Single-arm, Single-center, Exploratory Phase II Clinical Study of Envafolimab Combined With Chemoradiotherapy in the Treatment of Locally Advanced pMMR/MSS Rectal Cancer (ESTIMATE)

Preoperative radiotherapy combined with 5-fluorouracil/capecitabine is currently the standard treatment for locally advanced rectal cancer. Although this strategy effectively reduces the risk of local recurrence, it fails to effectively improve the overall survival rate of patients . The root cause is that 5-fluorouracil/capecitabine based local radiotherapy is not effective in controlling potential micrometastases. Therefore, many studies try to combine preoperative radiotherapy with more intense chemotherapy and targeted drugs at the same time, as well as induction chemotherapy before preoperative radiotherapy and consolidation chemotherapy after, in order to obtain better efficacy. However, a number of studies have shown that increasing cytotoxic drugs fail to effectively improve pathologic complete response rate (pCR) and long-term survival rate, and significantly increase therapeutic toxicity . Therefore, the idea of trying to increase the efficacy of cytotoxic drugs by accumulating them does not work.Based on the use of PD-1/PD-L1 antibody in colorectal cancer and other solid tumors, and referring to the scheme of PD-1/PD-L1 antibody combined with radiotherapy in other solid tumors, we added envafolimab to local radiotherapy for advanced rectal cancer for exploration, with a view to further improving the pCR rate and long-term survival of patients.

Study Overview

• Status: Recruiting
• Conditions: Envafolimab Combined With Chemoradiotherapy in the Treatment of Locally Advanced pMMR/MSS Rectal Cancer
• Intervention / Treatment: Drug: Envafolimab combined with chemoradiotherapy in the whole course of neoadjuvant therapy

Detailed Description

Inclusion criteria：

1. Disease characteristics • Histologically confirmed rectal adenocarcinoma; Immunohistochemical confirmation as pMMR or/and pCR or/and NGS test as MSS;

   • Tumor location within 12cm from anal margin;

   • Locally advanced rectal cancer (stage II-III, i.e. cT3-4 and/or N+) as assessed by the UICC/AJCC TNM staging system (8th edition, 2017);

     * Preoperative staging method: pelvic MRI/ transrectal ultrasound combined with preoperative staging.

   • No signs of intestinal obstruction; Or intestinal obstruction has been relieved after proximal colostomy surgery;
   • Preoperative chest, abdominal and pelvic CT to exclude distant metastasis.

2. Patient characteristics

   • Age: 18 ~75 years old;

   • Activity status score: ECOG 0-1;
   • Life expectancy: more than 2 years;
   • Hematology: WBC>3500×106/L; PLT>100000×106/L; Hb>10g/dL;
   • Liver function: SGOT and SGPT are less than 1.5 times of normal value; Bilirubin less than 1.5mg/dL;
   • Kidney function: creatinine <1.8mg/dL;
   • Other: non-pregnant or breastfeeding women; No other malignant disease (other than non-melanoma or carcinoma in situ of the cervix) within 5 years or during the same period; Does not have a mental illness that prevents informed consent; There were no other serious diseases associated with shorter survival.
   • Patients or family members can understand the study protocol and are willing to participate in the study, and sign a written informed consent;
   • Good patient compliance, voluntary follow-up, treatment, laboratory tests, and other research steps as scheduled.

3. Prior treatment • No previous rectal cancer surgery;

   • No previous chemotherapy or radiation therapy;

   • No previous biotherapy;

   • Previous endocrine therapy: No restriction.

   Exclusion criteria：

   • CRC for microsatellite highly unstable (MSI-H) or mismatch repair protein expression deficiency (dMMR);

   • Chronic hepatitis B or C with a history or active HIV infection (high copy of viral DNA);

   • Autoimmune diseases;

   • Other active clinical serious infections (>NCI-CTC version 3.0);

   • Stage I patients;

   • Preoperative evidence of distant metastasis;

   • Dysfluid, organ function decompensation;

   • A history of pelvic or abdominal radiotherapy;

