Irinotecan Plus Anlotinib or Further in Combination With Penpulimab for Second-line Treatment of mCRC

A Randomized, Uncontrolled, Exploratory Phase 2 Trial of Irinotecan Plus Anlotinib or Further in Combination With Penpulimab as Second-line Treatment of Metastatic Colorectal Cancer (ZL-IRIAN)

This is an exploratory, non-controlled, multi-cohort, phase II small-sample clinical study designed to evaluate the clinical benefit of second-line treatment with anlotinib plus irinotecan or further in combination with a PD-1 monoclonal antibody (penpulimab) in patients with advanced colorectal cancer after first-line treatment failure. To explore the rationality of the combination of chemotherapy and targeted therapy and immunotherapy strategy and obtain relevant survival and safety data. The study will fully evaluate the efficacy, PFS, OS, safety and related biomarkers of the regimen.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Anlotinib; Drug: Irinotecan; Drug: Penpulimab

Detailed Description

The design of this study is an open, non-controlled, multi-cohort, phase II, small-sample prospective clinical study, including eligible patients with metastatic colorectal cancer who received the second-line treatment, and two cohort were included, Cohort A received anlotinib and irinotecan chemotherapy (n=23), and the treatment of cohort B consisted of anlotinib and anti-PD-1 mab (penpulimab) plus irinotecan chemotherapy. Patients were firstly enrolled in cohort A, and if patients in cohort A achieved an response rate of no less than 15% (i.e., no less than 4 out of 23 patients receiving efficacy evaluation achieved CR/PR), the following patients would be enrolled in cohort B. If the response rate of patients in cohort A was less than 15%, subsequent cohort B enrollment (non-control) would be stopped.

A total of 46 patients enrolled in this study, actually.

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Chenchen Wang, M.D; Phone Number: +8613774232040; Email: wccnancy2003@aliyun.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Chenchen Wang, MD; Phone Number: +8613774232040; Email: wccnancy2003@aliyun.com
      • Principal Investigator: Weijian Guo, MD,PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Recurrent/metastatic colorectal adenocarcinoma confirmed by histopathological pathology report;
2. The patient received oxaliplatin in combination with fluorouracil as the first-line systemic therapy (with or without anti-EGFR mab or VEGF mab) and failed. Fluorouracil (5-FU, capecitabine, or S-1) and oxaliplatin must be included in the first-line regimens. Treatment failure was defined as: disease progression or intolerable toxicity occurred during treatment or within 3 months after the last treatment; Note: Early adjuvant/neoadjuvant therapy is permitted. If recurrence or metastasis occurs during adjuvant/neoadjuvant therapy or within 6 months after completion, adjuvant/neoadjuvant therapy is considered a failure of first-line chemotherapy for advanced disease;
3. With one or more measurable lesions, the longest diameter measured by spiral CT scan should be at least 10 mm, and the longest diameter measured by conventional CT scan should be at least 20 mm (RECIST standard, version 1.1);
4. the type of KRAS, NRAS, BRAF, and MSI were known, requiring wild type of BRAF. Cohort A required patients with MSS/pMMR status.
5. ECOG score was 0-1;
6. Life expectancy ≥12 weeks;
7. The patient has recovered from damage caused by other anti-tumor therapy, received cytotoxic drugs, radiotherapy or surgery for ≥4 weeks, and the wound has completely healed;
8. Bone marrow capacity and liver and kidney function were sufficiently reserved within 7 days before screening: absolute neutrophil (ANC) count ≥1.5x109 /L; Hemoglobin ≥ 8.0g/ dL; Platelet count ≥80 x109 /L; Total bilirubin < 1.5 times upper normal limit (ULN); ALT and AST< 2.5x ULN (with liver metastasis <5x ULN); Serum creatinine ≤1 x ULN, the clearance rate of endogenous creatinine >50ml/min;
9. Women of childbearing age should take effective contraceptive measures;
10. Subjects voluntarily joined the study and signed informed consent with good compliance and follow-up.

