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.

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