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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01507103
First received: January 6, 2012
Last updated: July 23, 2015
Last verified: July 2015
  Purpose

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).


Condition Intervention Phase
Rectal Cancer
Biological: Tecemotide (L-BLP25)
Drug: cyclophosphamide (CPA)
Other: Chemoradiotherapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

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) [ Time Frame: Baseline and Week 14 (post-surgery) ] [ Designated as safety issue: No ]
    Tumor biopsy samples were collected prior to tecemotide (L-BLP25) administration 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.

  • Change from Baseline in Interferon (IFN)-gamma Secretion of Mononuclear Cells in Response to Mucinous Glycoprotein (MUC1) by Enzyme-linked Immunosorbent Spot (ELISPOT) at post-baseline [ Time Frame: Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial) ] [ Designated as safety issue: No ]
    IFN-gamma secretion of mononuclear cells in response to MUC1 was 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 [ Time Frame: Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial) ] [ Designated as safety issue: No ]
    IFN-gamma secretion of mononuclear cells in response to CEA was 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) [ Time Frame: Baseline and Week 14 (post-surgery) ] [ Designated as safety issue: No ]
    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 post-baseline [ Time Frame: Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial) ] [ Designated as safety issue: No ]
    Immunological changes in peripheral blood were evaluated based on fluorescence analysis cell sorter (FACS) phenotypic characterization of T cells (CD3+CD4+ and CD3+CD8+) and of markers of activation and proliferation (ICOS, CD27, BTLA, PD-1); regulatory cells such as CD3+CD4+ (or CD8+) CD45RA+CD25+FoxP3+CD127 T cells and myeloid-derived suppressor cells (CD11b+CD33+CD66b+ HLA-DR-); cytotoxic cells such as CTL (CD3+CD8+) and NK cells (CD3CD56+) and their killing activity (Granzyme B, Perforin, CD107a); B cells (CD19+), pDC (CD123+), and mDC (CD11c+) and cytokine profile (e.g., IL-6, IL-10, IFN-gamma, TNF-alpha, IL-17) by Luminex and/or immunoassay and pre-operative circulating serum CEA levels (at baseline and during treatment).Immunological Response in peripheral blood was measured on a continuous scale. 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.

  • Immunological Response to Treatment in Relation to Microsatellite Instability (MSI) Status [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
    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).


Enrollment: 124
Study Start Date: February 2012
Study Completion Date: June 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Chemoradiotherapy+tecemotide (L-BLP25)+CPA Biological: Tecemotide (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.
Other Name: EMD531444
Drug: cyclophosphamide (CPA)
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.
Other Names:
  • L01AA01
  • Endoxana
Other: Chemoradiotherapy
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.
Experimental: Chemoradiotherapy+tecemotide (L-BLP25) Biological: Tecemotide (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.
Other Name: EMD531444
Other: Chemoradiotherapy
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.
Active Comparator: Chemoradiotherapy Other: Chemoradiotherapy
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01507103

Locations
Netherlands
NKI (Nederlands Kanker Instituut)
Amsterdam, Netherlands
Sponsors and Collaborators
Merck KGaA
Investigators
Study Director: Barbara Guenther Merck KGaA
  More Information

No publications provided

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01507103     History of Changes
Other Study ID Numbers: EMR063325-013, 2011-000847-25
Study First Received: January 6, 2012
Last Updated: July 23, 2015
Health Authority: Austria: Agency for Health and Food Safety
Belgium: Federal Agency for Medicinal Products and Health Products
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Paul-Ehrlich-Institut
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Portugal: National Pharmacy and Medicines Institute

Keywords provided by Merck KGaA:
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

Additional relevant MeSH terms:
Rectal Neoplasms
Colorectal Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Cyclophosphamide
Molecular Mechanisms of Pharmacological Action
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on August 27, 2015