safety and efficacy of anlotinib in combination with irinotecan in patients with pretreated advanced colorectal cancer

Conditions: Colo-rectal Cancer

Summary: 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