Registry Study in MSI/dMMR Solid Tumors

Solid Tumor Clinical Trial

Official title:

Multi-center, Non-interventional, Prospective Registry Study on the Treatment of Solid Tumors With Mismatch Repair Deficiency or Microsatellite Instability

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06004713
• Other study ID #: LGH2023093
• Status: Recruiting
• Start date: October 7, 2023
• Est. completion date: February 2026

Study information

• Verified date: July 2023
• Source: Peking University Cancer Hospital & Institute
• Contact: zhenghang Wang
• Phone: 18813186790
• Email: zhenghang_wang[@]bjmu.edu.cn
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This study is a multi-center, non-interventional, prospective clinical observational study, aiming to evaluate the effectiveness and safety of subsequent treatment in dMMR/MSI solid tumor patients who have never received ICIs under real-world conditions. Particular attention is paid to the efficacy in populations where treatment plans are adjusted based on ctDNA, and potential predictive or prognostic biomarkers are explored.

Description:

This study plans to enroll patients in the following four cohorts:

• Cohort A: Initially only receiving PD1/PDL1 monotherapy;

• Cohort B: Initially receiving simultaneous blockade of PD1/PDL1 and CTLA4;

• Cohort C: Initially receiving PD1/PDL1 monotherapy combined with chemotherapy or targeted therapy;

• Cohort D: Initially not using ICIs, receiving other standard treatments for this tumor type

To explore the role of ctDNA testing in therapeutic decision-making, patients with the first evaluation of SD in cohort A are divided into two groups: ctDNA testing/intervention group (Group A1) and ctDNA testing/non-intervention group (Group A2). In group A1, if there is no early response to ctDNA, the researchers and the patient will decide to add CTLA4 antibody or other potentially effective treatments after thorough communication. If there is an early response to ctDNA, then continue with PD1/PDL1 monoclonal antibody treatment. Patients in group A2 undergo ctDNA testing, but still continue with PD1/PDL1 monoclonal antibody treatment according to the RECIST v1.1 standard when the first evaluation of SD is made. Meanwhile, explore the role of 1-year ctDNA-MRD in guiding treatment in patients with long-term tumor control, and explore the guiding role of re-biopsy of tumor tissue or ctDNA testing in helping making treatment regimen after progression on ICIs.

Number of Subjects:

• This study will recruit patients nationwide for data collection over a period of 3 years. The plan is to enroll 100 cases in Cohort A, including 25 cases in Group A1 and 25 cases in Group A2; 30 cases in Cohort B; 30 cases in Cohort C; and 30 cases in Cohort D.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 190
• Est. completion date: February 2026
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Sign the informed consent form and voluntarily participate in this study;

• Age = 18 years old; age should also be =75 years old in Cohorts B, C, D;

• Histologically or cytologically confirmed to have a solid malignant tumor and confirmed by immunohistochemistry to be dMMR or confirmed by PCR/NGS to be MSI;

• The researcher determines that the patient can receive anti-tumor treatment;

• Have evaluable lesions

Exclusion Criteria:

• Other malignant tumors within 5 years before joining the study, except for cured skin squamous cell carcinoma, basal cell carcinoma, non-muscle invasive bladder cancer, localized low-risk prostate cancer (defined as stage =T2a, Gleason score =6 points, and prostate cancer diagnosed with PSA =10 ng/mL (if measured). Patients who have received radical treatment and have no prostate specific antigen (PSA) biochemical recurrence can participate in this study), cervical/breast carcinoma in situ, and Lynch syndrome;

• Evidence already exists that the patient is a pregnant or lactating woman;

• Previous treatment with immune checkpoint inhibitors or T cell co-stimulatory drugs, including but not limited to PD1, CTLA4, LAG3, and other immune checkpoint blockers, therapeutic vaccines, etc.; patients exposed to ICIs in perioperative setting are allowed to be enrolled if disease relapse after more than 6 months since the last dose of ICIs;

• Other situations deemed by the researcher to be unsuitable for inclusion in the study

Related Conditions & MeSH terms

• MSI-H
• Neoplasms
• Solid Tumor

Locations

Country	Name	City	State
China	Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute	Beijin	Beijing
China	Department of Medical Oncology, Peking University First Hospital	Beijing
China	Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University	Beijing
China	Department of Oncology, Peking University Shougang Hospital	Beijing
China	Department of Oncology, The Affiliated Hospital of Qingdao University	Qingdao	Shandong
China	Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute	Shengyang	Liaoning
China	Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University	Shijiazhuang	Hebei
China	Department of Gastroenterology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital	Taiyuan	Shanxi
China	Department of Gastrointestinal Oncology, Tianjin Medical University Cancer Institute and Hospital	Tianjin
China	Department of Oncology, The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan

Sponsors (1)

Lead Sponsor	Collaborator
Peking University Cancer Hospital & Institute

Country where clinical trial is conducted

China, 

References & Publications (15)

Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699. — View Citation

Bui QL, Mas L, Hollebecque A, Tougeron D, de la Fouchardiere C, Pudlarz T, Alouani E, Guimbaud R, Taieb J, Andre T, Colle R, Cohen R. Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer. Cancers (Basel). 2022 Jan 14;14(2):406. doi: 10.3390/cancers14020406. — View Citation

Chen M, Wang Z, Liu Z, Liu N, Fang W, Zhang H, Jin X, Li J, Zhao W, Qu H, Song F, Chang Z, Li Y, Tang Y, Xu C, Zhang X, Wang X, Peng Z, Cai J, Li J, Shen L. The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study. Cancers (Basel). 2022 Oct 21;14(20):5158. doi: 10.3390/cancers14205158. — View Citation

