Alternative Dosing for CRLX101(NLG207) Alone, With Avastin and With mFOLFOX6 in Advanced Solid Tumors

Exclusion Criteria

• •Subject has received:
• •* chemotherapy or small molecular targeted therapy \<2 weeks prior to W1D1
• •* approved antibody therapy \<5 half-lives from W1D1 (or 4 weeks since last therapy, whichever is the shortest)
• •* local palliative radiation \<14 days from W1D1
• •* invasive surgery requiring general anesthesia \<30 days from W1D1
• •* chemotherapy with nitrosoureas or mitomycin C \<45 days from W1D1
• •Uncontrolled grade 2 or greater toxicity except alopecia related to any prior treatment (i.e., chemotherapy, targeted therapy, radiation or surgery) within 7 days prior to W1D1 unless approved by the Medical Monitor
• •Prolongation of QT/QTc interval (QTc interval \>470) using the Fredericia method of QTc analysis
• •Women who are pregnant or nursing
• •Any known human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS) or any concurrent infection requiring IV antibiotics
• •Any known clinically significant or concurrent acute liver disease, including viral hepatitis
• •Primary brain malignant tumors
• •Subjects with uncontrolled symptomatic central nervous system (CNS) involvement
• •Subjects requiring steroids at stable dose (\>4 mg/day dexamethasone or equivalent) for at least 2 weeks
• •Uncontrolled hypertension \>150/100 mmHg
• •Concurrent participation in any other investigational therapeutic study, unless non-interventional study and approved by Sponsor
• •History of stroke, deep venous thrombosis (DVT), transient ischemic attack (TIA), unstable angina, or myocardial infarction within 3 months prior to W1D1
• •Uncontrolled concurrent disease or illness including but not limited to:
• •* symptomatic congestive heart failure (NYHA Class III or IV) per the NYHA Classification, unstable angina pectoris, clinically significant cardiac arrhythmia
• •* unstable or untreated cardiac conditions or ejection fraction of \<50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
• •* diabetes mellitus (i.e., fasting blood glucose \>220 despite acceptable chronic diabetes therapy)
• •* psychiatric illness that would limit compliance with study requirements, as determined by the Investigator
• •Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for the study.
• •Known hypersensitivity to any component of CRLX101 or excipient or documented medical condition that would prohibit adequate pre-medication with antihistamine.
• •Presence of ≥Grade 1 cystitis
• •Minor surgical procedure, excluding placement of a vascular access device, within 24 hours prior to W1D1.
• •Cardiovascular disease defined as congestive heart failure (NYHA Class II, III, or IV) per the NYHA Classification, angina pectoris requiring nitrate therapy, or myocardial infarction within the last 6 months prior to therapy
• •Uncontrolled hypertension (defined as the presence of systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg on two separate occasions. Blood pressure must be controlled to a systolic blood pressure \<150 mmHg and/or to diastolic blood pressure \<100 mmHg prior to study treatment), or any prior history of hypertensive crisis or hypertensive encephalopathy
• •Peripheral vascular disease \>Grade 1
• •Known congenital long QT syndrome, history of torsades de pointes or ventricular tachycardia.
• •Known history of pulmonary hypertension or non-infectious interstitial pneumonitis.
• •History or evidence of thrombotic or hemorrhagic disorders: including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA), intracerebral hemorrhage or sub- arachnoid hemorrhage ≤ 6 months prior to W1D1
• •Chronic daily aspirin \>325 mg/day or clopidogrel (\>75 mg/day)
• •History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization
• •Any of the following serious, non-healing conditions:wound, ulcer, or bone fracture
• •Proteinuria at screening as demonstrated by either: urine dipstick ≥2+ (subjects discovered to have a ≥2+ proteinuria on dipstick urinalysis at baseline should undergo 24-hour urine collection and must demonstrate \<1g of protein in 24 hours to be eligible): 24-hour urine collection demonstrates \>1g of protein in 24 hours
• •Immunocompromised subjects, including known seropositivity for human immunodeficiency virus (HIV), or current or chronic hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen \[HbsAg\] or antibody to hepatitis C virus \[anti HCV\] with confirmatory testing). \[Note: testing is not mandatory to be eligible for the study. However, if a subject is at risk for having undiagnosed hepatitis C virus (HCV) (due to history of injection drug use or due to geographic location for example), testing at screening should be considered\]
• •Chronic treatment with corticosteroids (prednisone \>12.5 mg/day or dexamethasone \>2 mg/day excluding inhaled steroids
• •Known hypersensitivity to 5FU, oxaliplatin or other platinum agent, or to their excipients
• •Known dihydropyridine dehydrogenase (DPD) enzyme deficiency (testing not required)
• •Baseline peripheral neuropathy grade ≥ 2
• •Progressive disease within ≤ 6 months of completing an oxaliplatin containing adjuvant therapy
• •Interstitial lung disease with ongoing signs and symptoms at the time of informed consent