrams per square meter \[mg/m\^2\] to a maximum of 600 mg) was administered intravenously, 3 days prior to the start of vaccination, followed by weekly subcutaneous vaccinations with tecemotide (L-BLP25) (930 mcg) for 8 weeks, followed by a maintenance treatment phase starting at Week 14, in which subcutaneous vaccinations with tecemotide (L-BLP25) (930 mcg) were administered every 6 weeks until PD was documented. | 114 |
| Placebo + Saline Single dose of saline (sodium chloride, 9 grams per liter \[g/L\]) was administered intravenously, 3 days prior to the start of vaccination, followed by weekly subcutaneous vaccinations with placebo doses matched to tecemotide (L-BLP25) 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 PD was documented. | 58 |
| Total | 172 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ongoing treatment at data cut-off date | 19 | 15 |
Baseline characteristics
| Characteristic | Tecemotide (L-BLP25) + Cyclophosphamide | Placebo + Saline | Total |
|---|---|---|---|
| Age, Continuous | 63.0 Years STANDARD_DEVIATION 9.31 | 60.1 Years STANDARD_DEVIATION 9.81 | 62.0 Years STANDARD_DEVIATION 9.55 |
| Sex: Female, Male Female | 16 Participants | 11 Participants | 27 Participants |
| Sex: Female, Male Male | 98 Participants | 47 Participants | 145 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 107 / 114 | 53 / 57 |
| serious Total, serious adverse events | 24 / 114 | 12 / 57 |
Outcome results
Primary
Overall Survival (OS) Time
OS time was defined as the time from randomization to death. Participants without event were censored at the last date known to be alive or at the clinical cut-off date (01 May 2014), whichever was earlier.
Time frame: Time from randomization to death or last day known to be alive reported between day of first subject randomized in Step 2 (i.e. 03 Feb 2010), until clinical cut-off date (i.e. 01 May 2014).
Population: ITT analysis set included all subjects randomly allocated to a treatment (tecemotide \[L-BLP25\] or placebo).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Overall Survival (OS) Time | 32.4 Months |
| Placebo + Saline | Overall Survival (OS) Time | 32.2 Months |
p-value: 0.82895% CI: [0.614, 1.479]Log Rank
Secondary
Progression Free Survival (PFS) Time - Investigator Read
PFS time was defined as the duration from randomization to either first observation of objective PD (based on RECIST v1.0) or occurrence of death due to any cause. Participants without event still on treatment at time of analysis, or who stopped treatment for reasons other than PD or PD without radiological confirmed progression, were censored at the last imaging date. Participants without event who were lost to follow-up were censored at the date of lost to follow-up, except if they missed 2 consecutive scheduled doses, in which case they were considered as having disease progression at time of first missed administration.
Time frame: Time from randomization to disease progression, death or last tumor assessment, reported between day of first subject randomized in Step 2 (i.e. 03 Feb 2010), until clinical cut-off date (i.e. 01 May 2014).
Population: ITT analysis set included all subjects randomly allocated to a treatment (tecemotide \[L-BLP25\] or placebo).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Progression Free Survival (PFS) Time - Investigator Read | 11.6 Months |
| Placebo + Saline | Progression Free Survival (PFS) Time - Investigator Read | 8.0 Months |
Secondary
Time To Progression (TTP) - Investigator Read
TTP was defined as the time from date of randomization to date of radiological diagnosis of PD (based on Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.0). In the event that radiological confirmation could not be obtained but participant was withdrawn from trial treatment or died due to disease progression, TTP was measured from date of randomization to the date of discontinuation of trial treatment. Participants without event who died from causes other than disease progression were censored at date of death. Participants without event who were lost to follow-up were censored at the date of lost to follow-up, except if they missed 2 consecutive scheduled doses, in which case they were considered as having disease progression at time of first missed administration. Participants without event with ongoing treatment at time of analysis, or who had stopped treatment for reasons other than PD, were censored on the date of last treatment administration.
Time frame: Time from randomization to PD, reported between day of first subject randomized in Step 2 (i.e. 03 Feb 2010), until clinical cut-off date (i.e. 01 May 2014).
Population: ITT Analysis Set included all subjects randomly allocated to a treatment (tecemotide \[L-BLP25\] or placebo).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Time To Progression (TTP) - Investigator Read | 11.3 Months |
| Placebo + Saline | Time To Progression (TTP) - Investigator Read | 7.0 Months |
Secondary
Time to Treatment Failure (TTF)
TTF was defined as the duration from date of randomization to the date of discontinuation of any trial treatment (cyclophosphamide or saline, tecemotide \[L-BLP25\] or placebo vaccine) for any reason as reported by the Investigator. Participants who had missed 2 consecutive scheduled doses and were subsequently lost to follow-up were considered as treatment failures with event date as date of first missed administration. Participants without event still on treatment at time of analysis were censored on the date of last treatment administration.
Time frame: Time from randomization to discontinuation of trial treatment, reported between day of first subject randomized in Step 2 (i.e. 03 Feb 2010), until clinical cut-off date (i.e. 01 May 2014).
Population: ITT analysis set included all subjects randomly allocated to a treatment (tecemotide \[L-BLP25\] or placebo).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tecemotide (L-BLP25) + Cyclophosphamide | Time to Treatment Failure (TTF) | 8.0 Months |
| Placebo + Saline | Time to Treatment Failure (TTF) | 6.2 Months |