Trial Title:
Evaluation of the Efficacy and Safety of Interleucin-2 Combined With PD-1 Monoclonal Antibody and CAPOX in Preoperative Neoadjuvant Therapy for Locally Advanced Rectal Cancer - a Single-center, Single-arm, Open-label Clinical Trail
NCT ID:
NCT06108596
Condition:
Locally Advanced Rectal Adenocarcinoma
Conditions: Official terms:
Rectal Neoplasms
Interleukin-2
Conditions: Keywords:
Immunotherapy treatment
IL-2
Rectal cancer
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Sintilimab with Interleukin-2+CAPOX
Description:
Sintilimab with Interleukin-2+CAPOX
Arm group label:
Experimental group
Summary:
Evaluation of the efficacy and safety of interleucin-2 combined with PD-1 monoclonal
antibody and CAPOX in preoperative neoadjuvant therapy for locally advanced rectal cancer
- a single-center, single-arm, open-label clinical trail.
Detailed description:
The global incidence rate of rectal cancer is approximately 732,000 cases/year, of which
a significant proportion is locally advanced rectal cancer (i.e., T3-4 or N+). Currently,
for locally advanced rectal cancer, the NCCN guidelines recommend treatment with
neoadjuvant radiotherapy and chemotherapy + total mesorectal excision + adjuvant
chemotherapy, reducing the local recurrence rate of locally advanced rectal cancer from
over 30% to less than 10%. However, this treatment mode still has a low overall sphincter
preservation rate, a high distant metastasis rate, and limited overall survival (OS)
benefits. In recent years, the emergence of total neoadjuvant therapy (TNT) strategies,
including induction chemotherapy + concurrent chemoradiotherapy + surgery, concurrent
chemoradiotherapy + consolidation chemotherapy (two or even three drugs) + surgery, and
concurrent chemoradiotherapy + consolidation immunotherapy combined with chemotherapy +
surgery, have all improved the long-term prognosis of locally advanced rectal cancer to
varying degrees. However, the TNT mode is not suitable for all rectal cancer patients.
For patients with low or moderate-risk rectal cancer or those who cannot tolerate
intensive radiotherapy and chemotherapy, TNT increases the potential risk of
overtreatment and associated toxicity.
The emergence of immunotherapy, including adoptive cell transfer (ACT) and immune
checkpoint inhibitors (ICB), provides new insights into the treatment of locally advanced
rectal cancer. However, most colorectal cancer patients have a limited response to
immunotherapy. For ACT, many clinical studies report that exogenously infused antitumor T
cells have poor tumor tissue infiltration, resulting in extremely limited immune
responses. This inefficiency in T cell delivery may be due to high interstitial fluid
pressure, pathological vascular networks, tumor-associated fibroblasts, or the "physical
barrier" of the extracellular matrix (ECM), as well as the immunosuppressive tumor
microenvironment. As for immune checkpoint inhibitors (ICIs), especially PD-1/PD-L1
targeted therapies, they have shown significant promise in the treatment of various solid
tumors, including breast cancer, lung cancer, gastric cancer, and colorectal cancer.
Studies such as CheckMate-142 and KEYNOTE-177 have confirmed the excellent efficacy of
PD-1/PD-L1 inhibitors in the treatment of colorectal cancers with mismatch repair protein
defects (dMMR) or high microsatellite instability (MSI-H). Institutions like the Memorial
Sloan Kettering Cancer Center (MSKCC), Sun Yat-sen University Cancer Center, and the
Sixth Affiliated Hospital of Sun Yat-sen University have conducted research on PD-1
inhibitors for neoadjuvant treatment of locally advanced rectal cancer, with complete
remission rates as high as 75% to 100%. However, this patient population is very small,
accounting for about 15% of early-stage colorectal cancers and only 5% of advanced
colorectal cancers, especially less than 5% in rectal cancer. Meanwhile, microsatellite
stable (MSS) patients make up the vast majority of colorectal cancers, and they benefit
little from single-agent immunotherapy.
In this population, low tumor mutation burden (TMB) and insufficient immunogenicity,
leading to inadequate immune cell infiltration, are considered one of the main resistance
mechanisms to immunotherapy. Therefore, enhancing immune cell infiltration and boosting
the therapeutic effect of immunotherapy in low-responsive colorectal cancer has
significant clinical importance. Currently, some clinical experiments are being conducted
in this area. For instance, radiotherapy theoretically synergizes with immunotherapy,
possibly through the release of tumor antigens, remodeling of the immune
microenvironment, and increasing antitumor immune responses, thus producing a combined
therapeutic effect. Prospective phase II studies suggest that radiotherapy combined with
immunotherapy achieves a higher pCR rate in pMMR/MSS locally advanced rectal cancer.
Additionally, various immune cells in the tumor microenvironment (TME) can impair tumor
immune responses, leading to tumor resistance to PD-1 therapy. Much evidence suggests
that T cells in or near tumor tissues, although activated, cannot attack tumor cells.