Exclusion Criteria:

1. A history of other malignant tumors within 5 years, except cured cervical carcinoma in situ or basal cell carcinoma of the skin;
2. Patients with hypertension that could not be controlled by antihypertensive medication (systolic blood pressure >140mmHg, diastolic blood pressure >90mmHg), coronary heart disease of grade I or above, arrhythmia of grade I or above (including prolonged QTc interval > 450ms in males and > 470 ms in females) and cardiac dysfunction of grade I or above;
3. Symptomatic brain or meningeal metastases (unless the patient was treated for >6 months, imaging results were negative within 4 weeks prior to study entry, and tumor-related clinical symptoms were stable at study entry); with a history of uncontrolled epileptic seizures, central nervous system dysfunction, or mental disorders;
4. Uncontrolled pleural or abdominal effusion;
5. Undergoing kidney dialysis;
6. severe or uncontrolled infection;
7. pregnant or lactating women who are fertile but have not taken adequate contraceptive measures;
8. Multiple factors affecting oral medication (inability to swallow, chronic diarrhea and intestinal obstruction);
9. Abnormal coagulation function (PT>16s, APTT>43s, TT>21s, Fbg< 2G /L), bleeding tendency or receiving thrombolytic or anticoagulant treatment; patients with gastrointestinal bleeding risk should not be enrolled, including the following conditions :(1) active peptic ulcer lesions and fecal occult blood (++); (2) patients with history of black stools and hematemesis within 3 months;
10. Prior exposure to any anti-PD-1 or anti-PD-L1, PD-L2, CD137, CTLA-4 antibody therapy, or any other antibody or drug that specifically targets T-cell costimulation or immune checkpoint pathways.
11. Former treatment of irinotecan for 1 or more cycles;
12. Prior exposure to any anti-VEGFR small molecule inhibitors (e.g. Apatinib, regorafenib, Fruquintinib, Anlotinib, etc.)
13. Participated in clinical trials of other drugs within four weeks
14. Urine routine examination indicated urine protein > 2+, or 24-hour urine protein quantification ≥1.0g/24h
15. Use of immunosuppressive agents within 4 weeks prior to the first dose of study therapy, excluding nasal, inhaled, or other topical or physiological doses of systemic glucocorticoids (i.e., no more than 10 mg/ d of prednisone or equivalent doses of other glucocorticoids), or hormone use for the prevention of contrast agent allergy.
16. Residual liver volume is less than 50% of the total liver volume. -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: cohort A; Anlotinib + Irinotecan: Anlotinib, 10mg, oral, once daily, D1-10, q2W; Irinotecan, 180mg/m2, iv drip, d6, q2w.	Drug: Anlotinib; Anlotinib 8mg or 10mg, d1-9，q2w; Drug: Irinotecan; Irinotecan 180mg/m2, d6, q2w
Experimental: cohort B; Anlotinib + Penpulimab + Irinotecan: Anlotinib, 8mg, oral, once daily, d1-10, q2w; Penpulimab 200mg, i.v. d6, q2w; Irinotecan, 180mg/m2, iv infusion, d6, q2w.	Drug: Anlotinib; Anlotinib 8mg or 10mg, d1-9，q2w; Drug: Irinotecan; Irinotecan 180mg/m2, d6, q2w; Drug: Penpulimab; Penpulimab 200mg, d6, q2w

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	objective response rate	the rate of patients with CR and PR, through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	overall survival	from the time signing of ICF until the date of death from any cause, assessed up to 36 months
PFS	progression free survival	from the time signing of ICF until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
DCR	disease control rate	the rate of patients with CR, PR and SD, through study completion, an average of 1 year
DoR	duration of response	the time between the first tumor evaluation for CR or PR and the first evaluation for PD(Progressive Disease) or death from any cause, assessed up to 36 months
AEs	the adverse events of all enrolled patients	the adverse events rate and types of all enrolled patients, through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Weijian Guo, M.D, Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2022
• Primary Completion (Estimated): May 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: January 25, 2022
• First Submitted That Met QC Criteria: February 6, 2022
• First Posted (Actual): February 8, 2022

Study Record Updates

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

More Information

Terms related to this study

• Keywords: metastatic colorectal cancer; target therapy; second-line treatment; enlotinib; penpulimab
• 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; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Irinotecan
• Other Study ID Numbers: ZL-IRIAN

Drug and device information, study documents

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