   • Multiple primary cancers;
   • Patients whose seizures require management (such as steroid or antiepileptic therapy);
   • A history of other malignancies within 5 years, except for cured cervical carcinoma insitu or skin basal cell carcinoma;
   • Chronic inflammatory bowel disease, intestinal obstruction; Substance abuse and medical, psychological or social conditions that may interfere with the patient's participation in the study or the evaluation of the findings;
   • A known or suspected allergy to the study drug or to any drug administered in connection with this trial;
   • Any unstable conditions or conditions that could compromise patient safety and compliance;

   Describe the medication or treatment in detail:

   1.1 Induction therapy stage (2 cycles of chemotherapy combined with immunotherapy)

1 Envafolimab: 200mg, subcutaneous injection, Q2W, 2 cycles (simultaneous administration on the first day of chemotherapy).

2mFOLFOX6: Q2W, 2 cycles: oxaliplatin 85mg/m2 intravenous infusion for 2h, day 1. Calcium folinate 400mg/m2 intravenous infusion for 2 hours, day 1. Fluorouracil was injected intravenously at 400mg/m2 on day 1, followed by 1200mg/ (m2·d) × 2d with continuous intravenous infusion (total 2400mg/m2, infusion for 46~48h). 1.2 Simultaneous chemoradiotherapy (long-term radiotherapy

Chemotherapy combined with immunotherapy for 3 cycles)

Radiation therapy: 50Gy/25f, 2Gy daily, 5 days a week for 5 weeks.

Body position fixation: prone position, full bladder, body fixator or vacuum bag fixation;

CT scan: Before the scan, intravenous contrast agent was injected to develop the intestine, fill the bladder, empty the intestine, and collect two sets of CT images of plain scan and enhanced phase (only plain scan images can be collected for those allergic to contrast agent).

Radiotherapy equipment: linear accelerator;

Target area and irradiation field: The target area includes the primary rectal area and lymphatic drainage area. The treatment plan is designed by IMRT radiotherapy. The target area coverage and normal tissue limit are determined by the radiotherapy doctor according to the specific conditions of the patient.

2 Capecitabine: 825mg/m2 orally (1650mg/m2/d) twice a day in the morning and evening, 5 days a week, synchronized with radiation therapy, for a total of 25 days.

3 Envafolimab: 200mg, subcutaneous injection, Q2W, 3 cycles (given on day 1, day 15, day 29 of radiotherapy).

1.3 Consolidation treatment stage (2 cycles of chemotherapy combined with immunotherapy)

1. Envafolimab: 200mg, subcutaneous injection, Q2W, 2 cycles, synchronous administration on the first day of chemotherapy.
2. mFOLFOX6: Q2W, 2 cycles: oxaliplatin 85mg/m2 intravenous infusion for 2h, day 1. Calcium folinate 400mg/m2 intravenous infusion for 2 hours, day 1. Fluorouracil was injected intravenously at 400mg/m2 on day 1, followed by 1200mg/ (m2·d) ×2d with continuous intravenous infusion (total 2400mg/m2, infusion for 46~48h).

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yunfeng Li, master; Phone Number: 13330445776; Email: 13330445776@qq.com
• Study Contact Backup: Name: Xuan Zhang, doctoral candidate; Phone Number: 17387911546; Email: 1025415085@qq.com

Study Locations

• China
  • Yunnan
    • Kunming, Yunnan, China, 650000
      • Recruiting
      • Envafolimab
      • Contact: Yunfeng Li, master; Phone Number: 13330445776; Email: 13330445776@qq.com
      • Contact: Xuan Zhang, doctoral candidate; Phone Number: 17387911546; Email: 1025415085@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1) Disease characteristics

  • Histologically confirmed rectal adenocarcinoma; Immunohistochemical confirmation as pMMR or/and pCR or/and NGS test as MSS;
  • Tumor location within 12cm from anal margin;

  • Locally advanced rectal cancer (stage II-III, i.e. cT3-4 and/or N+) as assessed by the UICC/AJCC TNM staging system (8th edition, 2017);

    * Preoperative staging method: pelvic MRI/ transrectal ultrasound combined with preoperative staging.

