Tecemotide (L-BLP25) in Rectal Cancer

Study Overview
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Brief Summary
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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).

Official Title
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A Multi-center, Randomized, Open-label, Mechanism of Action Trial on the Biological Effects of the Therapeutic Cancer Vaccine Stimuvax® (L-BLP25) in Rectal Cancer Subjects Undergoing Neoadjuvant Chemoradiotherapy

Conditions
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Rectal Cancer

Intervention / Treatment
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* Biological: Tecemotide (L-BLP25)
* Drug: cyclophosphamide (CPA)
* Other: Chemoradiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects with histologically documented resectable rectal adenocarcinoma in Stage 2-4 Availability of tumor biopsy sufficient for immunological analysis 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 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 Eastern Cooperative Oncology Group performance status of 0 or 1 Written informed consent Greater than or equal to (>=) 18 years of age Exclusion Criteria: Previous chemotherapy and/or previous radiotherapy of the pelvic region Relapsing disease Previous vaccination with any MUC1 vaccine and other therapeutic cancer vaccines Previous organ transplantation (bone marrow or solid organs) Subjects with metastatic disease (except for solitary, resectable liver or lung metastases) 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) Autoimmune diseases Recognized immunodeficiency disease including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; subjects who have hereditary or congenital immunodeficiencies 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 Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemoradiotherapy+tecemotide (L-BLP25)+CPA<br> | Biological: Tecemotide (L-BLP25)<br>* 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.<br>* Other names: EMD531444;Drug: cyclophosphamide (CPA)<br>* 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.<br>* Other names: Endoxana;Other: Chemoradiotherapy<br>* 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.<br>|
| Experimental: Chemoradiotherapy+tecemotide (L-BLP25)<br> | Biological: Tecemotide (L-BLP25)<br>* 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.<br>* Other names: EMD531444;Other: Chemoradiotherapy<br>* 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.<br>|
| Active Comparator: Chemoradiotherapy<br> | Other: Chemoradiotherapy<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Week 14 (post-surgery) | 
| 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). | 18 weeks | 
| 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. | Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial) | 
| 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. | Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline and Week 14 (post-surgery) | 
| 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. | Baseline and Week 18 (follow-up / end-of trial) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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