Safety and Efficacy of Anlotinib in Combination With Irinotecan in Patients With Pretreated Advanced Colorectal Cancer

Study Overview
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Brief Summary
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Patients with pretreated advanced colorectal cancer are recruited to the phase I portion of this prospective non-randomised study in an escalated dose cohort. The primary endpoint of the dose-escalation phase is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of anlotinib when given in combination with irinotecan. The phase II (dose-expansion) portion is designed to characterize the safety and potential efficacy of the combination therapy in pretreated advanced colorectal cancer patients.

Official Title
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Safety and Efficacy of Irinotecan Combined With Anlotinib in Patients With Pretreated Advanced Colorectal Cancer

Conditions
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Colo-rectal Cancer

Intervention / Treatment
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* Drug: Anlotinib Hydrochloride with Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: willing and able to provide written informed consent and comply with the requirements of the study histologically- or cytologically-confirmed advanced colorectal cancer failed or intolerable to at least one prior therapy have evidence of measurable disease per RECIST v1.1 Eastern Collaborative Oncology Group (ECOG) Performance Status ≤ 1 weight ≥40kg life expectancy >12 weeks Exclusion Criteria: Subjects meeting any of the following criteria are ineligible for participation in the study: history of any anti-cancer therapy (including investigational agents) within 28 days prior to study entry presence of toxicity of prior anti-cancer therapy that has not resolved to Grade 1, as determined by National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 symptomatic brain metastasis requiring active treatment any previous malignancy, except for non squamous-cell carcinoma of skin or carcinoma-in-situ of the uterine cervix within 5 years prior to study entry active or clinically unstable infection requiring systemic therapy unable to swallow oral medications or with gastrointestinal disorders that might interfere with proper absorption of oral drugs active digestive ulcer disease, inflammatory bowel disease, intestinal obstruction or any other condition that, in the clinical judgment of the Principal Investigator, may cause severe gastrointestinal bleeding or perforation unstable pulmonary embolism, deep vein thrombosis, or other significant arterial/venous thromboembolic event ≤2 months prior to study entry history of stroke or transient ischemic attack (TIA) within 12 months prior to study entry any of the following abnormal findings in organ or marrow function 1 week prior to study entry: Leukocytes < 1.5*10^9/L, or Platelets < 100*10^9/L, or Hb< 90g/L Total bilirubin > 1.5 × institutional upper limit of normal (ULN), or AST (aspartate amino transferase)/ALT (alanine amino transferase)> 3 × institutional ULN for liver metastases, > 1.5 × institutional ULN in case of no liver metastases any electrolyte imbalance of clinical significance creatinine > institutional ULN and creatinine clearance < 60 mL/min spot urine protein ≥(2+) or 24-hour proteinuria ≥1.0g/24h APTT (activated partial thromboplastin time) or INR (international normalized ratio for prothrombin time) > 1.5 × institutional ULN treatment refractory hypertension defined as a blood pressure of systolic> 140 millimeter of mercury (mm Hg) and/or diastolic > 90 mm Hg which cannot be controlled by a single anti-hypertensive agent LVEF (left ventricular ejection fraction ) <50% history of acute coronary syndromes (including myocardial infarction and unstable angina), coronary artery bypass graft within 6 months prior to study entry, or history or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association (NYHA) present with non-healing fractures of bone or wounds of skin pregnant or lactating female sexually active female (of childbearing potential) or male unwilling to adopt an effective method of birth control during the course of the study serious and/or unstable pre-existing psychiatric disorder familial, sociological or geographical conditions that, in the clinical judgment of the Principal Investigator, do not permit compliance with the protocol known immediate or delayed hypersensitivity reaction to anlotinib, irinotecan or their excipients administration of irinotecan in prior treatments

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anlotinib plus Irinotecan<br> | Drug: Anlotinib Hydrochloride with Irinotecan<br>* Dose escalation of anlotinib starts from 8mg qd d1-14/q21d in combination with fixed dose of irinotecan at 180mg/m2 d1/q14d.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD | the maximum tolerated dose (MTD) of Anlotinib when administered in combination with fixed dose of irinotecan in advanced colorectal cancer patients. | 6 months | 
| ORR | the overall response rate (ORR) of Anlotinib when administered in combination with fixed dose of irinotecan in advanced colorectal cancer patients. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DCR | the disease control rate (DCR) of the combination of Anlotinib with Irinotecan in pretreated advanced colorectal cancer patients. | 18 months | 
| PFS | the progression free survival (PFS) of the combination of Anlotinib with Irinotecan in pretreated advanced colorectal cancer patients. | 18 months |