Everolimus Combined With PD-1 in Advanced Colorectal Cancer Patients

The Combination of Everolimus and PD-1 in the Treatment of Locally Advanced and Advanced Colorectal Cancer That Cannot be R0 Resected

The goal of this clinical trial is to learn about efficacy of Everolimus in combination with PD-1 in patients with locally advanced and advanced colorectal cancer that cannot be R0 resected. The main question is to explore the survival time, safety and tolerability of the treatment. At the same time, the correlation between biomarkers (including PD-L1 expression, tumor mutation load, lymphocyte subpopulation, cytokines, TCR, intestinal microbes, and others) and the efficacy and drug resistance mechanism will be analyzed, so as to provide reference for the subsequent guidance of the screening of benefit groups.

Study Overview

• Status: Not yet recruiting
• Conditions: Colon Cancer
• Intervention / Treatment: Drug: Everolimus; Drug: PD-1

Detailed Description

Everolimus is an oral protein kinase inhibitor of the mTOR (mammalian target of rapamycin) serine/threonine kinase signal transduction pathway. Studies have shown that immunotherapy combined with protein kinase inhibitor has initial efficacy in the treatment of colorectal cancer. Therefore, the objective of this study is to evaluate the efficacy and safety of Everolimus in combination with PD-1 in patients with locally advanced and advanced colorectal cancer that cannot be R0 resected.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Dawei Li, PhD; Phone Number: +8613774201693; Email: li_dawei@fudan.edu.cn
• Study Contact Backup: Name: Yanjun Wang, PhD; Phone Number: +8613837266702; Email: m13837266702@163.com

Study Locations

• China
  • Henan
    • Anyang, Henan, China
      • Anyang Tumor Hospital
      • Contact: Yanjun Wang, PhD; Phone Number: +8613837266702; Email: m13837266702@163.com
  • Shanghai
    • Shanghai, Shanghai, China
      • Fudan University Shanghai Cancer Center
      • Contact: Dawei Li, PhD; Phone Number: +8613774201693; Email: li_dawei@fudan.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥18 years old, both sexes;
2. Patients with histologically or cytologically confirmed locally advanced and advanced colorectal cancer that cannot be R0 resected;
3. Recist1.1-defined disease progression or intolerance to prior standard therapy during or after standard therapy. Standard therapy was required to include all the following agents: fluorouracilines, chemotherapy agents such as irinotecan, and oxaliplatin, with or without an anti-VEGF monoclonal antibody (e.g., bevacizumab). Left-sided KRAS/NRAS/BRAF wild-type subjects received combined anti-EGFR mAb (cetuximab or panitumumab).
4. Before enrollment, the tumor tissue was PTEN mutations;
5. Patients with ECOG score of 0-1 and expected survival time ≥3 months, patients who can cooperate to observe adverse reactions and efficacy;
6. At least one measurable tumor lesion according to RECIST 1.1 criteria;

7. Good organ function:

   1. neutrophil ≥1.5*109/L; Platelet ≥100*109/L; Hemoglobin ≥9g/dl; Serum albumin ≥3g/dl;
   2. Thyroid stimulating hormone (TSH) ≤ 1 times the upper limit of normal, T3 and T4 in the normal range;
   3. bilirubin ≤ 1.5 times the upper limit of normal value; ALT and AST≤ 2 times the upper limit of normal;
   4. Serum creatinine ≤ 1.5 times the upper limit of normal, creatinine clearance ≥60ml/min;
   5. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 times the upper limit of the normal range, unless the patient is receiving anticoagulant therapy and the PT value is within the intended range for anticoagulant therapy;
   6. Activated partial thromboplastin time (aPTT) ≤ 1.5 times the upper limit of normal;
8. There were no serious concomitant diseases that could make the survival time less than 5 years;
9. Negative pregnancy test in female subjects (for female patients of childbearing potential); Infertile female patients;
10. Male patients of childbearing potential and female patients of childbearing potential and at risk of pregnancy must agree to use adequate contraception for the entire duration of the study and for 12 months after receiving treatment with the protocol;
11. Signed and dated informed consent indicating that the patient has been informed about all relevant aspects of the study;
12. Patients who are willing and able to comply with the visit schedule, treatment plan, laboratory tests, and other study procedures;
13. Willing to comply with the arrangement during the study period can not participate in any other clinical research on drugs and medical devices.

Exclusion Criteria:

1. Pathological diagnosis of other intestinal tumors, such as gastrointestinal stromal tumor;
2. Prior treatment with PD-1 antibody;
3. Prior treatment with mTOR inhibitor;
4. Previous or concurrent history of other malignant tumors, excluding adequately treated non-melanoma skin cancer, cervical carcinoma in situ and thyroid papillary carcinoma;
5. Active autoimmune disease, history of autoimmune disease (such as interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes); It does not include autoimmune-mediated hypothyroidism treated with stable doses of thyroid replacement hormone; Type I diabetes on stable doses of insulin; Vitiligo or cured childhood asthma/allergy without any intervention in adulthood;
6. A history of immunodeficiency, including HIV positive, other acquired or congenital immunodeficiency diseases, or organ transplantation or allogeneic bone marrow transplantation;
7. Contraindications to antiangiogenic drugs (such as active bleeding, gastrointestinal bleeding, hemoptysis, etc.);
8. History of interstitial lung disease (excluding radiation pneumonitis without steroid treatment) and non-infectious pneumonia;
9. Patients with active pulmonary tuberculosis infection detected by medical history or CT examination, or with a history of active pulmonary tuberculosis infection within 1 year before enrollment, or with a history of active pulmonary tuberculosis infection more than 1 year before enrollment but without regular treatment;
10. The subject has active hepatitis B (HBV DNA ≥2000 IU/mL or 104 copies/mL), hepatitis C (hepatitis C antibody positive and HCV-RNA above the detection limit of the assay)
11. Severe cardiopulmonary and renal dysfunction;
12. Have hypertension that is not well controlled with antihypertensive medication (systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90mmHg);
13. A history of psychotropic substance abuse, alcohol or drug abuse;
14. Other factors that may affect subject safety or trial compliance as judged by the investigator. Severe medical conditions requiring concomitant treatment (including mental illness), serious laboratory abnormalities, or other family or social factors.

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: Everolimus in combination with PD-1; Patients will be treated with Everolimus and PD-1	Drug: Everolimus; Patients receive oral everolimus once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.; Drug: PD-1; 200mg intravenously every 3 weeks (Q3W), was administered until the occurrence of unacceptable toxic effects, or disease progression, withdrawal of consent, or withdrawal as judged by the investigator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
objective response rate (ORR)	The proportion of participants whose best outcome is complete remission or partial remission	2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
disease control rate (DCRs)	The proportion of patients without disease progression (PD).	2 year
advert events	Assessment of the safety profile of regimen according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v 5.0).	2 year
progression-free survival (PFS）	Time from initiation of treatment to disease progression or death from any cause.	2 year
overall survival (OS)	The time between the start of the participants' treatment and their death from any cause.	2 year

Collaborators and Investigators

• Sponsor: Fudan University
• Collaborators: Anyang Tumor Hospital
• Investigators: Principal Investigator: Dawei Li, PhD, Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: March 3, 2024
• First Submitted That Met QC Criteria: March 3, 2024
• First Posted (Actual): March 8, 2024

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 3, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: immunotherapy; mTOR inhibitor
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; MTOR Inhibitors; Everolimus
• Other Study ID Numbers: EVOLUTION

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No