- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04917263
IMMUNOlogical Microenvironment in REctal Adenocarcinoma Treatment. (IMMUNOREACT2)
IMMUNOlogical Microenvironment in REctal Adenocarcinoma Treatment. Predictors of Sustained Complete Response After Neoadjuvant Chemo/Radiotherapy for Locally Advanced Rectal Cancer
Background The current management on rectal cancer based on TNM staging has some limitations. In locally advanced rectal cancer after neoadjuvant therapy the persistence of a complete response to therapy cannot be accurately predicted by the simple tumor regression grade. The current guidelines recommend the complete rectal resection with a total mesorectal excision. The implications for patients' quality of life are evident even in case of sphincter sparing surgery. Moreover, in both cases the cancer sample available for the analysis can be small or inexistent. Hypothesis The main hypothesis underlying our research is that the aggressiveness of rectal cancer is determined by the complex interactions between the malignant cells and their immune microenvironment. The second hypothesis is that relevant trace of this cross talk between tumor cells and immune microenvironment can be detected in the normal mucosa surrounding the cancer according to the concept of field cancerization.
Aims The aim of this project is to analyze the healthy rectal mucosa surrounding the cancer to identify traces of immunosurveillance mechanisms and of field cancerization and to use them to obtain a composite prognostic test to predict recurrence after complete response at neoadjuvant therapy in case of locally advanced rectal cancer.
Experimental Design This prognostic test will be constructed on the combinatory analysis of the transcriptome, immune and epithelial cells cross-talk, immune checkpoints and miRNA expression in normal rectal mucosa surrounding cancer. The project aim is to identify, among locally advanced rectal cancer, those with sustained complete response to neoadjuvant chemo/radiotherapy. The study is articulated in two steps. In step A, we will retrospectively analyze archival tissue samples in order to identify the most performing biomarkers; in step B, we will validate the prognostic performance of the markers identified in phase I through a prospective analysis of rectal mucosa specimen.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Locally advanced rectal cancer: which treatment after complete response after neoadjuvant therapy? Combined treatment for locally advanced rectal cancer achieves a 5-year overall survival close to90% [15]. This multimodal approach can be also applied to elderly patients with stage III rectal cancer obtaining improved oncological outcomes [16]. Some patients with rectal cancer who receive neoadjuvant chemoradiotherapy (nCRT) achieve a pathologic complete response (pCR) and may be eligible for less radical surgery or non-operative management [17]. Moreover, complete regression of the rectal cancer after neoadjuvant chemoradiation therapy have been confirmed by clinical and radiographic evaluation-this is known as complete clinical response (cCR). The "watch and wait" approach was first proposed by Dr. Angelita Habr-Gama in Brazil in 2009. Those patients with cCR are followed with rigorousphysical, endoscopical, and imaging surveillance [18]. Several studies aimed to identify variables that predict pCR after nCRT for rectal cancer. A large retrospective review of the NCDB performed from 2006 to 2011, including a total of 23,747 patients identified the clinical factors associated with pCR. They were lower tumor grade, lower clinical T and N stage, higher radiation dose, and delaying surgery by more than 6-8weeks after the end of radiation, while lack of health insurance was linked with a lower likelihood of pCR [17]. Another study identified predictive factors in the models included tumor length, tumor circumferential extent, age, and ApoA1 [19]. A different study showed that responders after neoadjuvant chemoradiation had a lower incidence of cytokeratin 20 positive circulating tumor cells compared to non-responders, which might be a result of effective systemic and local treatment prior to surgery [20]. Finally, the role of immune microenvironment was investigated analyzing Foxp3(+), CD3(+), CD4(+), CD8(+) and IL-17(+) cell density in post-CRT surgical samples from 128 patients with rectal cancer. Stromal Foxp3(+) cell density was strongly associated with tumor regression grade. A low stromal Foxp3(+) cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared to41% of patients who did not. Low stromal Foxp3(+) cell density was also associated with improved recurrence-free survival. Regulatory T cells in the tumor microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer [21].
Hypotheses and Specific aims The main hypothesis underlying our research is that aggressiveness of rectal cancer is determined by the complex interactions between the malignant cells and the local immune microenvironment. Our hypothesis is that the local immune activation may involve the "healthy" rectal mucosa surrounding the cancer and the sampling of this mucosa may provide useful information about rectal cancer behavior. In fact, a combination of different factors, including molecular signaling networks (i.e. checkpoint genes) within different cell population, presence of soluble chemical factors and quantity/quality of immune cells infiltrate will decide rectal cancer behavior and its response to neoadjuvant chemoradiation. Moreover, tumor cells actively interact with the microenvironment secreting and degrading extracellular matrix components, and the release of soluble molecules (e.g. miRNA) can significantly influence the inflammatory and immune responses of the "healthy" rectal mucosa surrounding the cancer. By using state of the art histological/molecular/immunological markers and bio-statistical analysis tools we aim to identify clinically relevant molecular targets to design effective therapeutic strategies for rectal cancer patients.
