SCRT Sequential Penpulimab in Combination With CAPEOX in the Neoadjuvant Treatment of MSS Locally Advanced Rectal Cancer

Rectal Cancer Clinical Trial

— N-PRC  

Official title:

Efficacy and Safety of Short-course Radiotherapy Sequential Penpulimab in Combination With CAPEOX in the Neoadjuvant Treatment of Microsatellite Stable Locally Advanced Rectal Cancer: a Single-centre, Single-arm, Phase 2 Study

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05576480
• Other study ID #: N-PRC
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: October 2022
• Est. completion date: December 2026

Study information

• Verified date: October 2022
• Source: Ruijin Hospital
• Contact: Ren Zhao, MD, PHD
• Phone: +8618917762018
• Email: zhaorensurgeon[@]aliyun.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this phase 2 study is to learn about the efficacy and safety of short-course radiotherapy (SCRT) sequential Penpulimab in combination with CAPEOX in the neoadjuvant treatment of microsatellite stable (MSS) locally advanced rectal cancer. The main question it aims to answer is the role of immune checkpoint inhibitors in the neoadjuvant treatment of MSS rectal cancer. Participants will receive neoadjuvant treatment of SCRT sequential Penpulimab in combination with CAPEOX. Participants will undergo a clinical re-staging assessment at the end of neoadjuvant therapy to determine whether to adopt a watch-and-wait strategy or undergo radical surgery.

Description:

Today there has been an outbreak progress in immunotherapy for tumors, where immune checkpoint inhibitors targeting PD-1/PD-L1 have been approved for the treatment of a variety of tumors, bringing long-term benefits to some patients, especially colorectal cancer and other solid tumors with dMMR/MSI-H have been identified as the best indication population for immunotherapy. However, the majority of patients presented with microsatellite stable (MSS) or pMMR status had a low response rate to immunotherapy. How to improve the response to immunotherapy in these patients has been a challenge in the field of colorectal cancer immunotherapy. A number of preclinical and small clinical studies have identified immunotherapy in combination with other treatments such as chemotherapy, radiotherapy, anti-angiogenic drugs and targeted therapies as potentially viable options to overcome immune resistance and improve the outcome of MSS colorectal cancer. Preclinical and small clinical studies have demonstrated that radiotherapy may induce antigen release from tumors with low neoantigen load and activate dendritic cells, thereby activating CD8+ T lymphocyte-mediated anti-cancer immune responses. In patients with locally advanced rectal cancer, neoadjuvant chemoradiotherapy can increase PD-L1 expression in tumor cells, suggesting that the combination of radiotherapy and PD-1/PD-L1 inhibitors may have a synergistic effect. To further improve the treatment outcomes of locally advanced rectal cancer, we designed an exploratory observational study to observe the efficacy and safety of a regimen of short-course radiotherapy combined with chemotherapy and the addition of the PD-1 monoclonal antibody in locally advanced rectal cancer, and to initially explore the feasibility a watch-and-wait strategy for patients with rectal cancer who have reached pCR.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 55
• Est. completion date: December 2026
• Est. primary completion date: October 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Informed consent

• 18 years < age = 75 years

• ECOG score is 0-1

• Patients with pathologically confirmed rectal adenocarcinoma, assessed by MRI as mid-low rectal cancer (the lower border of the tumor is less than 10cm from the anal verge), clinical stage II-III (cT1-2N1-2M0 or T3-4N0-2M0) according to the 8th Edition of AJCC Cancer Staging Manual

• Without emergency operation due to complication (bleeding, perforation or obstruction) caused by rectal cancer

• Microsatellite Instability detection using PCR capillary electrophoresis results in MSS

• Without any anti-tumor treatment

• No distant metastasis

• Have an imaging measurable or clinically assessable lesion

• Adequate organ and bone marrow function

• Female participants of childbearing age or male participants whose sexual partners are women of childbearing age are required to use effective contraception for the entire treatment period and for 6 months after the end of the treatment period

Exclusion Criteria:

