Rectal Cancer
Conditions
Keywords
Tecemotide (L-BLP25), Cyclophosphamide (CPA), Mode of action, Neoplasms, Neoplasms by Site, Carcinomas, Antineoplastic Agents, Neoadjuvant, Radiotherapy Pharmacologic Actions, Immunosuppressive Agents, Immunologic Function, Therapeutic Uses, Molecular Mechanisms of Pharmacological Action
Brief summary
The objective of this mechanistic study is to determine the impact of tecemotide (L-BLP25) administration on the mucinous glycoprotein 1 - (MUC1) specific immune response in subjects with newly diagnosed rectal cancer who are eligible for neoadjuvant therapy. Tecemotide (L-BLP25) is designed to induce an immune response that may lead to immune rejection of tumor tissues that aberrantly express MUC1 antigen. MUC1 is highly expressed in all colorectal cancers and since the adaptive immune system plays a role in the prognosis of rectal cancer, it is reasonable to speculate that tecemotide (L-BLP25) administration might boost the tumor-specific immune response and increase the number of tumor-infiltrating lymphocytes (TILs).
Interventions
BIOLOGICALTecemotide (L-BLP25)
Subjects will receive 8 consecutive weekly subcutaneous vaccinations with 806 microgram (mcg) of tecemotide (L-BLP25) at Weeks 1, 2, 3, 4, 5, 6, 7 and 8, which will be administered concomitantly with the chemoradiotherapy, followed by a 9th subcutaneous injection 7 to 11 days prior to surgery.
A single intravenous infusion of 300 milligram per square meter (mg/m\^2) (to a maximum 600 mg) of CPA will be given 3 days before the first tecemotide (L-BLP25) administration.
OTHERChemoradiotherapy
Radiotherapy of 45-52 grays (Gy) will be applied 5 times per week, over a minimum period of 5 weeks. Capecitabine at a dose of 825 mg/m\^2, twice daily or equivalent dose of 5-fluorouracil (5-FU) will be given orally, starting at the first day of radiotherapy and given 5 to 7 days per week during the time of radiotherapy.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female subjects with histologically documented resectable rectal adenocarcinoma in Stage 2-4 2. Availability of tumor biopsy sufficient for immunological analysis 3. Indication to receive neoadjuvant concomitant chemoradiotherapy consisting of a radiation dose of 45-52 Gy and capecitabine 825 mg/m\^2 orally twice daily. The use of an equivalent schedule based on 5-FU is acceptable 4. Magnetic resonance imaging small pelvis / computed tomography thorax/abdomen (or X-ray thorax) to document absence of metastatic disease. Imaging must not be older than 6 weeks prior to randomization 5. Eastern Cooperative Oncology Group performance status of 0 or 1 6. Written informed consent 7. Greater than or equal to (\>=) 18 years of age
Exclusion criteria
1. Previous chemotherapy and/or previous radiotherapy of the pelvic region 2. Relapsing disease 3. Previous vaccination with any MUC1 vaccine and other therapeutic cancer vaccines 4. Previous organ transplantation (bone marrow or solid organs) 5. Subjects with metastatic disease (except for solitary, resectable liver or lung metastases) 6. Inadequate hematological function (that is, platelet count less than 140\*10\^9 per liter \[/L\], or white blood cell less than 2.5\*10\^9/L, or hemoglobin less than 90 gram per liter). Clinically significant hepatic dysfunction (that is alanine aminotransferase greater than 2.5\*upper limit of normal \[ULN\], or aspartate aminotransferase greater than 2.5\*ULN, or bilirubin greater than 1.5\*ULN). Inadequate renal function (that is serum creatinine greater than 1.5\*ULN) 7. Autoimmune diseases 8. Recognized immunodeficiency disease including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; subjects who have hereditary or congenital immunodeficiencies 9. Clinically significant cardiac disease, for example, New York Heart Association Classes III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, myocardial infarction in the previous 6 months as confirmed by medical history and an electrocardiogram 10. Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Tumor Immune Response Evaluated by Immunohistochemical (IHC) Analysis of Tumor Infiltrating Lymphocytes (TILs) at Week 14 (Post-surgery) | Baseline and Week 14 (post-surgery) | Tumor biopsy samples were collected prior to baseline and after the surgery. The TILs were evaluated in 3 of the most abundant high-power fields (x40) per sample and the mean value considered (after excluding the lowest and the highest value). The tumor immune response was calculated as number of TILs divided by 100 tumor cells. |
| Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status: Number of Subjects Per MSI Category | 18 weeks | A potential association between MSI status (present or absent) and the primary endpoints (difference from baseline to surgery in CD8+ and CD8+/GrB+ T cell infiltration) was evaluated. Determination of mismatch repair protein (MRP)-expression (hMLH1, hMSH2, hMSH6 and hPMS2) was performed for the detection of the MSI-H-phenotype by IHC and/or on tumor deoxyribonucleic acid (DNA) sample using 5 microsatellite markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). |
| Change From Baseline in Interferon (IFN)-Gamma Secretion of Mononuclear Cells in Response to MUC1 by Enzyme-linked Immunosorbent Spot (ELISpot) at Post-baseline | Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial) | IFN-gamma secretion of mononuclear cells in response to MUC1 was to be measured by ELISpot. The maximal post-baseline value out of Week 5, Week 11-13 (pre-surgery), and Week 16-18 (follow-up / end-of trial) was evaluated in comparison to Baseline. |
| Change From Baseline in IFN-gamma Secretion of Mononuclear Cells in Response to Carcinoembryonic Antigen (CEA) by ELISpot at Post-baseline | Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial) | IFN-gamma secretion of mononuclear cells in response to CEA was to be measured by ELISpot. The maximal post-baseline value out of Week 5, Week 11-13 (pre-surgery), and Week 16-18 (follow-up / end-of trial) was evaluated in comparison to Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peritumoral Immune Response at Week 14 (Post-surgery) | Baseline and Week 14 (post-surgery) | Immunological changes in the tumor microenvironment were evaluated based on IHC expression of CD3+, CD4+, and Ki67+CD3+ T cells; regulatory T cells (FOXP3+) and myeloid-derived suppressor cells (CD33+CD14-); other immune cells such as NK cells (CD3-CD57+), B cells (CD20+), macrophages (CD68+), and dendritic cells (S100+). Peritumoral immune response was calculated as number of lymphoid cells at the margin of the tumor or in the tumor bed (if there is complete pathological response). |
| Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Baseline and Week 18 (follow-up / end-of trial) | Immunological changes in peripheral blood were evaluated based on fluorescence analysis cell sorter phenotypic characterization of T cells (CD3+CD4+ and CD3+CD8+) and of markers of activation and proliferation (CD27, BTLA); and regulatory cells such as CD3+CD4+ (or CD8+) CD45RA+CD25+FoxP3+CD127 T cells. Immunological Response in peripheral blood was measured on a continuous scale. |
Countries
Netherlands
Participant flow
Recruitment details
First/last participant (informed consent): Feb 2012/Dec 2013. Study completion date: Jun 2014.
Pre-assignment details
Enrolled: 140 screened for eligibility; 16 excluded (mainly due to non-fulfillment of inclusion or exclusion criteria), 124 subjects randomized.
Participants by arm
| Arm | Count |
|---|---|
| Chemoradiotherapy+Tecemotide (L-BLP25)+CPA Single dose of cyclophosphamide (300 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) (actual delivered dose was 806 mcg) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery. | 39 |
| Chemoradiotherapy+Tecemotide (L-BLP25) Weekly subcutaneous vaccinations with tecemotide (L-BLP25) (actual delivered dose was 806 mcg) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery. | 41 |
| Chemoradiotherapy Radiotherapy of 45-52 Gy will be applied 5 times per week, over a minimum period of 5 weeks. Capecitabine at a dose of 825 mg/m\^2, twice daily or equivalent dose of 5-FU will be given orally, starting at the first day of radiotherapy and given 5 to 7 days per week during the time of radiotherapy. | 42 |
| Total | 122 |
Baseline characteristics
| Characteristic | Chemoradiotherapy+Tecemotide (L-BLP25)+CPA | Chemoradiotherapy+Tecemotide (L-BLP25) | Chemoradiotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 10.74 | 62.2 years STANDARD_DEVIATION 10.12 | 60.3 years STANDARD_DEVIATION 8.77 | 61.3 years STANDARD_DEVIATION 9.84 |
| Gender Female | 9 Participants | 14 Participants | 10 Participants | 33 Participants |
| Gender Male | 30 Participants | 27 Participants | 32 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 38 / 39 | 41 / 41 | 41 / 42 |
| serious Total, serious adverse events | 10 / 39 | 10 / 41 | 12 / 42 |
Outcome results
Primary
Change From Baseline in IFN-gamma Secretion of Mononuclear Cells in Response to Carcinoembryonic Antigen (CEA) by ELISpot at Post-baseline
IFN-gamma secretion of mononuclear cells in response to CEA was to be measured by ELISpot. The maximal post-baseline value out of Week 5, Week 11-13 (pre-surgery), and Week 16-18 (follow-up / end-of trial) was evaluated in comparison to Baseline.
