Colorectal Cancer, Microsatellite Instability-high (MSI-H), Mismatch Repair-deficient (dMMR), Neoadjuvant Therapy
Conditions
Brief summary
Colorectal cancer of Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) accounts for approximately 15% of all colorectal cancer patients, with a higher proportion in right colon cancer. Previous studies have found that colon cancer patients with dMMR/MSI-H cannot benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy. Once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and the prognosis is significantly worse than that of mismatch repair-proficient (pMMR)/microsatellite stability (MSS). A phase II clinical study of anti-PD-1 immunotherapy based on mismatch repair (MMR) status published in 《N Engl J Med》 showed that the objective response rate (ORR) of advanced colorectal cancer patients with dMMR received anti-PD-1 is 40%, and a longer response time can be obtained compared to conventional chemotherapy. Anti-PD-1 neoadjuvant therapy has proven to be safe and feasible in lung cancer, bladder cancer and malignant melanoma, and can achieve more than 40% of major pathological response. However, there are no reports of anti-PD-1 neoadjuvant therapy for the dMMR/MSI-H colorectal cancer. Therefore, the aim of this study was to find the best multidisciplinary treatment for resectable colorectal cancer patient with the dMMR/MSI-H phenotype and to explore whether cyclooxygenase (COX) inhibitors combined with anti-PD-1 monoclonal antibody (mAb) could further improve efficacy.
Detailed description
The PICC trial is an investigator-initiated, multi-cohort platform trial designed to evaluate the efficacy and safety of neoadjuvant toripalimab, with or without celecoxib, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer. Each cohort within the PICC platform was independently conducted and analyzed according to prespecified objectives. The initial exploratory cohort, PICC-1, was originally planned to enroll 20 eligible patients to receive neoadjuvant toripalimab plus celecoxib or toripalimab alone, with the primary objective of assessing feasibility and safety. The study was amended in August 2020 to change the primary objective to evaluating whether 6 cycles of neoadjuvant toripalimab with or without celecoxib improves the pathological complete response (pCR) rate compared with historical controls, with an updated planned enrollment of 34 eligible patients, who were to be randomized 1:1 between the two treatment groups. In May 2021, an additional 16 eligible patients were included in this exploratory cohort for translational research purposes. The study was amended in April 2022 to add a new cohort, PICC-2, which was designed to formally compare the efficacy and safety of 12 cycles of neoadjuvant toripalimab plus celecoxib versus toripalimab monotherapy in patients with dMMR or MSI-H locally advanced colorectal cancer. A total of 110 eligible patients are planned to be randomized 1:1 between the two treatment groups. The study was amended in June 2025 to add a new cohort, PICC-3, which was designed to evaluate the 3-year event-free survival (EFS) of 12 cycles of toripalimab plus celecoxib administered as neoadjuvant or definitive therapy in patients with dMMR or MSI-H locally advanced colorectal cancer. Approximately 108 eligible patients are expected to be enrolled.
Interventions
DRUGNeoadjuvant toripalimab plus celecoxib for 6 cycles
Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 6 cycles, and celecoxib was given orally at 200 mg twice daily from day 1 to day 14 of each cycle, followed by surgery.
DRUGNeoadjuvant toripalimab monotherapy for 6 cycles
Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 6 cycles, followed by surgery.
DRUGNeoadjuvant toripalimab plus celecoxib for 12 cycles
Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 12 cycles, and celecoxib was given orally at 200 mg twice daily from day 1 to day 14 of each cycle, followed by surgery.
DRUGNeoadjuvant toripalimab monotherapy for 12 cycles
Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 12 cycles, followed by surgery.
DRUGToripalimab plus celecoxib as neoadjuvant or definitive therapy
Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 12 cycles, and celecoxib was given orally at 200 mg twice daily from day 1 to day 14 of each cycle, followed by surgery or non-operative management based on restaging (non-operative management was recommended for patients with a complete clinical response).
Sponsors
Sun Yat-sen University
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Patients and treating physicians are not masked to the study treatment. Investigators who assess radiological, endoscopic, and pathological responses are masked to the treatment allocation and to all other study data.
Intervention model description
The PICC trial is an investigator-initiated, multi-cohort platform trial designed to evaluate the efficacy and safety of neoadjuvant toripalimab, with or without celecoxib, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer. Each cohort within the PICC platform was independently conducted and analyzed according to prespecified objectives.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Willing and able to provide written informed consent. 2. Histological or cytological documentation of adenocarcinoma of the colon or rectum. 3. Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR). 4. Male or female subjects aged 18 to 75 years. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Determined CT or MRI scans (done within 14 days of registration) of the chest, abdomen and pelvis: locally advanced (cT3-4 or cN1-2 \[with the definition of a clinically positive lymph node being any node ≥ 1.0 cm\]). 7. Non complicated primary tumor (obstruction, perforation, bleeding). 8. No previous any systemic anticancer therapy for colorectal cancer disease. 9. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment.
Exclusion criteria
1. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization. 2. Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment. 3. Heart failure grade III/IV (NYHA-classification). 4. Unresolved toxicity higher than CTCAE v.4.0 Grade 1 attributed to any prior therapy/procedure. 5. Subjects with known allergy to the study drugs or to any of its excipients. 6. Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study. 7. Breast- feeding or pregnant women 8. Lack of effective contraception. 9. 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 or other drug/antibody that acts on T cell costimulation or checkpoint pathways. 10. With any distant metastasis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological complete response (pCR) rates (PICC-1 and PICC-2 cohorts) | 1 year | The proportion of patients who achieved a pCR, which was defined as the absence of residual viable tumor cells in the primary tumor and all sampled lymph nodes at surgery. |
| Event-free survival (EFS) (PICC-3 cohort) | 3 years | Defined as the time from randomization until the date of one of the following events (whichever occurred first): disease progression that precluded surgery, local R2 resection, local recurrence after an R0/1 resection, distant metastases, a new primary colorectal cancer, or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | 5 years | Defined as the time from randomization to death from any cause. |
| R0 resection rates | 1 years | The proportion of patients achieved a complete resection with negative margin. |
| Surgical and perioperative treatment safety | 1 years | Assessed by evaluation of treatment-related adverse events |
| Surgery feasibility | 30 days after surgery | Any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative toripalimab dose |
Countries
China
Contacts
Primary ContactYanhong Deng, M.D.
Outcome results
None listed