Thus, enhancing T cell tumor infiltration and activating their antitumor effects are key
methods to enhance PD-1 therapy. Recent basic research results show that elevated levels
of TGF-β and VEGF in tumor tissues suppress the aforementioned cytokines, enhancing tumor
T cell infiltration and the efficacy of anti-PD-1 therapy. Moreover, a phase Ib clinical
trial from Australia suggests that Pixatimod (a TLR9 agonist) combined with Nivolumab
shows tolerability and clinical benefits in MSS mCRC patients, and researchers also
observed pharmacodynamic changes and biomarker signals related to clinical benefits in
the combination scheme. Similarly, another phase I clinical trial suggests that low
molecular weight heparin (LMWH) enhances the efficacy of anti-PD-1 in MSS colorectal
cancer by increasing CD8+T cell infiltration. These results highlight the immense
prospects of PD-1 therapy combined with immune enhancement in antitumor immunotherapy.
IL-2 (Interleukin-2) is an essential cytokine, primarily produced by activated T cells.
It plays a pivotal role in the immune system by promoting the growth and differentiation
of T cells, enhancing the activity of cytotoxic T cells (CTLs) and natural killer cells
(NK cells), and participating in immune responses against pathogens and tumors. In past
tumor treatments, the primary application of IL-2 was to initiate and amplify the body's
immune attack on tumors. In the treatment of certain diseases, such as malignant melanoma
and renal cancer, monotherapy with appropriate doses of IL-2 has proven beneficial. For
instance, a low dose of IL-2 20IU subcutaneous injection can induce immune activation
while producing fewer clinical side effects. However, the complications of high-dose IL-2
treatment can be severe, including hypotension, respiratory distress, and renal
impairment. Although IL-2 has some application in tumor immunotherapy, its efficacy is
often limited, benefiting only a minority of patients. Current research is exploring ways
to enhance the effectiveness of IL-2, including the development of novel IL-2 variants
that improve the molecule's selectivity and stability, as well as combination therapies
with other immune modulators, such as checkpoint inhibitors. In certain conditions, such
as Lymphocytic Choriomeningitis Virus (LCMV) infection, the combined treatment of PD-1
and IL-2 has shown remarkable clinical efficacy. In vivo experiments indicate that,
compared to PD-1 monotherapy, the combination of PD-1+IL-2 for LCMV significantly alters
the differentiation program of PD-1+TCF1+ stem-like CD8+T cells, producing effector CD8+T
cells distinct at the transcriptional and epigenetic levels, very similar to those
observed after acute viral infections. Furthermore, in head and neck squamous cell
carcinoma (HNSCC), a bispecific immune cytokine PD1-IL2v can notably activate immune
cells, including NK cells and CD8+T cells, and inhibit the proliferation and metastasis
of tumor cells. These discovered mechanisms elucidate the potential synergy between IL-2
treatment and PD-1 blockade, providing guidance and a theoretical foundation for our
clinical trial using the combination of PD-1 and IL-2 in patients with locally advanced
rectal cancer.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Men and women aged 18-75 years old;
- ECOG performance status score of 0 or 1;
- Histologically proven rectal adenocarcinoma;
- Clinical staged T3-T4 or any T with lymph node positive (N+);
- Adequate haematological, hepatic, and renal function: neutrophil count ≥1.5×109 /L;
platelet count ≥75×109 /L; serum total bilirubin ≤1.5×upper normal limits (UNL);
aspartate aminotransferase ≤2.5×UNL; alanine aminotransferase ≤2.5×UNL; serum
creatinine≤1.5×UNL.
Exclusion Criteria:
- Metastatic disease (stage IV);
- Relapsed colorectal cancer;
- Complicated with active bleeding, perforation, or requiring emergency surgery;
- Previous systemic anticancer therapy for colorectal cancer disease
- Patients with other active concurrent non-colorectal cancer;
- Any active or history of autoimmune disease, or history of syndrome that required
systemic steroids or immunosuppressive medications;
- Patients with interstitial lung disease, non-infectious pneumonia or uncontrollable
systemic diseases (such as: diabetes, hypertension, pulmonary fibrosis and acute
pneumonia);
- Patients with any Grade 2 or above toxicity as classified by the common terminology
criteria for adverse events (CTCAE) (version 5.0) (except for anemia, alopecia and
skin pigmentation) which is induced by previous treatment and has not subside;
- Previously received anti-programmed death-1 (PD-1) or its ligand (PD-L1) antibody,
anti- cytotoxic T lymphocyte-associated antigen 4 (cytotoxic T-lymphocyte-associated
Protein 4, CTLA-4) antibody Women in pregnancy or lactation;
- Known positive history or positive test for Human Immunodeficiency Virus or Acquired
Immunodeficiency Syndrome (AIDS);
- History of known or suspected allergies to any related drugs used in the trial;
- Women who are pregnant or nursing.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Jiangsu Province Hospital
Address:
City:
Nanjing
Zip:
210000
Country:
China
Status:
Recruiting
Contact:
Last name:
Yueming Sun
Start date:
December 21, 2023
Completion date:
December 31, 2024
Lead sponsor:
Agency:
The First Affiliated Hospital with Nanjing Medical University
Agency class:
Other
Source:
The First Affiliated Hospital with Nanjing Medical University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06108596
