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Tecemotide (L-BLP25) in Rectal Cancer (SPRINT)

Primary Purpose

Rectal Cancer

Status
Completed
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Tecemotide (L-BLP25)
cyclophosphamide (CPA)
Chemoradiotherapy
Sponsored by
Merck KGaA, Darmstadt, Germany
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 exclusion criteria could apply

Sites / Locations

  • NKI (Nederlands Kanker Instituut)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Chemoradiotherapy+tecemotide (L-BLP25)+CPA

Chemoradiotherapy+tecemotide (L-BLP25)

Chemoradiotherapy

Arm Description

Outcomes

Primary Outcome Measures

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.
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).
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.
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.

Secondary Outcome Measures

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).
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.

Full Information

First Posted
January 6, 2012
Last Updated
January 12, 2017
Sponsor
Merck KGaA, Darmstadt, Germany
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1. Study Identification

Unique Protocol Identification Number
NCT01507103
Brief Title
Tecemotide (L-BLP25) in Rectal Cancer
Acronym
SPRINT
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
February 2012 (undefined)
Primary Completion Date
June 2014 (Actual)
Study Completion Date
June 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck KGaA, Darmstadt, Germany

4. Oversight

Data Monitoring Committee
No

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rectal Cancer
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
124 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Chemoradiotherapy+tecemotide (L-BLP25)+CPA
Arm Type
Experimental
Arm Title
Chemoradiotherapy+tecemotide (L-BLP25)
Arm Type
Experimental
Arm Title
Chemoradiotherapy
Arm Type
Active Comparator
Intervention Type
Biological
Intervention Name(s)
Tecemotide (L-BLP25)
Other Intervention Name(s)
EMD531444
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide (CPA)
Other Intervention Name(s)
L01AA01, Endoxana
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Chemoradiotherapy
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change From Baseline in Tumor Immune Response Evaluated by Immunohistochemical (IHC) Analysis of Tumor Infiltrating Lymphocytes (TILs) at Week 14 (Post-surgery)
Description
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)
Title
Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status: Number of Subjects Per MSI Category
Description
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
Title
Change From Baseline in Interferon (IFN)-Gamma Secretion of Mononuclear Cells in Response to MUC1 by Enzyme-linked Immunosorbent Spot (ELISpot) at Post-baseline
Description
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)
Title
Change From Baseline in IFN-gamma Secretion of Mononuclear Cells in Response to Carcinoembryonic Antigen (CEA) by ELISpot at Post-baseline
Description
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)
Secondary Outcome Measure Information:
Title
Change From Baseline in Peritumoral Immune Response at Week 14 (Post-surgery)
Description
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)
Title
Change From Baseline in Immunological Response in Peripheral Blood at Week 18 (Follow-up / end-of Trial)
Description
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barbara Guenther
Organizational Affiliation
Merck KGaA, Darmstadt, Germany
Official's Role
Study Director
Facility Information:
Facility Name
NKI (Nederlands Kanker Instituut)
City
Amsterdam
Country
Netherlands

12. IPD Sharing Statement

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Tecemotide (L-BLP25) in Rectal Cancer

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