• Recurrent rectal cancer

• Previous treatment with pelvic radiotherapy, rectal cancer surgery, chemotherapy, targeted therapy, immune checkpoint inhibitors (including but not limited to PD-1, PD-L1, CTLA-4)

• Proven inability to receive radiotherapy or allergy to the components of Penpulimab, capecitabine, oxaliplatin or their excipients

• Intestinal obstruction due to tumor (except in patients who have received a stoma)

• History of other primary malignancies, except for: malignancies in complete remission for at least 2 years prior to enrolment and not requiring other treatment during the study period; adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease recurrence; adequately treated carcinoma in situ with no evidence of disease recurrence

• Active, known or suspected autoimmune disease or history of this disease within the previous 2 years (patients with vitiligo, psoriasis, alopecia or Graves' disease not requiring systemic treatment within the last 2 years, hypothyroidism requiring only thyroid hormone replacement therapy and type I diabetes requiring only insulin replacement therapy may be enrolled)

• Any of the following within 6 months prior to the start of treatment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association classification II-IV), cerebrovascular event, transient ischaemic attack, severe arrhythmia requiring drug treatment or symptomatic pulmonary embolism

• History of allogeneic organ transplantation and allogeneic haematopoietic stem cell transplantation

• Uncontrolled comorbidities including but not limited to: HIV infected; Serious infections that are active or poorly controlled clinically

• Pregnant woman or lactating woman

• Patients who have participated in another drug clinical trial within 4 weeks

• Suffering from acute or chronic active hepatitis B (HBsAg-positive and HBV DNA = 200 IU/mL or = 103 copies/mL) or acute or chronic active hepatitis C (HCV-positive and HCV RNA-positive)

• Received live attenuated vaccine within 4 weeks prior to enrolment or planned during the study period

• Major surgical procedure within 4 weeks prior to enrolment

• History of interstitial pneumonia

• Other acute or chronic diseases, mental disorders, or laboratory test abnormalities that may result in: increasing the risk associated with research participation or drug administration, or interfering with the interpretation of the results of the study, and the patient was classified as not eligible to participate in this study according to the judgment of the researchers

Related Conditions & MeSH terms

• Locally Advanced
• Rectal Cancer
• Rectal Neoplasms

Intervention

Radiation:
• Short-course radiotherapy
5×5Gy in Week 1

Drug:
• Penpulimab
Apply once in the first week, then every 3 weeks from the third week for four cycles
• CAPEOX
Apply every 3 weeks from week 3 for 4 cycles

Procedure:
• TME surgery
Patient will receive radical rectal cancer surgery

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Ruijin Hospital	Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

References & Publications (2)

Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):29-42. doi: 10.1016/S1470-2045(20)30555-6. Epub 2020 Dec 7. Erratum in: Lancet Oncol. 2021 Feb;22(2):e42. — View Citation

Dossa F, Chesney TR, Acuna SA, Baxter NN. A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2017 Jul;2(7):501-513. doi: 10.1016/S2468-1253(17)30074-2. Epub 2017 May 4. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathological complete remission rate (pCR)	The proportion of complete remissions detected by postoperative pathological examination (%)	One month after surgery
Secondary	Clinical complete remission rate (cCR)	The proportion of complete remissions detected by imaging, endoscopy and digital rectal examination (%)	Three weeks after neoadjuvant therapy
Secondary	Objective response rate (ORR)	Sum of proportion in complete and partial remission (%)	One month after surgery
Secondary	3-year disease free survival rate (3y-DFS)	3-year disease free survival rate estimated based on Kaplan-Meier method	36 months after surgery
Secondary	R0 resection rate	Histologically complete resection rate (%)	One month after surgery
Secondary	Sphincter preservation rate	The proportion of low rectal cancer patients retaining the sphincter in radical surgery (%)	One month after surgery
Secondary	Early morbidity rate	Morbidity rate 30 days after surgery (%)	30 days after surgery
Secondary	Number and severity of adverse events	Number and severity of adverse events using CTCAE V5.0	36 months after surgery