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

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.


Eligibility Criteria:
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