Time frame: Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial)
Population: Data were not analyzed as no acceptable ELISpot assay is available
Primary
Change From Baseline in Interferon (IFN)-Gamma Secretion of Mononuclear Cells in Response to MUC1 by Enzyme-linked Immunosorbent Spot (ELISpot) at Post-baseline
IFN-gamma secretion of mononuclear cells in response to MUC1 was to be measured by ELISpot. The maximal post-baseline value out of Week 5, Week 11-13 (pre-surgery), and Week 16-18 (follow-up / end-of trial) was evaluated in comparison to Baseline.
Time frame: Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial)
Population: Data were not analyzed as no acceptable ELISpot assay is available
Primary
Change From Baseline in Tumor Immune Response Evaluated by Immunohistochemical (IHC) Analysis of Tumor Infiltrating Lymphocytes (TILs) at Week 14 (Post-surgery)
Tumor biopsy samples were collected prior to baseline and after the surgery. The TILs were evaluated in 3 of the most abundant high-power fields (x40) per sample and the mean value considered (after excluding the lowest and the highest value). The tumor immune response was calculated as number of TILs divided by 100 tumor cells.
Time frame: Baseline and Week 14 (post-surgery)
Population: Immunomonitoring analysis set included all subjects for whom at least the baseline ELISpot blood and tumor sample, tumor sample at surgery and pre-surgery ELISpot blood drawing are available and whose tumor biopsy at baseline is MUC1-positive. Within the data table, n=number of subjects analyzed for each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Tumor Immune Response Evaluated by Immunohistochemical (IHC) Analysis of Tumor Infiltrating Lymphocytes (TILs) at Week 14 (Post-surgery) | CD8+ (n=23, 27, 26) | 0.609 TILs per 100 tumor cells | Standard Deviation 5.4241 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Tumor Immune Response Evaluated by Immunohistochemical (IHC) Analysis of Tumor Infiltrating Lymphocytes (TILs) at Week 14 (Post-surgery) | CD8+/GrB+ (n=23, 27, 26) | 0.565 TILs per 100 tumor cells | Standard Deviation 3.1646 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Tumor Immune Response Evaluated by Immunohistochemical (IHC) Analysis of Tumor Infiltrating Lymphocytes (TILs) at Week 14 (Post-surgery) | CD8+ (n=23, 27, 26) | 0.543 TILs per 100 tumor cells | Standard Deviation 4.5009 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Tumor Immune Response Evaluated by Immunohistochemical (IHC) Analysis of Tumor Infiltrating Lymphocytes (TILs) at Week 14 (Post-surgery) | CD8+/GrB+ (n=23, 27, 26) | 0.216 TILs per 100 tumor cells | Standard Deviation 2.4187 |
| Chemoradiotherapy | Change From Baseline in Tumor Immune Response Evaluated by Immunohistochemical (IHC) Analysis of Tumor Infiltrating Lymphocytes (TILs) at Week 14 (Post-surgery) | CD8+ (n=23, 27, 26) | 1.538 TILs per 100 tumor cells | Standard Deviation 3.9509 |
| Chemoradiotherapy | Change From Baseline in Tumor Immune Response Evaluated by Immunohistochemical (IHC) Analysis of Tumor Infiltrating Lymphocytes (TILs) at Week 14 (Post-surgery) | CD8+/GrB+ (n=23, 27, 26) | 0.936 TILs per 100 tumor cells | Standard Deviation 2.7649 |
Comparison: Category: CD8+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm C) based on an analysis of covariance (ANCOVA) model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm Bp-value: 0.79495% CI: [-0.72, 0.65]type III SS F-test
Comparison: Category: CD8+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm B vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm Bp-value: 0.79495% CI: [-0.82, 0.43]type III SS F-test
Comparison: Category: CD8+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm B) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm Bp-value: 0.79495% CI: [-0.49, 0.82]type III SS F-test
Comparison: Category: CD8+/GrB+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm Bp-value: 0.65495% CI: [-0.52, 0.57]type III SS F-test
Comparison: Category: CD8+/GrB+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm B vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm Bp-value: 0.65495% CI: [-0.69, 0.31]type III SS F-test
Comparison: Category: CD8+/GrB+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm B) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm Bp-value: 0.65495% CI: [-0.31, 0.74]type III SS F-test
Primary
Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status: Number of Subjects Per MSI Category
A potential association between MSI status (present or absent) and the primary endpoints (difference from baseline to surgery in CD8+ and CD8+/GrB+ T cell infiltration) was evaluated. Determination of mismatch repair protein (MRP)-expression (hMLH1, hMSH2, hMSH6 and hPMS2) was performed for the detection of the MSI-H-phenotype by IHC and/or on tumor deoxyribonucleic acid (DNA) sample using 5 microsatellite markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27).