Therefore, the aim of the study is to identify a prognostic test that accurately predicts rectal cancer behavior even in case when the tumor samples are scarce (due to small size of early rectal cancer) or absent (in case of complete response to therapy). This prognostic test will be constructed on the combinatory analysis of the transcriptome, immune cells activation and checkpoints, epithelial cells activity as antigen presenting cells and miRNA expression in normal tissue specimens of prospectively collected rectal cancers. The question is how to identify, among locally advanced rectal cancer, those with immediate and sustained complete response to neoadjuvant chemo/radiotherapy. These patients might safely avoid a low rectal resection with all the consequences for their quality of life. In patients with locally advanced rectal cancer (N+) an ideal biomarker should be able to identify the cohort of patients that will have a complete response to neoadjuvant therapy and will not require further treatments.
Study design Tissue samples will be obtained from cancer tissue (if possible) and from normal rectal mucosa adjacent to the cancer at surgery. The very large number of patients need to answer the two questions imply a multicentric design. Complete medical record and follow-up will be collected from each center. The analysis will be centralized mostly in Azienda Ospedaliera di Padova. The study will be articulated in two parts each of them aiming to answer to one of the above described questions. Each part of the study will be articulated in a retrospective and exploratory step (A) and in a prospective validation step (B).
Study Type
Enrollment (Anticipated)
Contacts and Locations
Study Contact
- Name: Marco Scarpa, MD, PhD
- Phone Number: #39 049 821 2672
- Email: marco.scarpa@aopd.veneto.it
Study Locations
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Padova, Italy, 35128
- Recruiting
- Azienda Ospedale Università di Padova
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Contact:
- Marco Scarpa, MD, PhD
- Phone Number: #39 049 821 2055
- Email: marco.scarpa@aopd.veneto.it
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
We aim to analyze 66 patients with pathological complete response and 66 patients without complete response after neoadjuvant therapy for locally advanced rectal cancer. Given an expected proportion of 20% of patients with complete response, we estimate to enroll a total number of 66/0.20=330 patients with early rectal cancer. However, we will performed flow cytometry, transcriptomic analysis, mRNA microarray and mutational profiling only in 132 patients (66 patients with complete response and 66 patients without complete response) in order to test the non-inferiority of AUC.
Taking into account a 15-20% of locally advanced rectal cancer patients with pathological complete response to neoadjuvant therapy and a maximum of 7 prognostic factors (including markers and clinical factors) in the model, we aim to enroll 412 patients in this part of the study.
Description
Inclusion Criteria:
- locally advanced (cT3-4 and/or N+, TNM stage II-III) low and medium rectal cancer (<11 cm) or low rectum adenocarcinoma cT≤2, at risk for abdominoperineal amputation, undergoing neoadjuvant therapy will be included in the study group.
- Only neoadjuvant therapy protocols including long course radiotherapy (45 Gy) and fluoropyrimidine-based regimens will be included while short radiation therapy of radiation therapy or chemotherapy alone will be excluded
- at least 6 weeks after the end of the neoadjuvant therapy will be included
- Full availability of clinical records at least 1 year of follow up
Study Plan
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Other
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Retrospective
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we will perform immunohistochemistry, flow cytometry, transcriptomic analysis, mRNA microarray and mutational profiling
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Prospective
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we will perform immunohistochemistry, flow cytometry, transcriptomic analysis, mRNA microarray and mutational profiling
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
pathological complete response on the operative specimen
Time Frame: first post operative month
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pathological complete response to neoadjuvant chemo/radiotherapy in locally advanced rectal cancer
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first post operative month
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Marco Scarpa, MD, PhD, Clinica Chirurgica I, Azienda Ospedale Università di Padova
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Gastrointestinal Neoplasms
- Digestive System Neoplasms
- Gastrointestinal Diseases
- Intestinal Diseases
- Intestinal Neoplasms
- Rectal Diseases
- Colorectal Neoplasms
- Adenocarcinoma
- Rectal Neoplasms
Other Study ID Numbers
- AIRC IG2019 23381 IMMUNOREACT2
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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