A Phase (ph) 1 Dose Finding Study of X4P-001 (an Oral CXCR4 Inhibitor) and Axitinib in Patients with Advanced Renal Cell Carcinoma (RCC)

Background: X4P-001 is an oral, selective, allosteric inhibitor of the chemokine receptor CXCR4, and has been shown to down-regulate hypoxia inducible factor-2α (HIF-2α) and myeloid-derived suppressor cell (MDSC) trafficking in the tumor microenvironment. In multiple RCC xenograft models, the addition of X4P-001 to tyrosine kinase inhibitors (TKIs), including axitinib, increases the efficacy and delays the onset of TKI resistance. Methods: This is an ongoing phase 1/2 open-label study of X4P-001 in combination with axitinib in patients (pts) with histologically confirmed clear cell RCC who have received ³1 prior systemic therapy. The Ph1 portion of the study evaluates safety, tolerability, PK, PD and anti-tumor activity of the combination using a 3 + 3 dose escalation schema (escalating doses of X4P-001+ axitinib at 5 mg BID). Results: As of 27 April, 2017, sixteen (16) pts were enrolled in the Ph1 portion of the study. The median age was 64 years (range 50-76) and pts had received a median of 2 prior lines of therapy (range 1-5). The doses tested were 200 mg BID, 400 and 600 mg QD of X4P-001 + axitinib. Two doses limiting toxicities (DLTs) were observed at the X4P-001 600 mg QD dose level: one pt had multiple grade (G) 2 adverse events (AEs), including anorexia, cognitive disturbance, fatigue, nausea, vomiting, and somnolence; another pt had G3 dyspnea and fatigue. The MTD/RP2D was determined to be 400 mg QD of X4P-001 + axitinib. Treatment-related AEs (≥ 10%) of any grade were fatigue, diarrhea, hypertension, nausea, headache, anorexia, vomiting, dysphonia, proteinuria, dry eye, dry mouth, arthralgia, chest pain, cognitive disorder, dysgeusia, stomatitis, weight loss, and elevated creatinine. Treatment-related G3/4 AEs (≥ 10%) were fatigue and hypertension. In addition, one pt had SAE due to G2 diarrhea and G2 creatinine elevation. Of the 9 clinically evaluable pts, 3 had confirmed partial response, 5 had stable disease, and 1 had progressive disease. Median duration on treatment was 6.0 months (range 4.6-12.1). Conclusions: The combination treatment of X4P-001 and axitinib is well tolerated with preliminary evidence of clinical activity. The Ph2 portion of the study is ongoing. Clinical trial identification: NCT02667886 First received: January 20, 2016 Legal entity responsible for the study: X4 Pharmaceuticals Funding: X4 Pharmaceuticals Disclosure: D.F. McDermott: Paid consultant to Bristol-Myers Squib, Pfizer, Merck, Novartis, Eisai, Exelixis, Array BioPharm, Genentech BioOncology and receives research support from Prometheus S. Blanchette, L. Gan: Employee of X4 Pharmaceuticals. M.B. Atkins: Compensated consultant for Bristol-Myers Squibb, Merck, Roche, Pfizer, Novartis, Peleton, AstraZeneca, Nektar, Acceleron, Eisai and Exelixis and serve on Advisory Boards for X4 Pharma, Merck, Novartis, Roche, Pfizer, Galactone, Agenus and AVEO. All other authors have declared no conflicts of interest.