Safety and Efficacy Study of Chemotherapy Plus Apatinib as Second-line Therapy in Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of apatinib in combination with second-line FOLFOX or FOLFIRI for metastatic colorectal cancer in patients with disease progression during or after first-line therapy.

Detailed Description
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Angiogenesis is an important therapeutic target in metastatic colorectal carcinoma. Apatinib is a potent oral inhibitor of the intracellular domain and emerging as original antiangiogenic opportunities. We assessed the efficacy and safety of apatinib in combination with second-line FOLFOX or FOLFIRI for metastatic colorectal cancer in patients with disease progression during or after first-line therapy.

Official Title
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Study Evaluating the Safety and Efficacy of FOLFOX Plus Apatinib or FOLFIRI Plus Apatinib as Second-line Therapy in Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer, Chemotherapy, Angiogenesis

Intervention / Treatment
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* Drug: Chemotherapy + Apatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed inoperable colorectal adenocarcinoma excluding vermiform appendix cancer and anal canal cancer Age ≥18 years at the time of informed consent ECOG performance status (PS) of 0-1 Written informed consent prior to study-specific screening procedures Life expectancy of at least 90 days Withdrawal from first-line chemotherapy (regardless of containing molecular-targeted drugs) for metastatic colorectal cancer due to intolerable toxicity or progressive disease, or relapse within 180 days after the last dose of adjuvant chemotherapy Adequate organ function according to following laboratory values obtained within 14 days before enrolment (excluding patients who received blood transfusions or hematopoietic growth factors within 14 days before the laboratory test) Neutrophil count: ≥1500/mm3 Platelet count: ≥10.0 x 104/mm3 Hemoglobin: ≥9.0 g/dL Total bilirubin: ≤1.5 mg/dL AST, ALT: ≤100 IU/L (≤200 IU/I if liver metastases present) Serum creatinine: ≤1.5 mg/dL Measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) Adequate coagulation function [International Normalized Ratio (INR) ≤1.5 and Partial Thromboplastin Time (PTT) or activated PTT (aPTT) ≤1.5 x upper limit of normal (ULN)). Participants on full-dose anticoagulation must be on a stable dose of anticoagulant therapy and if on oral anticoagulation, must have an INR ≤3 and have no clinically significant active bleeding or pathological condition that carries a high risk of bleeding Consent to provide a historical colorectal cancer tissue sample for assessment of biomarkers and the tumor tissue sample is available Ability to provide signed informed consent Exclusion Criteria: History of other malignancy with a disease-free interval <5 years (other than curatively treated cutaneous basal cell carcinoma, curatively treated carcinoma in situ of the cervix, and gastroenterological cancer confirmed to be cured by endoscopic mucosal resection) With massive pleural effusion or ascites requiring intervention Radiological evidence of brain tumor or brain metastases Active infection including hepatitis Any of the following complication: i) Gastrointestinal bleeding or gastrointestinal obstruction (including paralytic ileus) ii) Symptomatic heart disease (including unstable angina, myocardial infarction, and heart failure) iii) Interstitial pneumonia or pulmonary fibrosis iv) Uncontrolled diabetes mellitus v) Uncontrolled diarrhea (that interferes with daily activities despite adequate therapy) Any of the following medical history: Myocardial infarction: History of one episode within one year before enrollment or two or more lifetime episodes i) Serious hypersensitivity to any of the study drugs ii) History of adverse reaction to fluoropyrimidines suggesting dihydropyrimidine dehydrogenase (DPD) deficiency Pregnant or lactating females, and males and females unwilling to use contraception Psychiatric disability that would preclude study compliance Otherwise determined by the investigator to be unsuitable for participation in the study Concurrent gastrointestinal perforation or history of gastrointestinal perforation with 1 year before enrollment History of pulmonary hemorrhage/hemoptysis ≥ Grade 2 (defined as bright red blood of at least 2.5mL) within 1 month prior to enrollment. History of laparotomy, thoracotomy, or intestinal resection within 28 days before enrollment Unhealed wound (except suture wounds from implantation of a central venous port), gastrointestinal ulcer, or traumatic fracture Current or recent (within 1 year) thromboembolism or cerebrovascular disease Currently receiving or requires anticoagulation therapy (> 325 mg/day of aspirin) Bleeding diathesis, coagulopathy, or coagulation factor abnormality (INR ≥1.5 within 14 days before enrollment) Uncontrolled hypertension Urine dipstick for proteinuria >+2

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: Chemotherapy + Apatinib<br>chemotherapy regimens include: Folfox (Oxaplatin 85 mg/m2 IV over 2 hours, day 1; Leucovorin 400 mg/m2 over 2 hours, day 1; 5-FU 400 mg/m2 IV bolus on day 1, then 1200mg/m2/day x 2 days; repeat every 2 weeks) or Folfiri (Irinotecan 150-180 mg/m2 IV over 30-90 minutes, day 1; Leucovorin 400 mg/m2 over 2 hours, day 1; 5-FU 400 mg/m2 IV bolus on day 1, then 1200mg/m2/day x 2 days; repeat every 2 weeks)； apatinib 500mg po qd | Drug: Chemotherapy + Apatinib<br>* chemotherapy regimens could be folfox or folfiri; apatinib 500mg po qd<br>* Other names: chemotherpy plus apatinib mesylate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Time | PFS was defined as the time from the date of randomization until the date of objectively determined progressive disease (PD) [according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1] or death due to any cause, whichever was first. PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). Participants who died without a reported prior progression were considered to have progressed on the day of their death. Participants who did not progress or were lost to follow-up were censored at the day of their last radiographic tumor assessment. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving an Objective Response (Objective Response Rate) | The objective response rate is equal to the proportion of participants achieving a best overall response of partial response or complete response (PR + CR). Response was defined using RECIST, v. 1.1 criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and normalization of tumor marker level of non-target lesions; PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions taking as reference the baseline sum diameter. | 1 year | 
| Overall Survival (OS) | OS was defined as the time in months from the date of randomization to the date of death from any cause. For participants not known to have died as of the cut-off date, OS was censored at the last known date alive. | 2 years |