Time frame: 18 weeks
Population: Immunomonitoring analysis set included all subjects for whom at least the baseline ELISpot blood and tumor sample, tumor sample at surgery and pre-surgery ELISpot blood drawing are available and whose tumor biopsy at baseline is MUC1-positive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status: Number of Subjects Per MSI Category | No | 25 subjects |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status: Number of Subjects Per MSI Category | Yes | 2 subjects |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status: Number of Subjects Per MSI Category | No | 32 subjects |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status: Number of Subjects Per MSI Category | Yes | 1 subjects |
| Chemoradiotherapy | Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status: Number of Subjects Per MSI Category | No | 30 subjects |
| Chemoradiotherapy | Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status: Number of Subjects Per MSI Category | Yes | 0 subjects |
Comparison: Category: CD8+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.p-value: 0.92195% CI: [-0.73, 0.67]type III SS F-test
Comparison: Category: CD8+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm B vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.p-value: 0.92195% CI: [-0.83, 0.44]type III SS F-test
Comparison: Category: CD8+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm B) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.p-value: 0.92195% CI: [-0.5, 0.83]type III SS F-test
Comparison: Category:CD8+/GrB+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm C) based on an ANCOVA model. Difference from baseline=Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.p-value: 0.8995% CI: [-0.54, 0.58]type III SS F-test
Comparison: Category:CD8+/GrB+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm B vs Arm C) based on an ANCOVA model. Difference from baseline=Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.p-value: 0.8995% CI: [-0.7, 0.31]type III SS F-test
Comparison: Category:CD8+/GrB+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm B) based on an ANCOVA model. Difference from baseline=Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.p-value: 0.8995% CI: [-0.32, 0.74]type III SS F-test
Secondary
Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial)
Immunological changes in peripheral blood were evaluated based on fluorescence analysis cell sorter phenotypic characterization of T cells (CD3+CD4+ and CD3+CD8+) and of markers of activation and proliferation (CD27, BTLA); and regulatory cells such as CD3+CD4+ (or CD8+) CD45RA+CD25+FoxP3+CD127 T cells. Immunological Response in peripheral blood was measured on a continuous scale.
