mFOLFOX6+Bevacizumab+PD-1 Monoclonal Antibody in Local Advanced MSS CRC

Colorectal Cancer Clinical Trial

— BASKET?  

Official title:

Safety and Efficacy of mFOLFOX6+ Bevacizumab+PD-1 Monoclonal Antibody Treatment Combinations in Patients With Local Advanced Microsatellite Stability Colorectal Cancer --an Open Label, Multicenter, Prospective Phase Ⅱ Study (BASKETII)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04895137
• Other study ID #: E2021056
• Status: Recruiting
• Phase: Phase 2
• Start date: May 1, 2021
• Est. completion date: May 1, 2024

Study information

• Verified date: July 2023
• Source: Sixth Affiliated Hospital, Sun Yat-sen University
• Contact: Jun Huang, MD
• Phone: +8613926451242
• Email: huangj97[@]mail.sysu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Immunotherapy has achieved significant therapeutic effect in DNA mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, for proficient mismatch repair(pMMR)/microsatellite stable(MSS) CRC, the curative effect of PD-1 monoclonal antibody was poor and most of the data came from stage Ⅳ patients with distant metastasis. Among the whole CRC patients, more than eighty-five percent were pMMR/MSS CRC. It would be very inspiring when major CRC patients(pMMR/MSS) could be benefit from immunotherapy. For T4NxM0 CRC patients, R0 resection was difficult to achieve. If the patients could not got R0 resection, which means the tumors were almost destined to recurrent and patients life time were counting down. Whether combined treatment of mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody could maximize the curative effect was still unknown. This study aims to evaluate the effect and safety of mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody treatment combinations in patients with local advanced(T4NxM0) pMMR/MSS CRC.

Description:

Immunotherapy has achieved significant therapeutic effect in DNA mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). MMR expression and MSS status are the important effective factors of immunotherapy. PD-1monocolnal antibody therapy has accessed excellent treatment effect in advanced dMMR/MSI-H CRC and neoadjuvant therapeutic effect in early colon cancer, more than fifty percent of dMMR/MSI-H CRC patients might get pathological complete response(pCR) after PD-1 monoclonal antibody treatment. The treatments had been proved to be safe and the toxicities were controllable. However, for proficient mismatch repair(pMMR)/microsatellite stable(MSS) CRC, the curative effect of PD-1 monoclonal antibody was poor and most of the data came from stage Ⅳ patients with distant metastasis. Among the whole CRC patients, more than eighty-five percent were pMMR/MSS CRC. It would be very inspiring when major CRC patients(pMMR/MSS) could be benefit from immunotherapy. For T4NxM0 CRC patients, R0 resection was difficult to achieve. If the patients could not got R0 resection, which means the tumors were almost destined to recurrent and patients life time were counting down. However, there were no standard conversion of neoadjuvant treatment recommendations for T4NxM0 CRC. Although PD-1 monoclonal antibody alone has poor effect in pMMR/MSS CRC, it seems to be effective in early stage of MSS CRC(Nicole study) or when it was combined with chemotherapy or target therapy. So far, whether combined treatment of mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody could maximize the curative effect was still unknown. This study aims to evaluate the effect and safety of mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody treatment combinations in patients with local advanced(T4NxM0) pMMR/MSS CRC.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 42
• Est. completion date: May 1, 2024
• Est. primary completion date: May 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Histological identified colon and upper rectum adenocarcinoma, Tumor biopsy immunohistochemical (IHC) identified pMMR, including all of the MSH1,MSH2,MSH6 and PMS2 protein expression and diagnosed as proficient mismatch repair(pMMR), or next generation sequencing identified (MSS); MRI identified tumor inferior margin higher than peritoneal reflection,

• Clinical staging T4NxM0, with or without positive MRF, with or without positive EMVI,

• 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,

• No intestinal obstruction symptom,or obstruction relieved after proximal colostomy,

• No rectal surgery history,

• No chemotherapy or radiotherapy history,

• 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,

• Endocrinotherapy history restriction:No

• informed consent assigned,

Exclusion Criteria:

• Arrhythmia need anti-arrhythmia treatment(except ß-blocking agent or Digoxin),symptomatic coronary heart disease or myocardial ischemia(myocardial infarction within 6 months) or congestive heart-failure (CHF) > NYHA grade II,

• Severe hypertension not well controlled by drugs,

• HIV infection history or active phase of chronic Hepatitis B or C(high copies of virus DNA),

• Active tuberculosis(TB),accepting anti-TB treatment or anti-TB treatment within 1 year before trial screen,

• Other active clinical severe infection(NCI-CTC V5.0),

• Outside pelvic distant metastasis evidences,

• Dyscrasia, organ dysfunction,

• Pelvic or abdominal radiotherapy history,

• Multiple CRC or Multi-primary tumors;

• Epilepsy need treatments(Steroid or anti-epilepsy therapy),

• Other malignant tumor history within 5 years,

• Over abuse of drugs, medical and psychological or social conditions that might interfere patients or evaluation of the study results,

• Any active autoimmune disease or autoimmune disease history (including but not restricted:interstitial pneumonia, uveitis,enteritis, hepatitis,hypophysitis, nephritis, hyperthyroidism, hypothyroidism, asthma need bronchodilators),

