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

This is an open-label, dose escalation study. Subjects enrolled in Schedule 1 will receive
weekly CRLX101 alone. The starting dose for Schedule 1 is 12 mg/m^2 and the next dose level
is 15 mg/m^2 (or 10 mg/m^2 if 12 mg/m^2 is not well tolerated). No other dose levels in
Schedule 1 will be explored.

Subjects enrolled in Schedule 2 will receive weekly CRLX101 in combination with bi-weekly
bevacizumab (10 mg/kg) The starting dose for Schedule 2 is 12 mg/m^ and the next dose is 15
mg/m^2. No other dose levels in Schedule 2 will be explored

Subjects enrolled in Schedule 3 will receive weekly CRLX101 for 3 of every 4 weeks in
combination with bi-weekly mFOLFOX6 (oxaliplatin 85 mg/m^2, leucovorin 400 mg/m^2 and 5FU
(fluorouracil) 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous infusion). The starting
dose for Schedule 3 is 12 mg/m^2 and the next dose is 15 mg/m^2.

In the absence of dose-limiting toxicities (DLTs) additional subjects may be enrolled
(expansion cohort) at the same, intermediate or lower dose levels following consultation
between the Investigator and Sponsor.

Enrollment of 6-8 subjects will occur in each cohort for all 3 Schedules.

The MTD is defined as the highest dose level at which fewer than 2 out of 6 subjects
experience a DLT. RP2D will be selected based on overall tolerability data from all subjects
treated at different dose cohorts in this study.

No intra-patient dose escalation is allowed.

Approximately 61 evaluable subjects are anticipated to be enrolled: 15 subjects in Schedule
1, 15 subjects in Schedule 2 and approximately 31 subjects are anticipated in Schedule 3
(approximately 16 in the dose escalation cohort and up to 15 in the expansion cohort).

The exact number of subjects is dependent on the actual number of subjects enrolled per
cohort and the number of cohorts investigated.

Inclusion Criteria: (All Subjects)

- Male or female adult subjects ≥18 years of age

- Diagnosis of histologically or cytologically confirmed for:

- For Schedule 1 and 2: advanced solid tumor malignancy that is refractory to
standard therapy and/or for whom no further standard therapy is available

- For Schedule 3: advanced/metastatic tumors for which mFOLFOX6 is appropriate, or
advanced/metastatic tumors that may be sensitive to each component of mFOLFOX6 or
sensitive to topoisomerase 1 inhibitors including pancreatic, colorectal,
esophageal, gastric, bladder or ovarian cancer, triple-negative breast cancer,
small cell lung cancer (SCLC), cholangiocarcinoma, among others

- For Schedules 1 and 2: Eastern Cooperative Oncology Group (ECOG) Performance Status of
0 to 2, For Schedule 3: ECOG Performance Status of 0 or 1

- Life expectancy >12 weeks in the opinion of the Investigator

- Subjects with acceptable pre-study* hematology and biochemistry labs ≤3 days prior to
Week 1 Day 1 (W1D1) defined as:

- absolute neutrophil count (ANC) ≥1.500 cells / µL (1.5 x 10°/L, without growth
factor support

- platelet count ≥100,000 cells/µL (100 x 10° cells/L), without growth factor
support

- hemoglobin ≥9 g/dL (90/g/L)

- serum total bilirubin ≤1.5 upper limit of normal (ULN), unless Gilbert's disease

- alanine transaminase (ALT) or aspartate transaminase (AST) ≤2.5 x ULN, (5 x ULN
for subjects with liver metastases)

- calculated or measured creatinine clearance ≥40 mL/min

- NOTE: If screening hematology and biochemistry labs are performed ≤3 days
prior to W1D1, additional pre-study labs do not need to be repeated to
confirm eligibility. However, if screening hematology and biochemistry labs
are performed greater than 3 days prior to W1D1, additional pre-study labs
will need to be performed to confirm continued eligibility to ensure labs
remain acceptable per protocol

- Females of childbearing potential must agree to use two effective methods of
contraception (or abstain completely from heterosexual intercourse) from the time of
informed consent and for 30 days following last dose of study drug

- NOTE: Females of childbearing potential are defined as women physically capable
of becoming pregnant unless the female subject cannot have children due to
surgery or other medical reasons (effective tubal ligation, ovaries or the uterus
removed, or are post-menopausal). Fertile males of childbearing potential are
defined as men who are sexually capable to impregnate the female partner even if
surgically sterilized (i.e., vasectomy).

- highly effective methods of contraception include intra-uterine device (IUD)
and hormonal contraception (oral, injectable, patches or implant)

- effective methods of contraception include barrier methods (latex condom,
diaphragm with spermicide, cervical cap, sponge)

- when possible, subjects should be strongly encouraged to include at least
one highly effective method of contraception

- Male subjects must agree to use appropriate method of barrier contraception (latex
condom with a spermicidal agent) or abstain completely from heterosexual intercourse
fro the time of informed consent and for 120 days following last dose of study drug
unless female partner absolutely cannot have children because of surgery or for other
medical reasons

- Negative urine pregnancy test

- Ability to understand and willingness to sign a written informed consent form

- Able to comply with study visit schedule and assessments

Exclusion Criteria: (All Subjects)

- 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

Exclusion Criteria for Subjects Enrolled in Schedule 2 Only

- 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

Exclusion Criteria for Subjects Enrolled in Schedule 3 Only

- 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