Combining Anlotinib and Irinotecan for Advanced Colorectal Cancer Treatment

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 study is testing whether a combination of two cancer drugs, anlotinib and irinotecan, with an additional treatment called penpulimab, can help people with advanced colorectal cancer who haven't responded to other treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 44 (estimated)
• Ages: 18 Years to 85 Years
• Sex: All
• Sponsor: Fudan University (Academic / other)
• Drugs / interventions: Apatinib, Fruquintinib, Anlotinib, chemotherapy, prednisone, penpulimab, immunotherapy
• Locations: 1 site (Shanghai, Shanghai Municipality)
• Trial ID: NCT05229003 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effectiveness of a combination treatment involving anlotinib and irinotecan, with an additional focus on the use of the PD-1 monoclonal antibody penpulimab for patients with metastatic colorectal cancer who have not responded to first-line therapy. The study is designed as a phase II, open-label, non-controlled trial with two cohorts: one receiving the combination of anlotinib and irinotecan, and the other receiving the same combination plus penpulimab. The primary goal is to assess the clinical benefit, safety, progression-free survival (PFS), overall survival (OS), and relevant biomarkers associated with the treatment regimen. A total of 46 patients will be enrolled, with specific response rate criteria determining the continuation of patient enrollment in the second cohort.

Who should consider this trial

Good fit: Ideal candidates for this study are patients with recurrent or metastatic colorectal adenocarcinoma who have failed first-line treatment involving oxaliplatin and fluorouracil.

Not a fit: Patients who have not received prior treatment for colorectal cancer or those with early-stage disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with advanced colorectal cancer who have limited treatment choices after first-line therapy failure.

How similar studies have performed: While this approach combines established therapies, the specific combination of anlotinib, irinotecan, and penpulimab in this context is novel and has not been extensively tested in prior studies.

Eligibility criteria

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. -

Where this trial is running

Shanghai, Shanghai Municipality

• Fudan University Shanghai Cancer Center — Shanghai, Shanghai Municipality, China (Recruiting)

Study contacts

• Principal investigator: Weijian Guo, M.D — Fudan University
• Study coordinator: Chenchen Wang, M.D

Conditions Metastatic Colorectal Cancer; metastatic colorectal cancer; second-line treatment; target therapy; enlotinib; penpulimab