Time frame: Baseline and Week 18 (follow-up / end-of trial)
Population: Immunomonitoring analysis set included all subjects for whom at least the baseline ELISpot blood and tumor sample, tumor sample at surgery and pre-surgery ELISpot blood drawing are available and whose tumor biopsy at baseline is MUC1-positive. Within the data table, n=number of subjects analysed for each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+CCR7+ (n=26,30,24) | -1.341 log2 (percentage of T cells) | Standard Deviation 4.1442 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16-Granzyme B+ (n=26,30,24) | 0.479 log2 (percentage of T cells) | Standard Deviation 1.6943 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+GranzymeB+ (n=26,30,24) | -0.013 log2 (percentage of T cells) | Standard Deviation 0.1051 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Lymphs Tube 3 (n=27,30,25) | -0.994 log2 (percentage of T cells) | Standard Deviation 0.4545 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+/LY (n=26,30,24) | 0.277 log2 (percentage of T cells) | Standard Deviation 0.5448 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+Granzyme B+/LY (n=26,30,24) | 0.264 log2 (percentage of T cells) | Standard Deviation 0.5885 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD4+BTLA4+ (n=26,30,24) | 0.063 log2 (percentage of T cells) | Standard Deviation 1.4413 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD19+BTLA4+ (n=27,29,23) | -0.030 log2 (percentage of T cells) | Standard Deviation 0.0489 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD4+CD127+FoxP3-CD45RA-CD25+CTLA4+(n=27,29,24) | 0.711 log2 (percentage of T cells) | Standard Deviation 1.3825 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+CD107a+ (n=26,30,24) | -1.216 log2 (percentage of T cells) | Standard Deviation 4.5484 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Lymphs Tube 2 (n=27,30,25) | -1.024 log2 (percentage of T cells) | Standard Deviation 0.4392 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+Granzyme B+/LY (n=26,30,24) | 0.243 log2 (percentage of T cells) | Standard Deviation 0.6969 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+Perforin+/LY (n=26,30,24) | 0.226 log2 (percentage of T cells) | Standard Deviation 0.5669 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+Perforin+/LY (n=26,30,24) | 0.240 log2 (percentage of T cells) | Standard Deviation 0.6997 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Background corrected CD3+CD4+IFNg+ (n=21,27,21) | 0.058 log2 (percentage of T cells) | Standard Deviation 0.9767 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16-CD107a+ (n=26,30,24) | 0.216 log2 (percentage of T cells) | Standard Deviation 1.201 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD4+CD27+ (n=26,30,24) | -0.181 log2 (percentage of T cells) | Standard Deviation 0.1848 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD8+CD127+FoxP3-CD25-CD45RA+CTLA4-(n=27,29,24) | -0.604 log2 (percentage of T cells) | Standard Deviation 0.8102 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD8+CD127-FoxP3-CD45RA-CD25+CTLA4+(n=27,29,24) | 0.050 log2 (percentage of T cells) | Standard Deviation 0.3933 |
| Chemoradiotherapy+Tecemotide (L-BLP25)+Cyclophosphamide | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+Perforin+ (n=26,30,24) | -0.050 log2 (percentage of T cells) | Standard Deviation 0.0769 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+Granzyme B+/LY (n=26,30,24) | -0.201 log2 (percentage of T cells) | Standard Deviation 1.0731 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+GranzymeB+ (n=26,30,24) | -0.046 log2 (percentage of T cells) | Standard Deviation 0.1259 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+Perforin+ (n=26,30,24) | -0.033 log2 (percentage of T cells) | Standard Deviation 0.1868 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD4+CD27+ (n=26,30,24) | -0.135 log2 (percentage of T cells) | Standard Deviation 0.1521 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+Granzyme B+/LY (n=26,30,24) | 0.047 log2 (percentage of T cells) | Standard Deviation 1.2787 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+Perforin+/LY (n=26,30,24) | 0.058 log2 (percentage of T cells) | Standard Deviation 1.2902 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16-CD107a+ (n=26,30,24) | -0.318 log2 (percentage of T cells) | Standard Deviation 1.5863 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD8+CD127-FoxP3-CD45RA-CD25+CTLA4+(n=27,29,24) | 0.152 log2 (percentage of T cells) | Standard Deviation 0.5386 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16-Granzyme B+ (n=26,30,24) | -0.241 log2 (percentage of T cells) | Standard Deviation 0.9628 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+/LY (n=26,30,24) | 0.090 log2 (percentage of T cells) | Standard Deviation 1.2968 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD19+BTLA4+ (n=27,29,23) | -0.028 log2 (percentage of T cells) | Standard Deviation 0.055 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Lymphs Tube 2 (n=27,30,25) | -0.941 log2 (percentage of T cells) | Standard Deviation 