Clinical trial NCT05576480: SCRT Sequential Penpulimab in Combination With CAPEOX in the Neoadjuvant Treatment of MSS Locally Advanced Rectal Cancer
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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Rectal Cancer
Locally Advanced
Keywords: Immunotherapy
Neoadjuvant Treatment
Locally Advanced Rectal Cancer
Microsatellite stable
Lead sponsor: Ruijin Hospital
Sponsor class: OTHER
Collaborators: name: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
First posted: 2022-10-12
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a two staged, single arm phase II trial of short-course radiotherapy sequential Penpulimab in combination with CAPEOX in the neoadjuvant treatment of microsatellite stable locally advanced rectal cancer. Twenty-three patients will be enrolled in the first phase and if the number of pathological complete remission is ≤ 3, the trial will be terminated; if \> 3, the trial will proceed to the second phase and continue to enroll up to 48 patients. Taking into account a 15% abscission rate, the total number of patients enrolled will be 55.
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Pathological complete remission rate (pCR)
timeFrame: One month after surgery
Secondary outcomes:
measure: Clinical complete remission rate (cCR)
timeFrame: Three weeks after neoadjuvant therapy
measure: Objective response rate (ORR)
timeFrame: One month after surgery
measure: 3-year disease free survival rate (3y-DFS)
timeFrame: 36 months after surgery
measure: R0 resection rate
timeFrame: One month after surgery
measure: Sphincter preservation rate
timeFrame: One month after surgery
measure: Early morbidity rate
timeFrame: 30 days after surgery
measure: Number and severity of adverse events
timeFrame: 36 months after surgery
Other outcomes:
Locations:
Study officials:
affiliation: Ruijin Hospitlal , Shanghai Jiaotong University School of Medicine
name: Ren Zhao, MD, PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.