| Eligibility |
Inclusion Criteria:
1. 18 years of age or older
2. Histologically or cytologically confirmed metastatic or recurrent colorectal cancers
3. The primary tumor must have been resected > 3 months prior to planned C1D1.
4. Patients who experienced progressive disease or relapse after receiving two or three
prior lines of systemic therapy in the locally advanced or metastatic setting. Prior
lines of systemic treatment must have included at least one fluoropyrimidine,
oxaliplatin, irinotecan, and bevacizumab containing chemotherapy regimen (in any
combination and may have been administered in the neoadjuvant setting).
1. Patients whose tumor is not right sided and RAS wild type must also have received
an anti-epidermal growth factor receptor (EGFR) therapy.
2. Patients with tumors harboring mutations or other alterations for which there are
available targeted therapies (e.g. BRAF V600E, HER2-positive, MSI-H/dMMR, etc.)
must have also received the relevant approved targeted therapies.
3. If patient received peri-operative treatment (neoadjuvant and/or adjuvant),
please consult the Sponsor Medical Monitor for review of prior treatment lines.
5. At least one lesion measurable as defined by RECIST v1.1
6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
7. Predicted life expectancy of at least 12 weeks
8. Adequate hepatic and renal function within 14 days of C1D1 as described below:
1. Total bilirubin = 1.5 X upper limit of normal (ULN)
2. Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) = 3.0 X ULN (=
5x ULN in case of hepatic metastasis)
3. Estimated creatinine clearance = 30 mL/min based on Cockcroft-Gault estimated
creatinine clearance
4. Urine protein = 1+ by spot urinalysis (or, if > 1+ then 24 hr urine protein <1.0
g/24 hr)
9. Female patients who are women of childbearing potential (WCBP) must have a negative
pregnancy test (serum-human chorionic gonadotropin [hCG] or urine-hCG) at Screening
within 14 days of C1D1
10. Female patients must be surgically sterile (or have a monogamous partner who is
surgically sterile) or be at least 2 years postmenopausal or commit to use 2
acceptable forms of birth control (defined as the use of an intrauterine device (IUD),
a barrier method with spermicide, condoms, any form of hormonal contraceptives, or
abstinence) for the duration of the study and for 4 months following the last dose of
study treatment. Male patients must be sterile (biologically or surgically) or commit
to the use of a reliable method of birth control (condoms with spermicide) for the
duration of the study and for 4 months following the last dose of study treatment
11. Signed and dated Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
approved Informed Consent Form (ICF) before any protocol-directed screening procedures
are performed
Exclusion Criteria:
1. From the time point of signed informed consent,
1. Less than 4 weeks have elapsed since patients had a surgery or major procedure
2. Less than 2 weeks have elapsed from the last treatment date since patients had
any radiation therapy
2. Prior to planned C1D1,
1. Less than 4 weeks have elapsed since patients had chemotherapy or targeted
therapy for colorectal cancer
2. Less than 4 weeks have elapsed since patients had anticancer immunotherapy or
investigational drug treatment
3. A history of the following cardiovascular diseases in past 5 years may be
exclusionary, as determined by the Sponsor Medical Monitor:
1. Congestive heart failure that corresponds to Class II or a higher class under New
York Heart Association (NYHA) classification or less than 50% of left ventricular
ejection fraction (LVEF)
2. Uncontrolled hypertension (systolic blood pressure [SBP]/diastolic blood pressure
[DBP] > 140/90 mmHg) (e.g., patient with SBP/DBP > 140/90 mmHg despite the best
care including anti-hypertensive medications)
3. Patients with a history of hypertensive crisis or pre-existing hypertensive
encephalopathy
4. Pulmonary hypertension
5. Myocardial infarction
6. Uncontrolled arrhythmia
7. Unstable angina
8. Patients with any significant vascular diseases (e.g., aortic aneurysm requiring
surgery or recent peripheral artery thrombosis) within 6 months prior to the
initial treatment of the investigational product
4. Symptomatic or uncontrolled central nervous system (CNS) metastasis (However, patients
with asymptomatic CNS metastasis can participate provided that systemic corticosteroid
treatment was discontinued at least 4 weeks prior to screening and that the patient is
radiologically and neurologically stable or improving)
5. A history of the following hemorrhage-related or gastroenterological disease:
1. Active hemorrhage, hemorrhagic diathesis, coagulopathy or tumor invasion into
great arteries
2. History of clinically significant and active (within 6 months)
gastroenterological disease, such as peptic ulcer, gastrointestinal (GI)
bleeding, GI or non-GI fistula, perforation, abdominal abscess, clinical symptoms
and signs of GI obstruction, need for parenteral hydration or nutrition, or
inflammatory bowel disease.
6. Patients who received antiplatelet drugs (aspirin, clopidogrel, etc.) or anticoagulant
drugs (warfarin, heparin, direct thrombin inhibitors, etc.) within 2 weeks prior to
C1D1, or are expected to need those drugs during the clinical study.
7. Patients requiring continuous treatment with systemic non-steroidal anti-inflammatory
drugs (NSAIDs) or systemic corticosteroids (the following cases are permitted):
1. NSAIDs: Up to 3 consecutive days' use is permitted
2. Corticosteroids: Topical use of corticosteroid, such as topical intra-articular
injection, intranasal administration, eye drops, inhaler, etc., or temporary
systemic corticosteroid use for treatment and prevention of patient's contrast
media allergy, or adverse event, is permitted
8. Severe infection requiring systemic antibiotics, antivirus drugs, etc., or other
uncontrolled acute active infectious diseases
9. Patients with evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection. Inactive hepatitis B carriers who tested HBsAg positive may enroll provided
that the patient's liver function values are normal. Also, patients with chronic HBV
infection which has been controlled by the site's treatment guideline may enroll. HCV
patients showing sustained viral response or patients with immunity to HBV infection
may enroll
10. Patients with other severe diseases or uncontrolled illnesses that warrant the
exclusion from the study (permitted only if medically controlled) including but not
limited to:
1. Pre-existing hemoptysis (= 1/2 teaspoon of bright red blood per episode) within
28 days prior to screening
2. Major, unhealed injury, active ulcer or untreated fracture
3. History of cerebrovascular incident (ischemic or hemorrhagic stroke), transient
ischemic attack or subarachnoid hemorrhage within 6 months prior to screening
4. Moderate to severe ascites and/or pleural effusion
11. Clinically significant abnormal electrocardiography (ECG) findings or history
determined as clinically significant by the Investigator
12. QT interval (Fridericia's formula) (QTcF) interval > 450 msec at the time of screening
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