Immunotherapy In Locally Advanced Rectal Cancer

NCT03854799 | Completed Phase 2

• 1 other identifier: 2017-003582-10
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 1

Brief Summary

Preoperative CTRT is considered the standard of care in the management of LARC. Preoperative CTRT approach results in significant tumor downstaging and local control with a complete pathological response rate of about 15% even if additional therapeutic strategies should be explored to improve outcomes, expecially for T4 cancers. Immunotherapy with PD-1/PD-L1 immunocheckpoint blockade (ICB), turned out a breakthrough in cancer treatment among different tumor types, including CRC. An ICB strategy could lead up to a 40% of response in metastatic CRC with deficient mismatch repair (MMR) status. Unfortunately, the activity of ICBs in MMR proficient mCRC is extremely low but it might be improved using immunomodulatory strategies as demonstrated by Bendell et al. In this context, the role of RT in revert the tolerance to a low neoantigen-burden (such as in MMR proficient CRCs) by the induction of antigen release from the tumour and activation of dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response has been widely elucidated. Moreover, antineoplastic agents can be exploited to target other crucial cellular effectors of immunosuppressive tumor microenvironment (i.e. regulatory T cells and myeloid-derived suppressor cells). In line with these evidences, Hecht et al. have recently reported that in rectal cancer patients, neoadjuvant CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. The integration of immunotherapy in the neoadjuvant setting (instead of adjuvant one) for the management of LARC is also supported by preclinical findings showing that in metastatic breast cancer mice models, neoadjuvant immunotherapy is superior in inducing long-term survivors, compared with adjuvant strategy with a greater magnitude of tumor-specific T cell expansion in neoadjuvant treated mice and a better anti-tumor T cell-mediated immune response. On the basis of such considerations, there is a strong biological and clinical rationale for testing the addition of avelumab, an anti-PD-L1 moab, to capecitabine-based CTRT in patients with technically resectable, LARC. The aim of this strategy is to lead to significant improvements of pCR and, ultimately, patients' survival.

Conditions

Colon Rectal Cancer

Outcome Measures

Primary Outcomes (1)

• The primary objective of this trial is to evaluate the rate of complete pathologic response (pCR)

  pCR rate is defined as the percentage of patients, relative to the total of enrolled subjects,achieving complete histological regression with no available tumor cells yT0N0

  24 months

Secondary Outcomes (4)

• R0 resection rate

  24 months

• Tumor downstaging

  24 months

• Local recurrence

  24 months

• Sphincter preservation rate

  24 months

Study Arms (1)

CHEMORADIOTHERAPY PLUS AVELUMAB

EXPERIMENTAL

CHEMORADIOTHERAPY PLUS AVELUMAB: CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70

Drug: Avelumab; Drug: Capecitabine; Radiation: EXTERNAL---BEAM IRRADIATION 50.4 GY

Interventions

Avelumab DRUG

Eligible patients will receive: CHEMORADIOTHERAPY PLUS AVELUMAB: * CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week * EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks * AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70 Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion.

CHEMORADIOTHERAPY PLUS AVELUMAB

Capecitabine DRUG

Eligible patients will receive: CHEMORADIOTHERAPY PLUS AVELUMAB: * CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week * EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks * AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70 Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion.

CHEMORADIOTHERAPY PLUS AVELUMAB

EXTERNAL---BEAM IRRADIATION 50.4 GY RADIATION

Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion.

CHEMORADIOTHERAPY PLUS AVELUMAB

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent to study procedures.
• Histologically proven diagnosis of rectal adenocarcinoma
• Locally advanced, resectable disease defined by the presence of at least one of the following features:
• cN+ (with the definition of a clinically positive lymph node being any node ≥ 1 cm)
• cT4
• high risk cT3 (according to magnetic resonance imaging \[MRI\] criteria): tumour extending to within 1 mm of or beyond the mesorectal fascia (ie, circumferential radial margin threatened or involved); lower third (≤ 6 cm from the anal verge); tumour extending 5 mm or more into perirectal fat
• Distal tumor margin at \< 12 cm from the anal verge
• No evidence of metastatic disease by computed tomography (CT) scan of the chest and abdomen and total body FDG-PET/CT scan
• Tumor must be amenable to curative resection (curative resection can include pelvic exenteration)
• No history of invasive rectal malignancy, regardless of disease-free interval
• No other rectal cancers (i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, or cloacogenic carcinoma) or synchronous colon cancer
• No clear indication of involvement of the pelvic side walls by imaging
• Age ≥ 18 years
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1
• Life expectancy of at least 5 years (excluding diagnosis of cancer)

You may not qualify if:

• Previous therapy with any antibody or drug targeting T cell coregulatory proteins, or immunosuppressive agents
• Previous pelvic RT
• Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
• Any of the following in the 6 months prior to treatment start: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure (≥ New York Heart Association Classification Class II), cerebrovascular accident/strock, transient ischemic attack, serious cardiac arhythmia requiring medication or symptomatic pulmonary embolism
• Uncontrolled coagulopathy
• Active infection requiring systemic therapy
• Current use of immunosuppressive medication, EXCEPT for the following: a. Intranasal, inhaled, topical steroids, or local steroids injection (e.g. intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• Prior organ transplantation including allogenic stem-cell transplantation
• Active tubercolosis
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
• Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines
• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)
• Pregnant female patients, breastfeeding female patients, and male patients able to father children and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in the protocol for the duration of the study
• Lack of upper gastrointestinal tract integrity or malabsorption syndrome; immune colitis; active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic)

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead

Study Sites (1)

Policlinico Gemelli

Rome, 00168, Italy

Location

MeSH Terms

Conditions

Colonic Neoplasms

Interventions

avelumab; Capecitabine

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2019
• First Posted: February 26, 2019
• Study Start: April 1, 2019
• Primary Completion: February 15, 2021
• Study Completion: September 30, 2023
• Last Updated: October 19, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)