Trial Title:
Safety and Efficacy of PD-1 ± mFOLFOX6 Neoadjuvant Therapy in Local Advanced sMPCC
NCT ID:
NCT06002789
Condition:
Multiple Cancer
Colorectal Cancer
Conditions: Official terms:
Colorectal Neoplasms
Antineoplastic Agents, Immunological
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Conditions: Keywords:
Synchronous multiple primary colorectal cancer
PD-1
Neoadjuvant treatment
MSI-H
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
MSI-H/MSS (dMMR/pMMR) mixed sMPCC or all-MSI-H (dMMR) sMPCC
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
MSI-H/MSS (dMMR/pMMR) mixed sMPCC: combination of mFOLFOX6+PD-1 monoclonal antibody neoadjuvant therapy
Description:
For MSI-H/MSS (dMMR/pMMR) mixed sMPCC, a combination of neoadjuvant chemotherapy with
mFOLFOX6 and immunotherapy with PD-1 monoclonal antibody are applied.
Arm group label:
MSI-H/MSS (dMMR/pMMR) mixed sMPCC or all-MSI-H (dMMR) sMPCC
Other name:
Mixed sMPCC
Intervention type:
Drug
Intervention name:
All-MSI-H (dMMR) sMPCC: single-drug PD-1 monoclonal antibody neoadjuvant therapy
Description:
For all-MSI-H (dMMR) sMPCC, single-drug PD-1 monoclonal antibody immunotherapy is
applied.
Arm group label:
MSI-H/MSS (dMMR/pMMR) mixed sMPCC or all-MSI-H (dMMR) sMPCC
Other name:
MSI-H sMPCC
Summary:
At present, radical resection ± preoperative neoadjuvant chemotherapy for colorectal
cancer is still the standard comprehensive treatment. In recent years, immunotherapy of
PD-1 monoclonal antibody has a significant effect in the second-line/first-line treatment
of dMMR/MSI-H advanced colorectal cancer and the neoadjuvant treatment of early
colorectal cancer. Synchronous multiple primary colorectal cancer (sMPCC) is a relatively
rare type of colorectal cancer (CRC) that refers to the simultaneous occurrence of 2 or
more independent primary malignancies in the colon or rectum. The recent large-scale,
single-center retrospective study of the investigator showed that compared with single
primary colorectal cancer (SPCRC)patients, the incidence of dMMR/MSI-H was significantly
higher in sMPCC patients. Besides, a certain proportion of sMPCC patients could both have
MSI and MSS tumors at the same time. There is no standard regimen for this patients so
far. This study intends to treat the MSI-H/MSS (dMMR/pMMR) mixed sMPCC patients with
combination of mFOLFOX6+PD-1 monoclonal antibody neoadjuvant therapy, and treat the
all-MSI-H (dMMR) sMPCC patients with single-drug PD-1 monoclonal antibody neoadjuvant
therapy. Given the current gaps in the guideline, the investigator intends to take the
lead in carrying out this open, multi-center, prospective clinical phase II study. This
study might provide a clinical evidence for individual treatment of sMPCC patients, in
preserving the functions and organs to the greatest extent.
Detailed description:
Colorectal cancer is one of the most common malignant tumors in the world. At present,
radical resection ± preoperative neoadjuvant chemotherapy for colorectal cancer is still
the standard comprehensive treatment recommended by the two major international
guidelines of NCCN and ESMO, as well as the Chinese CSCO guidelines. Mismatch repair
protein (MMR) expression and microsatellite instability (MSI) status are important
factors affecting the efficacy of immunotherapy. In recent years, immunotherapy of PD-1
monoclonal antibody has a significant effect in the second-line/first-line treatment of
dMMR/MSI-H advanced colorectal cancer and the neoadjuvant treatment of early colorectal
cancer, all of which have shown very good efficacy with great safety and tolerable
toxicity.
Synchronous multiple primary colorectal cancer (sMPCC) is a relatively rare type of
colorectal cancer (CRC) that refers to the simultaneous occurrence of 2 or more
independent primary malignancies in the colon or rectum of the same patient. Since 2000,
the annual incidence and mortality of CRC in China have continued to increase, and the
incidence of sMPCC has also increased. The overall incidence of sMPCC ranges from 1.1% to
8.1% of CRC patients. The recent large-scale, single-center retrospective study of the
investigator showed that among 239 sMPCC patients, the proportions of all-pMMR, all-dMMR,
and mixed types (pMMR/dMMR) were 189 (79.1%), 40 (16.7%), and 10 (4.2%), respectively.
Compared with single primary colorectal cancer (SPCRC) patients, the incidence of dMMR
was significantly higher in sMPCC patients (50/239 vs 872/13037). The results of NGS
detection of MSI status were consistent with the results of Immunohistochemistry (IHC),
21.8% (17/78) of sMPCC patients were MSI-H, while the proportion was only 5.3% (5/94) in
SPCRC patients. At present, single-drug PD-1 or combined with other immunotherapy has
become the first-line treatment for MSI-H SPCRC patients. However, there is no standard
regimen for some sMPCC patients who both have MSI-H and MSS lesions. Moreover, there are
no studies and reports on the treatment of mFOLFOX6+PD-1 monoclonal antibody in MSI-H/MSS
mixed sMPCC and PD-1 monoclonal antibody in all-MSI-H sMPCC.
