Neoadjuvant Chemoradiotherapy Combined With PD-1 Inhibitor and Thymalfasin for pMMR/MSS Locally Advanced Mid-low Rectal Cancer

Locally Advanced Rectal Cancer Clinical Trial

Official title:

Efficacy and Safety of Neoadjuvant Chemoradiotherapy Combined With PD-1 Inhibitor and Thymalfasin in pMMR/MSS Locally Advanced Middle and Low Rectal Cancer: An Open, Multi-center, Prospective, Single-arm Phase II Clinical Study

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06056804
• Other study ID #: ZDX+PD-1-LARC
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: December 1, 2023
• Est. completion date: July 1, 2027

Study information

• Verified date: November 2023
• Source: Beijing Friendship Hospital
• Contact: Zhongtao Zhang, MD
• Phone: +86 13801060364
• Email: Zhangzht[@]ccmu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open, prospective, multi-center, single-arm phase II clinical study assessing the efficacy and safety of neoadjuvant chemoradiotherapy combined with PD-1 inhibitor and thymalfasin in patients with pMMR/MSS locally advanced middle and low rectal cancer.

Description:

This study is an open, prospective, multi-center, single-arm phase II clinical study. In this study, patients with pMMR/MSS locally advanced middle and low rectal cancer were selected as the subjects and treated with neoadjuvant treatment protocol of long-course concurrent chemoradiotherapy combined with PD-1 monoclonal antibody and thymalfasin. The primary endpoint of the study was pathological complete response (pCR) rate. The secondary study endpoints were neoadjuvant rectal (NAR) score, objective response rate (ORR), R0 resection rate, anal preservation rate, 3-year disease-free survival (DFS) rate, 3-year local recurrence-free survival (LRFS) rate, 3-year overall survival (OS) rate, tumor regression grade (TRG), safety and tolerability.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 20
• Est. completion date: July 1, 2027
• Est. primary completion date: July 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Patients who were fully informed of the study and voluntarily signed the informed consent form;

2. Patients who were pathologically diagnosed with rectal adenocarcinoma via enteroscopic biopsy and met the following criteria:

?LARC at clinical stage II/III: cT1-4aN0-2M0; ? Distance between distal tumor and the anal verge =10 cm (measured by MRI); ? No distant metastasis; ? pMMR or MSS confirmed by immunohistochemistry or genetic test.

3. Men and women aged =18 and =75 years old, with ECOG score of 0-1 points;

4. Patients willing to accept the treatment protocol of neoadjuvant therapy + TME;

5. Patients whose major organ functions met the following requirements (The values of laboratory tests within 14 days before enrollment must meet the following criteria):

? Blood routine test: (no blood transfusion or use of granulocyte colony-stimulating factor or drug correction within 14 days before screening): a) neutrophil count =1.5 × 109/L; b) platelet count =75 × 109/L; c) hemoglobin level =90 g/L

? Biochemical test: (no albumin infusion within 14 days prior to screening): a) serum creatinine =1.5 × upper limit of normal (ULN) or creatinine clearance >50 mL/min; b) serum total bilirubin =1.5 × ULN; c) aspartate aminotransferase (AST), alanine aminotransferase (ALT) =2.5 × ULN

? Coagulation function: a) international normalized ratio (INR) =2.3 or prothrombin time (PT) =6 seconds longer than the range of normal control;

? Normal thyroid function

6. No immune system diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis (RA), systemic vasculitis, scleroderma, mixed connective tissue disease, autoimmune hemolytic anemia, hyperthyroidism, hypothyroidism, and ulcerative colitis);

7. Within 28 days before enrollment, women of childbearing age must have a negative serum pregnancy test and agree to take effective contraceptive measures during the use of investigational drug and within 60 days after the last drug administration. Female spouses of male subjects should also follow the above contraceptive requirements if they are of childbearing age;

8. Patients whose body and organ functions can tolerate major abdominal surgery.

Exclusion Criteria:

1. Patients currently or previously with malignant tumors other than rectal cancer (except for cured basal cell carcinoma of skin or cervical carcinoma in situ);

2. Patients treated with major surgery within 4 weeks before the start of research therapies;

3. Patients with any condition that affected the absorption of capecitabine in the gastrointestinal tract;

4. Patients with severe uncontrolled recurrent infections, or other severe uncontrolled concomitant diseases;

5. Patients with severe diseases with an estimated survival of =5 years;

6. Patients with congenital malformation, developmental disorder, genetic defect, or severe malnutrition;

7. Patients who were ready to receive or had received organ or bone marrow transplantation;

8. Pregnant or lactating women;

9. Patients with severe cardiovascular disease, hepatic or renal disease, respiratory disease, uncontrolled hypertension (systolic blood pressure =140 mmHg and/or diastolic blood pressure =90 mmHg), diabetic complication, various acute diseases or acute stage of chronic diseases;

