Colorectal Cancer (MSI-H)
Conditions
Keywords
colorectal cancer, microsatellite instability high, mismatch repair-deficient, neoadjuvant therapy, radiotherapy, immunotherapy, locally advanced
Brief summary
This phase II clinical trial evaluates the efficacy and safety of three neoadjuvant regimens in patients with locally advanced microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC): 1) Regimen A: Dual immune checkpoint blockade with nivolumab plus ipilimumab. 2) Regimen B: Nivolumab plus radiotherapy. 3) Regimen C: Nivolumab monotherapy. The primary objectives are to determine whether: 1) Dual immune checkpoint blockade (Regimen A) is superior to nivolumab monotherapy (Regimen C); and 2) Immunotherapy plus radiotherapy (Regimen B) is superior to nivolumab monotherapy (Regimen C). Methods: Participants will be randomized in a 1:1:1 ratio to one of the three arms. For patients with resectable tumors, surgical resection will be performed. In patients with low rectal cancer and poor prospects for sphincter preservation, a watch-and-wait (WW) strategy is an option if a clinical complete response (CR) is achieved following neoadjuvant therapy.
Interventions
DRUGNivolumab
Nivolumab 240 mg every 2 weeks
Ipilimumab 1 mg/kg every 3 weeks
RADIATIONPULSAR
Irradiation targeted to the primary lesion (5 Gy per fraction, total 4 fractions, delivered every 3 weeks).
PROCEDURERadical surgery
Surgical resection will be performed in resectable cases.
OTHERWatch & wait
For patients with low rectal cancer who are unable to preserve the anal sphincter, a watch-and-wait (WW) strategy can be considered if a clinical complete response (CR) is achieved.
Sponsors
Fudan University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histopathologically confirmed primary colorectal adenocarcinoma. 2. Radiographic assessment showed a stage II-III based on AJCC Stage 8th ed. 3. At least 18 years old. 4. MSI-H or dMMR. 5. The Eastern Cooperative Oncology Group performance status (ECOG PS) score is 0 or 1. 6. Physical state or organ function can tolerate the planned treatment of the study protocol. 7. Agreed to sign written informed consent before recruitment.
Exclusion criteria
1. Previously received any antitumor therapy for the disease under study, including surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc. 2. Pregnancy or breastfeeding women. 3. History of other malignancies within 5 years. 4. Serious medical illness, such as severe mental disorders, cardiac disease, uncontrolled infection, etc. 5. Immunodeficiency disease or long-term using of immunosuppressive agents. 6. Allergic to any component of the therapy. 7. Any other condition or disease that is not suitable to take the therapy included in the protocol. 8. Concurrent participation in another clinical study, unless participating in an observational (non-interventional) clinical study or in the survival follow-up phase of an interventional study. 9. Received any investigational drug or device treatment within 4 weeks prior to initial administration of the investigational drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete regression (CR) rate | 1 month after surgery or the completion of neoadjuvant therapy | Proportion of patients achieving either clinical CR (and undergoing WW) or pathological CR (confirmed by pathology) among all evaluable patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| R0 resection rate | 1 month after surgery | Proportion of patients who achieve R0 resection. |
| Objective response rate (ORR) | 6 months after the enrollment of the last subject | Proportion of patients with complete response (CR) or partial response (PR) to preoperative multimodal therapy. ORR will be evaluated using RESIST1.1 by CT/MRI of the chest, abdomen, and pelvis. |
| Event-free survival (EFS) | 36 months after the enrollment of the last subject | The EFS was defined as the time from randomization to the first determination of inoperable disease progression, postoperative local recurrence or distant metastasis, tumor regrowth, or death from any cause, whichever occurs first. |
| Overall survival (OS) | 36 months after the enrollment of the last subject | OS is defined as the time interval from enrollment to death of any reason or censoring. |
| Toxicities | From the time of enrollment, assessed up to 28 days after the last dose of study therapy | Number of participants with treatment-related adverse events (TrAEs) reported between the first dose and 28 days after the last dose of study therapy as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. |
| Surgical morbidity | During or one month after surgery | Surgery related adverse events (SRAEs) refer to complications which happen during or one month after surgery. Severe complications after surgery will be documented and classified by Clavien-Dindo classification, such as abdominal or GI tract bleeding, anastomotic fistula, pancreatic fistula of grade B or above, and incision complications (infection, bleeding, rupture). |
| Surgical mortality | During or one month after surgery | Death from any cause within 30 days of the date of surgery will be considered a surgical mortality death. |
Countries
China
Contacts
CONTACTMenglong Zhou, MD
Outcome results
None listed