Liposomal Irinotecan Plus Bevacizumab in Irinotecan-refractory Metastatic Colorectal Cancer

Liposomal Irinotecan Plus Bevacizumab in Irinotecan-refractory Metastatic Colorectal Cancer:a Multicenter, Phase I/II Trial.

To evaluate the efficacy and safety of liposomal irinotecan plus bevacizumab in irinotecan-refractory metastatic colorectal cancer

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Liposomal irinotecan; Drug: Bevacizumab

Detailed Description

The standard treatment regimen based on irinotecan with or without bevacizumab is commonly used in metastatic colorectal cancer. With administration of traditional irinotecan, the parent drug and active metabolite SN-38 exist in the form of active lactone and carboxylate, and the lactone ring structure is unstable in neutral and alkaline solutions. In physiological pH conditions, the active lactone rapidly hydrolyzes to the inactive carboxylate, thereby reducing the efficacy, so there is certain limitation in clinical application.

Liposomes Irinotecan load the active substance irinotecan into liposomes, so that it can be slowly released in the body and achieve the effect of reducing toxicity and increasing efficacy.After being rationally designed, irinotecan liposomes can also take advantage of the high permeability and retention effect (EPR) to specifically target the tumor area, increase the amount of drug taken up by cancer cells, reduce the dosage, improve efficacy, and reduce side effects.

We are currently conducting an Phase I/II study in mCRC patients who have previously received irinotecan. After determining the maximum tolerable dose (MTD) of irinotecan liposomes in the combined regimen of irinotecan liposomes and bevacizumab, we will further explore the safety and initial efficacy of irinotecan liposomes combined with bevacizumab.

• Study Type: Interventional
• Enrollment (Estimated): 74
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Yanhong Deng, PhD; Phone Number: 020-38379762; Email: dengyanh@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510655
      • The Sixth Affiliated Hospital of Sun Yat-Sen University
      • Contact: Yanghong Deng, Phd; Phone Number: 02038379762; Email: dengyanh@mail.sysu.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；
2. Histopathologically and/or cytologically confirmed unresectable metastatic colorectal adenocarcinoma；
3. Previous treatment with irinotecan , and have progression of disease during treatment or within three months thereafter；
4. At least one measurable lesion (according to RECIST v1.1)；
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 ~ 1；
6. The expected survival time ≥3 months；
7. Adequate bone marrow function : no blood transfusion and/or use of increasing leukocyte drugs (excluding oral medication) within 14 days prior to enrollment Absolute neutrophil count (ANC) ≥1.5×109/L Platelet count ≥100×109/L Hemoglobin (Hgb) ≥90 g/L；
8. Adequate hepatic function as evidenced by:

Total bilirubin ≤1.5 × upper limit of normal (ULN), Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN, ≤5 × ULN if liver metastases are present.

Serum albumin ≥30 g/L； (9Adequate renal function as evidenced by: serum creatinine (Cr) ≤1.5 × ULN or creatinine clearance ≥60 mL/min. proteinuria<2+（those with proteinuria ≥2+ at baseline had to demonstrate ≤1 g protein per 24 hours）； (10)Coagulation function: International normalised ratio (INR) ≤1.5, activated partial thromboplastin time (APTT) ≤1.5 × ULN； (11)Agree and be able to comply with the plan during the study period. Provide written informed consent before entering the study screening；

Exclusion Criteria:

1. Any other malignancy within 5 years, with the exception of cured in-situ carcinoma or basal cell carcinoma etc；
2. Patients with the primary lesion located in the left colon and RAS/BRAF wild-type who did not use cetuximab on the first-line；
3. Patients with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR)；
4. Massive pleural effusion or ascites requiring intervention；
5. Active, uncontrolled bacterial, viral, or fungal infections that require systemic treatment；
6. Active HIV infection；
7. Combined with uncontrollable systemic diseases within 6 months before the first administration；
8. Presence of severe gastrointestinal disease；
9. History of major surgery (such as laparotomy, thoracotomy or intestinal resection) within 28 days before the first administration,or plan to undergo major surgery during the study period；
10. Presence of interstitial pneumonia or pulmonary fibrosis；
11. History of allergy or hypersensitivity to drug or any of their excipients；
12. History of pulmonary hemorrhage/hemoptysis ≥Grade 2 (defined as bright red blood of at least 2.5mL) within one month before the first administration；
13. Presence of arterial embolism, severe bleeding (excluding bleeding caused by surgery) or tendency for existing embolism or severe bleeding within 6 months before the first administration；
14. Combined symptomatic brain metastasis, meningeal metastasis, spinal cord tumor invasion, and spinal cord compression syndrome；
15. Use of strong inhibitors or inducers of CYP3A, CYP2C8 and UGT1A1 within 14 days before the first administration；
16. Participate in other study and use study drug within 1 month or within 5 half-lives of the drug (whichever comes first) before the first administration；
17. Pregnant or breastfeeding women, or subjects of childbearing age who refuse contraception；
18. Patients who are not suitable to participate in this trial for any reason judged by the investigator；

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: Liposomal irinotecan plus bevacizumab; Patients received Liposomal irinotecan (a '3+3' design was adopted in the experimental arm, with 3 dose levels of 70mg/m2, 80mg/m2, and 90mg/m2 for dose exploration) every 2 weeks (Q2W). bevacizumab, 5mg/m2, every 2 weeks The two-drug combination therapy was continued every 2 weeks in a cycle until patients developed disease progression or met other criteria for termination of study treatment specified in the protocol.

Drug: Liposomal irinotecan; Liposomal irinotecan will be given biweekly at a dose from 70mg/m2 to 90mg/m2.; Drug: Bevacizumab; bevacizumab will be given biweekly at a dose of 5mg/m2; Other Names: avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) of liposomal irinotecan	Defined as the highest dose of DLT in<33% of subjects .	1 months
Objective Response Rate	Defined as the proportion of patients who achieved complete response (CR) and partial response (PR) according to RECIST v1.1.	5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-Limiting Toxicities (DLT) of liposomal irinotecan	Defined as adverse events that occur during the DLT observation period and are related to the study drug .	1 months
Disease Control Rate	Defined as the proportion of patients who achieved complete response (CR), partial response (PR), and stable disease (SD) according to RECIST v1.1.	5 months
Duration of Response	Defined as the time from response(when CR or PR is first diagnosed) to disease progression or death due to any cause.	5 months
Progression free Survival	Defined as the time between signing the informed consent form to the disease progression (according to RECIST v1.1 criteria) or death due to any cause.	1 years
Overall survival	Defined as the time between signing the informed consent form to death due to various causes.	1 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Investigators: Principal Investigator: Yanhong Deng, PhD, Sixth Affiliated Hospital, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Estimated): June 5, 2024
• Primary Completion (Estimated): June 5, 2025
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: May 23, 2024
• First Submitted That Met QC Criteria: May 23, 2024
• First Posted (Actual): May 30, 2024

Study Record Updates

• Last Update Posted (Actual): May 30, 2024
• Last Update Submitted That Met QC Criteria: May 23, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: bevacizumab; Liposomal irinotecan
• 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; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Topoisomerase I Inhibitors; Bevacizumab; Irinotecan
• Other Study ID Numbers: CSPC-DEY-CRC-K06

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