X4P-001 and Pembrolizumab in Patients With Advanced Melanoma

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 melanoma, ccRCC, and ovarian cancer, and increased expression of CXCR4 on tumor
cells has been associated with significantly decreased overall patient survival.

In animal cancer models, interference with CXCR4 function has been demonstrated to disrupt
the tumor microenvironment (TME) and unmask the tumor to immune attack by multiple
mechanisms, including:

- Decreasing the infiltration of MDSCs

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

- Eliminating tumor re-vascularization

Pembrolizumab is a humanized IgG4 kappa monoclonal antibody that blocks the interaction
between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is currently approved for the
treatment of unresectable or metastatic melanoma. Analysis of tumor samples before and during
treatment in an earlier study demonstrated that a clinical response was associated with an
increase in the density of CD8+ T cells in the tumor parenchyma (center), while disease
progression was associated with persistent low levels of those cells. In an autochthonous
murine model of pancreatic adenocarcinoma, persistent tumor growth despite administration of
anti-PD-L1 was similarly associated with failure of tumor-specific cytotoxic T cells to enter
the TME despite their presence in the peripheral circulation. This immunosuppressed phenotype
was associated with CXCL12 production by cancer-associated fibroblasts. Moreover,
administration of a CXCR4 antagonist (AMD3100) induced rapid T-cell accumulation among the
cancer cells and, in combination with anti-PD-L1, synergistically decreased tumor growth.

Based on these observations, the hypothesis is that effective CXCR4 antagonism by X4P-001
would be of potential benefit in patients with advanced melanoma and other cancers by
multiple mechanisms, resulting in increased anti-tumor immune attack.

Inclusion Criteria:

To be eligible for this study, a patient must meet all of the following inclusion criteria:

1. Be at least 18 years of age.

2. Has signed the current approved informed consent form.

3. Has a histologically confirmed diagnosis of malignant melanoma.

4. Has at least two separate cutaneous lesions suitable for punch biopsies (at least 3 mm
diameter).

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

6. For women of childbearing potential, must have a negative pregnancy test (serum or
urine) on Day 1 prior to initiating study treatment, and are not nursing.

7. Be willing and able to comply with the schedule, treatment, and biopsies specified by
this protocol.

Exclusion Criteria:

Patients with any of the following will be excluded from participation in the study:

1. Has performance status Grade 2 or higher (Eastern Cooperative Oncology Group [ECOG]
criteria).

2. Has ongoing acute clinical adverse events NCI CTCAE Grade 2 or greater resulting from
prior cancer therapies (except alopecia).

3. 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): angina, congestive heart failure,
diabetes, seizure disorder.

4. Has had within the past 6 months the occurrence of one or more of the following
events: myocardial infarction, cerebrovascular accident, hemorrhage (CTC Grade 3 or
4), chronic liver disease (meeting criteria for Child-Pugh Class B or C), a second
active malignancy requiring ongoing treatment during the trial, organ transplantation.

5. 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

6. 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).

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

- Hemoglobin <9.0 g/dL

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

- Platelets <100,000/μL

- Creatinine >2.0x ULN

- Serum aspartate transaminase (AST) >3x ULN

- Serum alanine transaminase (ALT) >3x ULN

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

- International normalized ratio (INR) >1.5x ULN (unless on therapeutic
anti-coagulation).

8. Has been previously treated with approved or investigational immunotherapy including
oncolytic viruses, or agents directed at CTLA-4, PD-1, or PD-L1 ("checkpoint
inhibitors").

9. Has previously received other anti-cancer therapy within 2 weeks prior to Day 1,
including radiation therapy or chemotherapy. For investigational anti-cancer
therapies, the interval will be determined in consultation with the Medical Monitor.

10. Has, within 2 weeks prior to Day 1, been regularly taking a medication prohibited
based on CYP3A4 interaction.

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

12. 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.