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

X4P-001 is an orally bioavailable C-X-C chemokine receptor type 4 (CXCR4) antagonist that has demonstrated activity in various tumor models. CXCR4 is the receptor for C-X-C chemokine ligand type 12 (CXCL12). CXCL12 has potent chemotactic activity for lymphocytes and myeloid-derived suppressor cells (MDSCs), 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 clear cell Renal Cell Carcinoma (ccRCC), ovarian cancer, and melanoma, and increased expression of CXCR4 on tumor cells has been associated with significantly decreased overall participant 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 cluster of differentiation 8+ (CD8+) T cells to T regulatory (Treg) cells

The hypothesis and evidence of published data support is that effective CXCR4 antagonism by X4P-001 would be of potential benefit in participants 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 participants with advanced ccRCC will evaluate X4P-001 both as a single agent (monotherapy) and also in combination with axitinib, a small molecule tyrosine kinase inhibitor (TKI) approved for second-line treatment of participants 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 ccRCC.
• Have received at least one prior course of treatment for ccRCC. Part C only: Prior treatment must include at least 1 course of vascular endothelial growth factor (VEGF)-directed therapy.
• Have on computed tomography (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 Response Evaluation Criteria in Solid Tumors (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 New York Heart Association (NYHA) Class III or IV heart failure or uncontrolled hypertension (systolic blood pressure [SBP] ≥160 millimeters of mercury [mm Hg]; diastolic blood pressure [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 mechanistic target of rapamycin (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 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade >1 resulting from prior cancer therapies (except alopecia, tyrosine kinase inhibitor [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 (for example, 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 grams (g)/deciliter (dL)
• Absolute neutrophil count (ANC) <1,500/microliter (μL)
• Platelets <75,000/μL
• Creatinine >2.0x upper limit of normal (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:
• TKI within 2 weeks.
• Radiation therapy within 2 weeks.
• Bevacizumab within 4 weeks.
• Other chemotherapy (for example, mitomycin-C, nitrosourea) or immunotherapy (for example, 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 cytochrome P3A4 (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 participant, or may preclude the participant's successful completion of the clinical trial.