  • No signs of intestinal obstruction; Or intestinal obstruction has been relieved after proximal colostomy surgery;
  • Preoperative chest, abdominal and pelvic CT to exclude distant metastasis. 2) Patient characteristics
  • Age: 18 ~75 years old;
  • Activity status score: ECOG 0-1;
  • Life expectancy: more than 2 years;
  • Hematology: WBC>3500×106/L; PLT>100000×106/L; Hb>10g/dL;
  • Liver function: SGOT and SGPT are less than 1.5 times of normal value; Bilirubin less than 1.5mg/dL;
  • Kidney function: creatinine <1.8mg/dL;
  • Other: non-pregnant or breastfeeding women; No other malignant disease (other than non-melanoma or carcinoma in situ of the cervix) within 5 years or during the same period; Does not have a mental illness that prevents informed consent; There were no other serious diseases associated with shorter survival.
  • Patients or family members can understand the study protocol and are willing to participate in the study, and sign a written informed consent;

  • Good patient compliance, voluntary follow-up, treatment, laboratory tests, and other research steps as scheduled.

    3) Prior treatment

  • No previous rectal cancer surgery;
  • No previous chemotherapy or radiation therapy;
  • No previous biotherapy;
  • Previous endocrine therapy: No restriction.

Exclusion Criteria:

• CRC for microsatellite highly unstable (MSI-H) or mismatch repair protein expression deficiency (dMMR); Chronic hepatitis B or C with a history or active HIV infection (high copy of viral DNA);

  • Autoimmune diseases;
  • Other active clinical serious infections (>NCI-CTC version 3.0);
  • Stage I patients;
  • Preoperative evidence of distant metastasis;
  • Dysfluid, organ function decompensation;
  • A history of pelvic or abdominal radiotherapy;
  • Multiple primary cancers;
  • Patients whose seizures require management (such as steroid or antiepileptic therapy);
  • A history of other malignancies within 5 years, except for cured cervical carcinoma in situ or skin basal cell carcinoma;
  • Chronic inflammatory bowel disease, intestinal obstruction; Substance abuse and medical, psychological or social conditions that may interfere with the patient's participation in the study or the evaluation of the findings;
  • A known or suspected allergy to the study drug or to any drug administered in connection with this trial;
  • Any unstable conditions or conditions that may compromise patient safety and compliance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: neoadjuvant therapy; Induction therapy stage: chemotherapy combined with immunotherapy for 2 cycles: Envafolimab: 200mg, subcutaneous injection, Q2W, 2 cycles; mFOLFOX6: Q2W, 2 cycles (concurrent administration of envollizumab on the first day of chemotherapy).; Concurrent chemoradiotherapy: long-term chemoradiotherapy combined with immunotherapy for 3 cycles: radiation therapy: 50Gy/25f, 2Gy every day, 5 days a week for 5 weeks; Capecitabine: 825mg/m2 orally (1650mg/m2/d) twice a day in the morning and evening, 5 days a week, simultaneous with radiation therapy, for a total of 25 days; Envafolimab: 200mg, subcutaneous injection, Q2W, 3 cycles (Envafolimab was administered on day 1, day 15, and day 29 of radiotherapy). Iii. Consolidation treatment stage: chemotherapy combined with immunotherapy for 2 cycles: Envafolimab: 200mg, subcutaneous injection, Q2W, 2 cycles; mFOLFOX6: Q2W, 2 cycles. (Concurrent administration of envafolimab on the first day of chemotherapy).

Drug: Envafolimab combined with chemoradiotherapy in the whole course of neoadjuvant therapy; Each enrolled patient was given 2 cycles of induction chemotherapy combined with immunization, followed by immunization combined with chemoradiotherapy, and finally 2 cycles of consolidation chemotherapy combined immunization

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pCR	Pathological complete response	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TRG	Pathological downphase rate	3 months

Collaborators and Investigators

• Sponsor: Yunnan Cancer Hospital
• Collaborators: Beijing Bethune Charitable Foundation

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2023
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: January 3, 2024
• First Submitted That Met QC Criteria: January 24, 2024
• First Posted (Estimated): February 2, 2024

Study Record Updates

• Last Update Posted (Estimated): February 2, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Rectal cancer; Envafolimab; pMMR/MSS; Local progressive stage; Full neoadjuvant therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: SLKYLX2023-006; STLKY0036 (Other Grant/Funding Number: Beijing Bethune Public Welfare Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No