• Any anti-infection vaccine injection 4 weeks before inclusion ,

• Long-term exposure to immune-suppressor, combination of systemic or topical use of corticosteroids (dose>10mg/day prednisolone or equivalent hormone);

• Known or suspicious allergy to any study related drugs,

• Any unstable state might cause damage to the safety and compliance of patients,

• Pregnant or breast feeding women who has ability to have children while without contraception,

• Refuse to sign informed consent

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Immunotherapy

Intervention

Drug:
• mFOLFOX6+Bevacizumab+PD-1 monoclonal antibody treatment combinations
mFOLFOX6+ Bevacizumab+PD-1 monoclonal antibody treatment combinations in patients with local advanced microsatellite stability colorectal cancer

Locations

Country	Name	City	State
China	Sun Yatsen University	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sixth Affiliated Hospital, Sun Yat-sen University

Country where clinical trial is conducted

China, 

References & Publications (12)

Antoniotti C, Borelli B, Rossini D, Pietrantonio F, Morano F, Salvatore L, Lonardi S, Marmorino F, Tamberi S, Corallo S, Tortora G, Bergamo F, Brunella DS, Boccaccino A, Grassi E, Racca P, Tamburini E, Aprile G, Moretto R, Boni L, Falcone A, Cremolini C. — View Citation

Bolhuis K, Kos M, van Oijen MGH, Swijnenburg RJ, Punt CJA. Conversion strategies with chemotherapy plus targeted agents for colorectal cancer liver-only metastases: A systematic review. Eur J Cancer. 2020 Dec;141:225-238. doi: 10.1016/j.ejca.2020.09.037. — View Citation

Chang H, Yu X, Xiao WW, Wang QX, Zhou WH, Zeng ZF, Ding PR, Li LR, Gao YH. Neoadjuvant chemoradiotherapy followed by surgery in patients with unresectable locally advanced colon cancer: a prospective observational study. Onco Targets Ther. 2018 Jan 17;11: — View Citation

Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol. 2015 Feb 1;194(3):9 — View Citation

Kim SA, Kim JW, Suh KJ, Chang W, Kim JW, Oh HK, Cho JY, Kim DW, Cho S, Kim JH, Kim K, Kang SB, Jheon S, Lee KW. Conversion surgery after cetuximab or bevacizumab plus FOLFIRI chemotherapy in colorectal cancer patients with liver- and/or lung-limited metas — View Citation

Li J, Cong L, Liu J, Peng L, Wang J, Feng A, Yue J, Li L, Wang X, Wang X. The Efficacy and Safety of Regorafenib in Combination With Anti-PD-1 Antibody in Refractory Microsatellite Stable Metastatic Colorectal Cancer: A Retrospective Study. Front Oncol. 2 — View Citation

Marmorino F, Boccaccino A, Germani MM, Falcone A, Cremolini C. Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge. Cancers (Basel). 2020 Aug 17;12(8):2317. doi: 10.3390/cancers12082317. — View Citation

Mise Y, Hasegawa K, Saiura A, Oba M, Yamamoto J, Nomura Y, Takayama T, Hashiguchi Y, Shibasaki M, Sakamoto H, Yamagata S, Aoyanagi N, Kaneko H, Koyama H, Miyagawa S, Shinozaki E, Yoshida S, Nozawa H, Kokudo N. A Multicenter Phase 2 Trial to Evaluate the E — View Citation

Qiu B, Ding PR, Cai L, Xiao WW, Zeng ZF, Chen G, Lu ZH, Li LR, Wu XJ, Mirimanoff RO, Pan ZZ, Xu RH, Gao YH. Outcomes of preoperative chemoradiotherapy followed by surgery in patients with unresectable locally advanced sigmoid colon cancer. Chin J Cancer. — View Citation

Sclafani F. PD-1 inhibition in metastatic dMMR/MSI-H colorectal cancer. Lancet Oncol. 2017 Sep;18(9):1141-1142. doi: 10.1016/S1470-2045(17)30512-0. Epub 2017 Jul 19. No abstract available. — View Citation

Scott E. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPa — View Citation

Yuan Y, Xiao WW, Xie WH, Cai PQ, Wang QX, Chang H, Chen BQ, Zhou WH, Zeng ZF, Wu XJ, Liu Q, Li LR, Zhang R, Gao YH. Neoadjuvant chemoradiotherapy for patients with unresectable radically locally advanced colon cancer: a potential improvement to overall su — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PCR rate	pathological complete remission rate in T4NxM0 colorectal cancer treated after mFOLFOX6+Bevacizumab+PD-1monoclonal antibody	1 year
Secondary	Incidence rate of Grade =3 PD-1monoclonal antibody-related adverse events	Incidence rate of participants with Grade =3 PD-1monoclonal antibody-related adverse events as assessed by CTCAE v4.0	1 year
Secondary	Incidence rate of Grade =3 chemotherapy-related adverse events	Incidence rate of participants with Grade =3 chemotherapy-related adverse events as assessed by CTCAE v4.0	1 year
Secondary	R0 resection rate	R0 resection rate in participants treated after mFOLFOX6+Bevacizumab+PD-1monoclonal antibody	1 year
Secondary	Down-stage rate	Down-stage rate of pathological stage after surgery compared with clinical stage before drug treatment	1 year
Secondary	3 years DFS Rate	3 years Disease Free Survival Rate	3 years
Secondary	3 years OS Rate	3 years Overall Survival Rate	3 years