This study intends to treat the MSI-H/MSS (dMMR/pMMR) mixed sMPCC patients with
combination of mFOLFOX6+PD-1 monoclonal antibody neoadjuvant therapy, and treat the
all-MSI-H (dMMR) sMPCC patients with single-drug PD-1 monoclonal antibody neoadjuvant
therapy. As one of the largest single centers for the diagnosis and treatment of
colorectal cancer in China, the Sixth Affiliated Hospital of Sun Yat-sen University has
performed nearly 4,000 cases of colorectal cancer surgery per year. Therefore, the
investigator intends to take the lead in carrying out this open, multi-center,
prospective clinical phase II study in the world. The investigator will give different
treatments by the result of microsatellite instability status of all lesions in sMPCC.
The pCR rate, incidence of AEs of neoadjuvant therapy, R0 resection rate, down-stage
rate, 3 years DFS rate and OS rate are analyzed. This study might provide a clinical
evidence for individual treatment of sMPCC patients, in preserving the functions and
organs to the greatest extent.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Histological confirmation of simultaneous multiple primary colorectal cancer
(sMPCC);
2. Tumor biopsy immunohistochemistry of at least one tumor lesion identified dMMR,
including the expression loss of one or more of the four proteins MSH1, MSH2, MSH6
and PMS2; or at least one tumor lesion identified MSI-H by polymerase chain reaction
or next-generation sequencing technique;
3. Clinical staging T3-4NxM0, with or without positive MRF, with or without positive
EMVI;
4. Staging method: all patients undergo chest,abdominal and pelvic enhanced CT, rectal
palpation, high resolution MRI examination，positive perienteric lymph node(LN):
short diameter ≥10mm LN or LN with typical metastatic shape and MRI character,
clinical data should be re-evaluated and judged by center evaluation group when
there are contradictory stagings，distant metastasis were excluded by chest and
abdominal enhanced CT and pelvic enhanced MRI;
5. No intestinal obstruction symptom，or obstruction relieved after proximal colostomy;
6. No colorectal surgery history;
7. No chemotherapy or radiotherapy history;
8. No biopharmaceutical treatment history(such as monoclonal antibody),
immunotherapy(such as anti PD-1antibody, anti PD-L1 antibody, anti PD-L2 antibody or
anti CTLA-4), or other research drug treatment;
9. No endocrinotherapy history restriction;
10. informed consent assigned.
Exclusion Criteria:
1. Arrhythmia need anti-arrhythmia treatment(except β-blocking agent or Digoxin),
symptomatic coronary heart disease or myocardial ischemia(myocardial infarction
within 6 months) or congestive heart-failure (CHF) > NYHA grade II;
2. Severe hypertension not well controlled by drugs;
3. HIV infection history or active phase of chronic Hepatitis B or C(high copies of
virus DNA);
4. Active tuberculosis(TB), accepting anti-TB treatment or anti-TB treatment within 1
year before trial screen;
5. Other active clinical severe infection(NCI-CTC AE V5.0);
6. Outside pelvic distant metastasis evidences;
7. Dyscrasia, organ dysfunction;
8. Pelvic or abdominal radiotherapy history;
9. Epilepsy need treatments(Steroid or anti-epilepsy therapy);
10. Other malignant tumor history within 5 years;
11. Over abuse of drugs, medical and psychological or social conditions that might
interfere patients or evaluation of the study results;
12. Any active autoimmune disease or autoimmune disease history (including but not
restricted: interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis,
nephritis, hyperthyroidism, hypothyroidism, asthma need bronchodilators);
13. Any anti-infection vaccine injection 4 weeks before inclusion;
14. Long-term exposure to immune-suppressor, combination of systemic or topical use of
corticosteroids (dose>10mg/day prednisolone or equivalent hormone);
15. Known or suspicious allergy to any study related drugs;
16. Any unstable state might cause damage to the safety and compliance of patients;
17. Pregnant or breast feeding women who has ability to have children while without
contraception;
18. Refuse to sign informed consent.
Gender:
All
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
The Sixth Affiliated Hospital, Sun Yatsen University
Address:
City:
Guangzhou
Country:
China
Status:
Recruiting
Contact:
Last name:
Jun Huang, MD
Phone:
13926451242
Email:
huangj97@mail.sysu.edu.cn
Start date:
May 1, 2022
Completion date:
September 1, 2026
Lead sponsor:
Agency:
Sixth Affiliated Hospital, Sun Yat-sen University
Agency class:
Other
Source:
Sixth Affiliated Hospital, Sun Yat-sen University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06002789
