CRLX101 in Combination With Bevacizumab for Metastatic Renal Cell Carcinoma (mRCC) Versus Standard of Care (SOC)

Open-label, randomized, controlled study in patients with metastatic RCC (mRCC) who have
completed 2 or 3 prior conventional molecularly targeted therapy regimens (i.e. lines)
including ≥ 1 VEGF-inhibiting therapies.

A total of 110 patients with 55 per treatment arm will be recruited from up to 40 clinical
sites.

Subjects will be randomized to either CRLX101 in combination with bevacizumab (CRLX101 15
mg/m^2 IV on days 1 and 15 of a 28-day cycle; in combination with bevacizumab 10 mg/kg IV on
days 1 and 15 of 28-day cycle) or standard of care (SOC).

Options for SOC treatment include the following agents to which the patient can have no
prior exposure: sorafenib; everolimus; pazopanib; axitinib; bevacizumab; sunitinib, or other
approved drug considered by the Medical Monitor to represent an acceptable standard of care
therapy.

Measurable disease will be assessed every 8 weeks (i.e. every 2 cycles). Study treatment,
for both investigational and reference therapy, will continue until confirmed disease
progression. Duration of study treatment on average is expected to be up to 6 months.

Other reasons for discontinuation of treatment may include Investigator determination of
clinical progression without CT-Scan confirmation, patient withdrawal, unresolved adverse
event, unacceptable toxicity, Investigator decision in consultation with the patient, death,
Sponsor determination due to protocol violation, or Sponsor decision to close the study.

Cross-over treatment will not be permitted on-study for either assigned treatment arm.

Bevacizumab has been chosen as a combination partner with CRLX101 for a number of reasons.

- Bevacizumab has proven activity in the treatment of patients with renal cell carcinoma.

- Bevacizumab has been successfully combined with many chemotherapy partners including
the topoisomerase-1 inhibitor irinotecan.

- It has been hypothesized that the combination of bevacizumab with CRLX101 may have
unique clinical activity in combination in the treatment of this disease due to the
simultaneous inhibition of distinct steps along the ~vHL ┐ HIF → (CAIX) → VEGF → VEGFR2
pathway

Primary Objective:

To assess progression free survival (PFS) in patients with metastatic renal cell carcinoma
(mRCC) treated with CRLX101 in combination with bevacizumab (CRLX101+bevacizumab) vs.
standard of care (SOC) per investigator's choice. This primary endpoint will be evaluated
according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.

Secondary Objectives

- To assess overall safety and tolerability of CRLX101+ bevacizumab compared to SOC.

- To assess overall survival (OS) of CRLX101+bevacizumab compared to SOC.

- To assess overall response rate (ORR) of CRLX101+bevacizumab compared to SOC.

- To assess overall PFS, OS, and ORR among patients with clear cell RCC treated with
CRLX101+bevacizumab compared to SOC.

- To assess overall PFS, OS, and ORR among patients with non-clear cell RCC treated with
CRLX101+bevacizumab compared to SOC.

- To describe the pharmacokinetics (PK) of CRLX101 when administered in combination with
bevacizumab.

Exploratory Objectives

- To analyze tumor tissue samples for biomarkers of efficacy in the CRLX101+bevacizumab
treatment group.

- To analyze plasma samples for biomarkers of efficacy before and during treatment and
correlate with efficacy outcomes for CRLX101+bevacizumab compared to SOC treatment
groups.

- To evaluate the pharmacokinetics (PK) of CRLX101 in urine over time when administered
in combination with bevacizumab in patients with and without non-infective cystitis.

Inclusion Criteria:

- Must have histologically confirmed renal cell carcinoma of any pathologic subtype.

- Must have unresectable metastatic disease, and have tumor(s) present that is (are)
evaluable by the RECIST, v1.1; may have spinal-associated metastases but must have
concluded dexamethasone therapy and be evaluated by the Investigator to have stable
CNS disease.

- Must have received 2 or 3 prior lines of conventional molecularly targeted therapy

- Must have full recovery from any toxicities from prior therapy CTCAE Grade 1 or less
with the exception of Grade 2 alopecia) prior to randomization.

- ECOG performance status 0 or 1.

- Age 18 years and older.

- Life expectancy of at least 3 months.

- Must have normal organ and marrow function reported within 14 days prior to
randomization

- Ability to understand and willingness to sign a written informed consent document.

- Able to comply with study visit schedule and assessments.

Exclusion Criteria:

- Any conventional molecularly targeted therapy within 2 weeks or, chemotherapy or
radiotherapy within 2 weeks (local) or 4 weeks (systemic) prior to entering the
study.

- Failure to recover to grade 1 or less all prior adverse events.

- Any major surgery within 4 weeks of study randomization.

- Any prior treatment with topoisomerase I therapy.

- Prior treatment with any drugs or therapies that will be administered during the
course of this trial including CRLX101, any topoisomerase 1 inhibitor, bevacizumab or
the conventional molecularly targeted agent intended for use as standard of care
treatment.

- Patients receiving any other current investigational therapeutic agent.

- Other active malignancies

- Patients with brain metastasis treated or untreated, or other CNS disease

- Any clinically significant cardiac disease defined as NYHA class III or IV.

- Uncontrolled hypertension

- Uncontrolled concurrent illness

- History of non-healing wounds or ulcers.

- Pregnancy, or inadequate contraception for men or women of childbearing age, or
lactating / breast-feeding

- Patients with known HIV or with solid organ transplant