Trial of X4P-001 in Patients With Advanced Renal Cell Carcinoma

X4P-001 is an orally bioavailable CXCR4 antagonist that has demonstrated activity in various
tumor models. CXCR4 (C-X-C chemokine receptor type 4) is the receptor for CXCL12 (C-X-C
chemokine ligand type 12). CXCL12 has potent chemotactic activity for lymphocytes and MDSCs
(myeloid-derived suppressor cells), and is important in homing of hematopoietic stem cells to
the bone marrow. CXCR4 is also expressed and active on multiple types of human cancers,
including ccRCC, ovarian cancer, and melanoma, and increased expression of CXCR4 on tumor
cells has been associated with significantly decreased overall patient survival.

Multiple observations implicate the CXCL12/CXCR4 axis in contributing to the lack (or loss)
of tumor responsiveness to angiogenesis inhibitors (also referred to as "angiogenic escape").
In animal cancer models, interference with CXCR4 function has been demonstrated to disrupt
the tumor microenvironment and unmask the tumor to immune attack by multiple mechanisms,
including:

- Eliminating tumor re-vascularization

- Decreasing the infiltration of MDSCs

- Increasing the ratio of CD8+ T cells to Treg cells

The hypothesis is that effective CXCR4 antagonism by X4P-001 would be of potential benefit in
patients with advanced ccRCC and other cancers by multiple mechanisms:

- Decreased recruitment of MDSCs, resulting in increased anti-tumor immune attack

- Sustained decrease in neoangiogenesis and tumor vascular supply

- Interference with the autocrine effect of increased expression by ccRCC of both CXCR4
and CXCL12, its only ligand, thereby, potentially reducing cancer cell metastasis

This initial clinical trial in patients with advanced ccRCC will evaluate X4P-001 both as a
single agent (monotherapy) and also in combination with axitinib, a small molecule TKI
(tyrosine kinase inhibitor) approved for second-line treatment of patients with ccRCC. This
combination has the potential to further improve outcomes by reducing the angiogenic escape
that typically occurs with TKI therapy.

Inclusion Criteria:

- Have a histologically confirmed diagnosis of predominant clear cell (conventional)
Renal Cell Carcinoma (ccRCC).

- Have received at least one prior course of treatment for ccRCC. Part C only: Prior
treatment must include at least 1 course of VEGF-directed therapy.

- Have on CT imaging done within 28 days of Day 1 findings consistent with advanced
ccRCC, including at least one extra-renal measurable target lesion meeting the
criteria of RECIST version 1.1.

- For women of childbearing potential and men, agree to use effective contraceptive
methods from screening, through the study, and for at least 4 weeks after the last
dose of study drug.

- For women of childbearing potential, have a negative pregnancy test (serum or urine)
on Day 1 prior to initiating study treatment.

- Be willing and able to comply with the protocol

Exclusion Criteria:

- Has life expectancy of less than 3 months.

- Has performance status Grade >2 (Eastern Cooperative Oncology Group [ECOG] criteria).

- Has NYHA Class III or IV heart failure or uncontrolled hypertension (SBP ≥160 mm Hg;
DBP ≥100 mm Hg).

- Has previously received X4P-001.

- Parts A and B only: Has received a prior course of axitinib.

- Parts A and B only: Has received mTOR inhibitor(s) as their only prior treatment for
ccRCC.

- Has a prior history or current evidence of intracranial (CNS) metastatic RCC, except
for

≤3 lesions treated by CyberKnife or excisional surgery, clinically stable for at least
4 weeks, and without evidence of recurrence on MRI imaging at screening.

- Has ongoing acute clinical adverse events NCI CTCAE Grade >1 resulting from prior
cancer therapies (except alopecia, TKI-related hand-foot syndrome, or thyroid
dysfunction).

- Has had within the past 6 months the occurrence or persistence of one or more of the
following medical conditions that could not be controlled with usual medical care
(e.g., required emergency care or hospitalization): hypertension, angina, congestive
heart failure, diabetes, seizure disorder.

- Has had within the past 6 months the occurrence of one or more of the following
events: myocardial infarction, cerebrovascular accident, deep vein thrombosis,
pulmonary embolism, hemorrhage (CTC Grade 3 or 4), chronic liver disease (meeting
criteria for Child-Pugh Class B or C), a second active malignancy (excluding basal
cell carcinoma and cervical carcinoma in situ), organ transplantation.

- Has had within the 4 weeks prior to initiation of study drug, or is expected to have
during the study period, surgery requiring general anesthesia.

- Has, at screening, serologic laboratory tests meeting one or more of the following
criteria:

- An indeterminate or positive test for antibody to human immunodeficiency virus (HIV-1
or -2).

- An indeterminate or positive test for antibody to hepatitis C virus (HCV), unless
documented to have no detectable viral load on two independent samples.

- A positive test for hepatitis B surface antigen (HBsAg).

- Has, at screening, safety laboratory tests meeting one or more of the following
criteria:

- Hemoglobin <8.0 g/dL

- Absolute neutrophil count (ANC) <1,500/μL

- Platelets <75,000/μL

- Creatinine >2.0x ULN

- Serum aspartate transaminase (AST) >2.5x ULN

- Serum alanine transaminase (ALT) >2.5x ULN

- Total bilirubin >1.5x ULN (unless due to Gilbert's Syndrome)

- International normalized ratio (INR) >1.5x ULN

- Has received other anti-cancer therapy within the following specified intervals prior
to Day 1:

- Tyrosine Kinase Inhibitor (TKI) within 2 weeks.

- Radiation therapy within 2 weeks.

- Bevacizumab within 4 weeks.

- Other chemotherapy (e.g., mitomycin-C, nitrosourea) or immunotherapy (e.g., antibody,
cytokine) within 4 weeks

- For investigational anti-cancer therapies, the interval will be determined in
consultation with the Medical Monitor.

- Has, within 2 weeks prior to Day 1, received a medication prohibited based on CYP3A4
interaction

- Has, within 2 weeks prior to Day 1, received systemic corticosteroids exceeding
prednisone 10 mg per day or equivalent; for other immunosuppressive agents, the
exclusionary dose and duration will be determined in consultation with the Medical
Monitor.

- Is, within 2 weeks prior to Day 1, nursing.

- Has, at the planned initiation of study drug, an uncontrolled infection.

- Has any other medical or personal condition that, in the opinion of the Investigator,
may potentially compromise the safety or compliance of the patient, or may preclude
the patient's successful completion of the clinical trial.