10. Patients diagnosed with congenital or acquired immune deficiency (such as HIV infection), lymphoma, leukemia, or other autoimmune diseases, or those suffering active tuberculosis or receiving anti-tuberculous therapy;

11. Patients who received immunotherapy within 3 months before screening, such as long-term treatment with prednisone at a dose >10 mg/day or corticosteroid at an equivalent dose (more than 14 consecutive days through oral administration or infusion), or immunosuppressant;

12. Patients who received blood or blood-related products, including immunoglobulin, within 3 months, or those who planned to use them at the beginning of the study;

13. Patients treated with other investigational drugs within 1 month before screening;

14. Patients with a history of allergy or intolerance to any investigational drug or its components;

15. Patients with suspected or known alcohol or drug dependence;

16. Patients with dMMR or MSI-H confirmed by immunohistochemistry or genetic test;

17. Patients with T4b or MRF(+) according to baseline rectal MRI;

18. Patients with other conditions unsuitable for this clinical trial judged by the investigator.

Related Conditions & MeSH terms

• Locally Advanced Rectal Cancer
• Rectal Neoplasms

Intervention

Drug:
• capecitabine
825-1000mg/m2,po,bid
• tislelizumab
200mg,iv.gtt,q3w
• thymalfasin
4.8mg,sc,biw

Radiation:
• long-term radiotherapy
50 Gy/25 f, 2 Gy/day

Locations

Country	Name	City	State
China	Beijing Friendship Hospital,Capital Medical University	Beijing
China	Peking Union Medical College Hospital	Beijing

Sponsors (2)

Lead Sponsor	Collaborator
Beijing Friendship Hospital	Peking Union Medical College Hospital

Country where clinical trial is conducted

China, 

References & Publications (4)

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

Danielli R, Cisternino F, Giannarelli D, Calabro L, Camerini R, Savelli V, Bova G, Dragonetti R, Di Giacomo AM, Altomonte M, Maio M. Long-term follow up of metastatic melanoma patients treated with Thymosin alpha-1: investigating immune checkpoints synergy. Expert Opin Biol Ther. 2018 Jul;18(sup1):77-83. doi: 10.1080/14712598.2018.1494717. — View Citation

King RS, Tuthill C. Evaluation of thymosin alpha 1 in nonclinical models of the immune-suppressing indications melanoma and sepsis. Expert Opin Biol Ther. 2015;15 Suppl 1:S41-9. doi: 10.1517/14712598.2015.1008446. Epub 2015 Feb 2. — View Citation

Renga G, Bellet MM, Pariano M, Gargaro M, Stincardini C, D'Onofrio F, Mosci P, Brancorsini S, Bartoli A, Goldstein AL, Garaci E, Romani L, Costantini C. Thymosin alpha1 protects from CTLA-4 intestinal immunopathology. Life Sci Alliance. 2020 Aug 14;3(10):e202000662. doi: 10.26508/lsa.202000662. Print 2020 Oct. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The expression of CD68	The density, H-score of each marker in paraffin-embedded tissue sections detected by mIHC	up to 3 months after surgery
Other	The expression of CD86	The density, H-score of each marker in paraffin-embedded tissue sections detected by mIHC	up to 3 months after surgery
Other	The expression of CD163	The density, H-score of each marker in paraffin-embedded tissue sections detected by mIHC	up to 3 months after surgery
Other	The expression of CD4	The density, H-score of each marker in paraffin-embedded tissue sections detected by mIHC	up to 3 months after surgery
Other	The expression of CD8	The density, H-score of each marker in paraffin-embedded tissue sections detected by mIHC	up to 3 months after surgery
Primary	pCR rate	pathological complete response rate	within 10 days after surgery
Secondary	ORR	objective response rate; The ORR rate is the result of complete response (CR) rate plus partial response (PR) rate.	before surgery
Secondary	3-y DFS rate	3-year disease free survival rate	3 years
Secondary	3-y LRFS rate	3-year local recurrence free survival rate	3 years
Secondary	3-y OS rate	3-year overall survival rate	3 years
Secondary	TRG	Tumor regression grade	within 10 days after surgery
Secondary	R0 resection rate	rate of R0 resection	within 10 days after surgery
Secondary	anal preservation rate	proportion of patients with preserved anal sphincter	instantly after surgery
Secondary	NAR score	neoadjuvant rectal score	within 10 days after surgery
Secondary	incidence of surgical complications	incidence of surgical complications within 30 days after surgery	within 30 days after surgery
Secondary	TRAE	incidence of treatment-related adverse event	from commencing of treatment to the 30th day after surgery
Secondary	irAE	incidence of immune-related adverse event	from commencing of PD-1 inhibition to the 30th day after surgery