The Clinical Efficacy of Drug Sensitive Neoadjuvant Chemotherapy Based on Organoid Versus Traditional Neoadjuvant Chemotherapy in Advanced Rectal Cancer

Neoadjuvant Therapy Clinical Trial

Official title:

A Prospective Multicenter Randomized Controlled Trial of the Clinical Efficacy of Neoadjuvant Therapy Based on Organoids Drug Sensitivity Versus Empirical Neoadjuvant Therapy in the Treatment of Advanced Rectal Cancer

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05352165
• Other study ID #: MISC-WXXR-001
• Status: Not yet recruiting
• Phase: N/A
• Start date: January 1, 2023
• Est. completion date: December 31, 2025

Study information

• Verified date: April 2022
• Source: Shanghai Minimally Invasive Surgery Center
• Contact: Jing Sun, PhD
• Phone: +86-21-64370045
• Email: sj11788[@]rjh.com.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a prospective multicenter randomized controlled trial study. According to the enrollment criteria, patients with locally advanced rectal cancer who need neoadjuvant therapy before radical surgery were randomly divided into the organoids drug sensitivity group and the standard whole-course neoadjuvant therapy group. The Organoids drug sensitivity group was treated with personalized neoadjuvant therapy under the guidance of tumor organoids drug sensitivity technology combined with standard long-term radiotherapy. The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience. The tumor pathological complete remission rate (pCR), postoperative complication rate, postoperative tumor withdrawal grade, postoperative recurrence rate, treatment tolerance rate, R0 resection rate, and sphincter preservation rate were observed and compared.

Description:

Based on the need for individualized treatment in the era of precision medicine, an in vitro model that can accurately predict the response of patients to treatment is urgently needed, so that suitable patients can receive effective treatment and patients whose treatments are ineffective can avoid adverse reactions. The emergence of tumor organoids technology makes this vision possible. Tumor-organoid (Patient-Derived Organoids, PDOs) is a kind of micro-organ with a three-dimensional structure, which is cultivated in the environment of 3D matrix glue in vitro. Based on the individualized neoadjuvant therapy based on the drug sensitivity technology of tumor-organoid, the best neoadjuvant therapy can be selected and the clinical efficacy and drug tolerance can be quickly predicted, which is of great significance in the field of accurate tumor therapy. The preliminary study of our group also completed the organ-like library of more than 100 patients with local advanced rectal cancer. It was proved that the organoids of the organoids library had high homology with the original tumor tissue, and the detection period of drug sensitivity of organoids was less than 2 weeks, which was much less than 2 months of PDX drug sensitivity technology in mice, which did not affect the time window of clinical drug treatment, and the results of drug sensitivity were basically consistent with the clinical efficacy. Therefore, we have reason to believe that tumor organoids chemosensitivity technology, as an economical, high-throughput, and efficient technology for tumor research, is expected to play an important role in clinical individualized treatment of tumors. Our previous study found that tumor-based organoids drug sensitivity technology can be used as an effective and reliable clinical assistant tool to guide and assist doctors to formulate the best treatment strategy for tumor patients. Personalized neoadjuvant therapy has better clinical efficacy than standard whole-course neoadjuvant therapy. Therefore, in this study, through a prospective, multicenter, multi-arm umbrella clinical study, patients with locally advanced rectal cancer who need neoadjuvant therapy are randomly divided into two groups: the organoids drug sensitivity group and the standard whole-course neoadjuvant therapy group. To compare the clinical efficacy of personalized neoadjuvant therapy based on tumor organoids chemosensitivity combined with standard long-term radiotherapy with the clinical efficacy of standard whole-course neoadjuvant therapy in locally advanced rectal cancer. This technology can be used in the clinical use of advanced rectal cancer new auxiliary decision-making system so that the standardization of comprehensive treatment of rectal cancer can be implemented in China, which is of great significance for the development of the national economy and the improvement of medical level in China.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 192
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• 1) Age: 18-75. 2) qualitative diagnosis: adenocarcinoma was confirmed by enteroscopic biopsy. 3) Localization diagnosis: the tumor is located in the rectum (the distance between the tumor and the anal margin = 12cm). 4) plain scan of thoracoabdominal pelvis and enhanced CT or MRI evaluation of rectal cancer staging: The primary tumor invades the muscular layer of the intestinal wall into the surrounding well-known structure, with or without lymph node metastasis in the proper rectal fascia. b. TNM clinical or pathological stage of tumor: T3-T4N0-2M0. 5) physical condition (ECOG) score = 1. 6) all patients agreed to receive adjuvant chemotherapy for 3 to 6 months after operation. 7) sign informed consent and participate in the project voluntarily.

