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

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to test different doses of X4P-001 given alone and in combination with axitinib in patients diagnosed with advanced renal cell carcinoma. The goals of the study are to determine the safety and tolerability of X4P-001, as well as the potential effect it may have on the body and the cancer tumor.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase 1/2 Trial of X4P-001 as Single Agent and in Combination With Axitinib in Patients With Advanced Renal Cell Carcinoma

Conditions
-----------------
Clear Cell Renal Cell Carcinoma

Intervention / Treatment
-----------------
* Drug: X4P-001
* Drug: axitinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>X4P-001 + axitinib dose escalation | Drug: X4P-001<br>* Continuous, oral, once-daily dosing<br>Drug: axitinib<br>* Continuous, oral, twice-daily dosing<br>* Other names: Inlyta;|
| Experimental: Part B<br>Randomized assignment to one of two regimens: X4P-001 at the Part A maximum tolerated dose (MTD), in combination with axitinib X4P-001 at 0.5x Part A MTD, in combination with axitinib | Drug: X4P-001<br>* Continuous, oral, once-daily dosing<br>Drug: axitinib<br>* Continuous, oral, twice-daily dosing<br>* Other names: Inlyta;|
| Experimental: Part C<br>X4P-001 monotherapy | Drug: X4P-001<br>* Continuous, oral, once-daily dosing<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (Safety and tolerability) | Safety assessments including vital signs, physical exams, laboratory tests, and adverse event monitoring | Up to 80 weeks, from time of enrollment through study completion or early termination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The treatment effect of X4P-001, as single agent and in combination with axitinib, will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to determine tumor response. | Up to 80 weeks, from time of enrollment through study completion or early termination | 
| Disease Control Rate | The treatment effect of X4P-001, as single agent and in combination with axitinib, will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to determine the disease control rate. | Up to 80 weeks, from time of enrollment through study completion or early termination | 
| Progression Free Survival | The treatment effect of X4P-001, as single agent and in combination with axitinib, will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to determine progression free survival time. | Up to 80 weeks, from time of enrollment through study completion or early termination | 
| Maximum Plasma Concentration (Cmax) | Cmax data will be collected to determine the pharmacokinetics of escalating dose levels of X4P-001 administered orally. | Up to 8 hrs post-dose | 
| Area Under the Curve (AUC) | AUC data will be collected to determine the pharmacokinetics of escalating dose levels of X4P-001 administered orally. | Up to 8 hrs post-dose | 
| Minimum Plasma Concentration (Cmin) | Cmin data will be collected to determine the pharmacokinetics of escalating dose levels of X4P-001 administered orally. | Up to 7 weeks |