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

Study Overview
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Brief Summary
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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.

Detailed Description
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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=20), 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 3 out of 20 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 44 patients were planned to be enrolled in this study. It is expected to start in February 2022, with recruitment ending in January 2023 and follow-up ending in January 2024.

Official Title
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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)

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Anlotinib
* Drug: Penpulimab
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recurrent/metastatic colorectal adenocarcinoma confirmed by histopathological pathology report; 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; 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); the type of KRAS, NRAS, BRAF, and MSI were known, requiring wild type of BRAF. Cohort A required patients with MSS/pMMR status. ECOG score was 0-1; Life expectancy ≥12 weeks; 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; 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; Women of childbearing age should take effective contraceptive measures; Subjects voluntarily joined the study and signed informed consent with good compliance and follow-up. Exclusion Criteria: A history of other malignant tumors within 5 years, except cured cervical carcinoma in situ or basal cell carcinoma of the skin; 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; 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; Uncontrolled pleural or abdominal effusion; Undergoing kidney dialysis; severe or uncontrolled infection; pregnant or lactating women who are fertile but have not taken adequate contraceptive measures; Multiple factors affecting oral medication (inability to swallow, chronic diarrhea and intestinal obstruction); 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; 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. Former treatment of irinotecan for 1 or more cycles; Prior exposure to any anti-VEGFR small molecule inhibitors (e.g. Apatinib, regorafenib, Fruquintinib, Anlotinib, etc.) Participated in clinical trials of other drugs within four weeks Urine routine examination indicated urine protein > 2+, or 24-hour urine protein quantification ≥1.0g/24h 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. Residual liver volume is less than 50% of the total liver volume. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients were first enrolled into cohort A, and when the efficacy of cohort A reached a certain percentage, the enrollment of cohort B started then.
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| OS | overall survival | from the time signing of ICF until the date of death from any cause, assessed up to 36 months | 
| 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 | 
| DCR | disease control rate | the rate of patients with CR, PR and SD, through study completion, an average of 1 year | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic colorectal cancer, second-line treatment, target therapy, enlotinib, penpulimab