Exclusion Criteria:

• 1) simultaneous or metachronous multiple primary malignant tumors. 2) preoperative imaging examination or pathological results showed that: Lateral lymph node metastasis. b. Distant organ metastasis. 3) previous history of malignant tumors. 4) abnormal function of heart, lung, liver, kidney, hematopoiesis and bone marrow reserve, which can not tolerate neoadjuvant therapy and operation. 5) have mental illness or other serious cardiovascular disease. 6) pregnant or lactating women. 7) Emergency surgery (perforation, bleeding, intestinal obstruction, etc.). 8) BRAF mutation was found by gene detection.

Related Conditions & MeSH terms

• Neoadjuvant Therapy
• Rectal Neoplasms

Intervention

Drug:
• standard long-term therapy
The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience.
• FOLFOX and standard long-term radiotherapy
FOLFOX and standard long-term radiotherapy based on organoids drug sensitivity
• FOLFIRI and standard long-term radiotherapy
FOLFIRI and standard long-term radiotherapy based on organoids drug sensitivity
• 5-FU and standard long-term radiotherapy
5-FU and standard long-term radiotherapy based on organoids drug sensitivity
• 5-FU and pembrolizumab and standard long-term radiotherapy
5-FU and pembrolizumab and standard long-term radiotherapy based on organoids drug sensitivity
• Other individualized treatments
Other individualized treatments based on organoids drug sensitivity

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Shanghai Minimally Invasive Surgery Center	Shanghai OneTar Biomedicine Co., Ltd., Wuxi Branch of Ruijin Hospital

References & Publications (7)

Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl). 2021 Mar 17;134(7):783-791. doi: 10.1097/CM9.0000000000001474. — View Citation

Garcia-Aguilar J, Chow OS, Smith DD, Marcet JE, Cataldo PA, Varma MG, Kumar AS, Oommen S, Coutsoftides T, Hunt SR, Stamos MJ, Ternent CA, Herzig DO, Fichera A, Polite BN, Dietz DW, Patil S, Avila K; Timing of Rectal Cancer Response to Chemoradiation Consortium. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):957-66. doi: 10.1016/S1470-2045(15)00004-2. Epub 2015 Jul 14. — View Citation

Ludmir EB, Palta M, Willett CG, Czito BG. Total neoadjuvant therapy for rectal cancer: An emerging option. Cancer. 2017 May 1;123(9):1497-1506. doi: 10.1002/cncr.30600. Epub 2017 Mar 10. Review. — View Citation

Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009 May 14;459(7244):262-5. doi: 10.1038/nature07935. Epub 2009 Mar 29. — View Citation

Shamir ER, Ewald AJ. Three-dimensional organotypic culture: experimental models of mammalian biology and disease. Nat Rev Mol Cell Biol. 2014 Oct;15(10):647-64. doi: 10.1038/nrm3873. Epub 2014 Sep 17. Review. — View Citation

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12. Erratum in: CA Cancer J Clin. 2021 Jul;71(4):359. — View Citation

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathologic Complete Response	Neoadjuvant therapy and postoperative pathology confirmed that the primary tumor was in complete remission (stage ypT0) and had no residual tumor cells, regardless of whether the regional lymph nodes were involved or not.	3 years
Secondary	Postoperative complication	Intra-abdominal bleeding, anastomotic leakage, intra-abdominal infection, intestinal obstruction, postoperative diarrhea, wound infection, pulmonary infection, cardiovascular accident, cerebrovascular accident, etc.	3 years
Secondary	Tumor Regression Grading	Tumor pathological reaction is graded after neoadjuvant therapy, usually according to the proportion of fibrosis and residual tumor in the tumor.; The analytical system for evaluating treatment response recommended by NCCN is as follows: complete response-no living cancer cell residue, moderate reaction-single or small cluster cancer cell residue,mild reaction-residual cancer focus, interstitial fibrosi,adverse reaction-few or no cancer cell regression.	3 years
Secondary	Local recurrence	Recurrence occurs in the surgical area, with or without the rise of tumor markers. The tumor found in the anastomosis needs to be confirmed by pathological biopsy.	3 years
Secondary	Distant metastasis	CT or MRI or radionuclide scan can detect metastases in liver, lung and bone, with or without confirmed by pathology.	3 years
Secondary	Treatment tolerance rate	To evaluate the tolerance and completion of preoperative neoadjuvant therapy.	3 years
Secondary	R0 resection rate	R0 resection rate of laparoscopic radical surgery for rectal cancer after neoadjuvant therapy.	3 years
Secondary	anus-saving rate	anus-saving rate after radical resection of rectal cancer after neoadjuvant therapy	3 years