0.608 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+CD107a+ (n=26,30,24) | 1.966 log2 (percentage of T cells) | Standard Deviation 6.6322 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD4+BTLA4+ (n=26,30,24) | 0.122 log2 (percentage of T cells) | Standard Deviation 0.4833 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Lymphs Tube 3 (n=27,30,25) | -0.920 log2 (percentage of T cells) | Standard Deviation 0.5923 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+CCR7+ (n=26,30,24) | 0.541 log2 (percentage of T cells) | Standard Deviation 6.3502 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD8+CD127+FoxP3-CD25-CD45RA+CTLA4-(n=27,29,24) | -1.062 log2 (percentage of T cells) | Standard Deviation 1.1436 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Background corrected CD3+CD4+IFNg+ (n=21,27,21) | 0.544 log2 (percentage of T cells) | Standard Deviation 0.9521 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+Perforin+/LY (n=26,30,24) | -0.177 log2 (percentage of T cells) | Standard Deviation 0.992 |
| Chemoradiotherapy+Tecemotide (L-BLP25) | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD4+CD127+FoxP3-CD45RA-CD25+CTLA4+(n=27,29,24) | 0.674 log2 (percentage of T cells) | Standard Deviation 1.2689 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+Perforin+ (n=26,30,24) | -0.088 log2 (percentage of T cells) | Standard Deviation 0.2282 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Lymphs Tube 3 (n=27,30,25) | -0.936 log2 (percentage of T cells) | Standard Deviation 0.4746 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD8+CD127-FoxP3-CD45RA-CD25+CTLA4+(n=27,29,24) | -0.012 log2 (percentage of T cells) | Standard Deviation 0.5202 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD4+CD127+FoxP3-CD45RA-CD25+CTLA4+(n=27,29,24) | 1.035 log2 (percentage of T cells) | Standard Deviation 1.4996 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+CCR7+ (n=26,30,24) | -3.390 log2 (percentage of T cells) | Standard Deviation 5.1877 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16-CD107a+ (n=26,30,24) | 0.037 log2 (percentage of T cells) | Standard Deviation 1.0191 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+Perforin+/LY (n=26,30,24) | 0.101 log2 (percentage of T cells) | Standard Deviation 0.7617 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD8+CD127+FoxP3-CD25-CD45RA+CTLA4-(n=27,29,24) | -0.940 log2 (percentage of T cells) | Standard Deviation 1.2678 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+Perforin+/LY (n=26,30,24) | 0.411 log2 (percentage of T cells) | Standard Deviation 0.6019 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+GranzymeB+ (n=26,30,24) | -0.081 log2 (percentage of T cells) | Standard Deviation 0.2238 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Background corrected CD3+CD4+IFNg+ (n=21,27,21) | 0.359 log2 (percentage of T cells) | Standard Deviation 1.3187 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+Granzyme B+/LY (n=26,30,24) | 0.415 log2 (percentage of T cells) | Standard Deviation 0.604 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | Lymphs Tube 2 (n=27,30,25) | -0.952 log2 (percentage of T cells) | Standard Deviation 0.4761 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD19+BTLA4+ (n=27,29,23) | -0.017 log2 (percentage of T cells) | Standard Deviation 0.0352 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD4+CD27+ (n=26,30,24) | -0.099 log2 (percentage of T cells) | Standard Deviation 0.1913 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+CD107a+ (n=26,30,24) | -2.752 log2 (percentage of T cells) | Standard Deviation 6.479 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3-CD56+CD16+/LY (n=26,30,24) | 0.497 log2 (percentage of T cells) | Standard Deviation 0.6119 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16+Granzyme B+/LY (n=26,30,24) | 0.131 log2 (percentage of T cells) | Standard Deviation 0.7652 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD4+BTLA4+ (n=26,30,24) | -0.035 log2 (percentage of T cells) | Standard Deviation 0.4117 |
| Chemoradiotherapy | Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial) | CD3+CD56+CD16-Granzyme B+ (n=26,30,24) | -0.024 log2 (percentage of T cells) | Standard Deviation 0.6623 |
Secondary
Change From Baseline in Peritumoral Immune Response at Week 14 (Post-surgery)
Immunological changes in the tumor microenvironment were evaluated based on IHC expression of CD3+, CD4+, and Ki67+CD3+ T cells; regulatory T cells (FOXP3+) and myeloid-derived suppressor cells (CD33+CD14-); other immune cells such as NK cells (CD3-CD57+), B cells (CD20+), macrophages (CD68+), and dendritic cells (S100+). Peritumoral immune response was calculated as number of lymphoid cells at the margin of the tumor or in the tumor bed (if there is complete pathological response).
Time frame: Baseline and Week 14 (post-surgery)
Population: The pre-specified statistical threshold for reporting of results of planned analysis for either arm or interaction effect was not met in the analysis population. Hence the data was not assessed for the outcome measure.