Chida K, Kawazoe A, Kawazu M, Suzuki T, Nakamura Y, Nakatsura T, Kuwata T, Ueno T, Kuboki Y, Kotani D, Kojima T, Taniguchi H, Mano H, Ikeda M, Shitara K, Endo I, Yoshino T. A Low Tumor Mutational Burden and PTEN Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors. Clin Cancer Res. 2021 Jul 1;27(13):3714-3724. doi: 10.1158/1078-0432.CCR-21-0401. Epub 2021 Apr 29. — View Citation

Hollebecque A, Chung HC, de Miguel MJ, Italiano A, Machiels JP, Lin CC, Dhani NC, Peeters M, Moreno V, Su WC, Chow KH, Galvao VR, Carlsen M, Yu D, Szpurka AM, Zhao Y, Schmidt SL, Gandhi L, Xu X, Bang YJ. Safety and Antitumor Activity of alpha-PD-L1 Antibody as Monotherapy or in Combination with alpha-TIM-3 Antibody in Patients with Microsatellite Instability-High/Mismatch Repair-Deficient Tumors. Clin Cancer Res. 2021 Dec 1;27(23):6393-6404. doi: 10.1158/1078-0432.CCR-21-0261. Epub 2021 Aug 31. — View Citation

Kasi PM, Budde G, Krainock M, Aushev VN, Koyen Malashevich A, Malhotra M, Olshan P, Billings PR, Aleshin A. Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA-4 rescue in patients with mismatch repair deficient metastatic colorectal cancer. J Immunother Cancer. 2022 Jan;10(1):e003312. doi: 10.1136/jitc-2021-003312. — View Citation

Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. doi: 10.1126/science.aan6733. Epub 2017 Jun 8. — View Citation

Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, Miller R, Riaz N, Douillard JY, Andre F, Scarpa A. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019 Aug 1;30(8):1232-1243. doi: 10.1093/annonc/mdz116. — View Citation

Luo J, Wu S, Rizvi H, Zhang Q, Egger JV, Osorio JC, Schoenfeld AJ, Plodkowski AJ, Ginsberg MS, Callahan MK, Maher C, Shoushtari AN, Postow MA, Voss MH, Kotecha RR, Gupta A, Raja R, Kris MG, Hellmann MD. Deciphering radiological stable disease to immune checkpoint inhibitors. Ann Oncol. 2022 Aug;33(8):824-835. doi: 10.1016/j.annonc.2022.04.450. Epub 2022 May 6. — View Citation

Malla M, Loree JM, Kasi PM, Parikh AR. Using Circulating Tumor DNA in Colorectal Cancer: Current and Evolving Practices. J Clin Oncol. 2022 Aug 20;40(24):2846-2857. doi: 10.1200/JCO.21.02615. Epub 2022 Jul 15. — View Citation

Wang Z, Wang X, Xu Y, Li J, Zhang X, Peng Z, Hu Y, Zhao X, Dong K, Zhang B, Gao C, Zhao X, Chen H, Cai J, Bai Y, Sun Y, Shen L. Mutations of PI3K-AKT-mTOR pathway as predictors for immune cell infiltration and immunotherapy efficacy in dMMR/MSI-H gastric adenocarcinoma. BMC Med. 2022 Apr 21;20(1):133. doi: 10.1186/s12916-022-02327-y. — View Citation

Wang Z, Zhang Q, Qi C, Bai Y, Zhao F, Chen H, Li Z, Wang X, Chen M, Gong J, Peng Z, Zhang X, Cai J, Chen S, Zhao X, Shen L, Li J. Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer. J Immunother Cancer. 2022 Jun;10(6):e004703. doi: 10.1136/jitc-2022-004703. — View Citation

Wang Z, Zhao X, Gao C, Gong J, Wang X, Gao J, Li Z, Wang J, Yang B, Wang L, Zhang B, Zhou Y, Wang D, Li X, Bai Y, Li J, Shen L. Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment. J Immunother Cancer. 2020 Nov;8(2):e001297. doi: 10.1136/jitc-2020-001297. — View Citation

Zhang Q, Luo J, Wu S, Si H, Gao C, Xu W, Abdullah SE, Higgs BW, Dennis PA, van der Heijden MS, Segal NH, Chaft JE, Hembrough T, Barrett JC, Hellmann MD. Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade. Cancer Discov. 2020 Dec;10(12):1842-1853. doi: 10.1158/2159-8290.CD-20-0047. Epub 2020 Aug 14. — View Citation

Zhu M, Jin Z, Hubbard JM. Management of Non-Colorectal Digestive Cancers with Microsatellite Instability. Cancers (Basel). 2021 Feb 6;13(4):651. doi: 10.3390/cancers13040651. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS) determined by the researchers according to the RECIST 1.1 criteria..	Progression-free survival (PFS) is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic progressive disease (PD) or death due to any cause.	Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
Secondary	Overall survival	Overall survival (OS) is defined as the time from the date of first dose to the date of death from any cause.	Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
Secondary	Overall response rate	Objective response rate (defined as CR+PR) will be reported based on investigator's evaluation.	Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
Secondary	Disease control rate	Disease control rate (defined as CR+PR+SD) will be reported based on investigator's evaluation.	Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
Secondary	Duration of response	Duration of response (DOR) is defined as the time from the date of the first response to the first objective documentation of radiographic progressive disease (PD) or death due to any cause.	Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
Secondary	Treatment-related adverse event	A treatment-related adverse event (TRAE) is defined as any adverse event not present prior to the initiation of drug treatment or any adverse event already present that worsens in intensity or frequency following exposure to the drug treatment. TRAEs were graded using National Cancer Institute (NCI)-CTCAE version 5.0.	Informed consent to 30 days after last dose of treatment