Evaluation of Safety, Tolerability, PK & PD of Intravenous VX15/2503 in Patients With Advanced Solid Tumors

• Safety/tolerability as measured by number of patients with adverse events [ Time Frame: Up to one (1) year ] [ Designated as safety issue: Yes ]
  Subject incidence of treatment-emergent adverse events
• Maximum tolerated dose as measured by frequency of dose limiting toxicities [ Time Frame: Six (6) weeks ] [ Designated as safety issue: Yes ]

• Peak plasma concentration (Cmax) of VX15/2503 [ Time Frame: 0,1,4,8,24,48,96,148,240 and 336 hours after start of infusion ] [ Designated as safety issue: No ]
• Area under the plasma concentration versus time curve (AUC) of VX15/2503 [ Time Frame: 0,1,4,8,24,48,96,148,240 and 336 hours after start of infusion ] [ Designated as safety issue: No ]
• Half-life of VX15/2503 [ Time Frame: 0,1,4,8,24,48,96,148,240 and 336 hours after start of infusion ] [ Designated as safety issue: No ]

• Pharmacokinetics as measured by Cmax, CL, Vd, Vss and AUCs [ Time Frame: 0,1,4,8,24,48,96,148,240 and 336 hours after start of infusion ] [ Designated as safety issue: No ]
• Pharmacodynamics as measured by SEMA4D T cell saturation [ Time Frame: 0,1,4,8,24,48,96,148, 240 and 336 hours after start of infusion ] [ Designated as safety issue: No ]
• Immunogenicity as measured by number of patients who develop anti-drug antibody [ Time Frame: Up to one (1) year ] [ Designated as safety issue: No ]

• SEMA4D T cell percent saturation of VX15/2503 [ Time Frame: 0,1,4,8,24,48,96,148,240 and 336 hours after start of infusion ] [ Designated as safety issue: No ]
• Number of patients who develop anti-drug antibody [ Time Frame: Up to one (1) year ] [ Designated as safety issue: No ]
• Overall response rate (ORR) using RECIST 1.1 [ Time Frame: Up to one (1) year ] [ Designated as safety issue: No ]
• Progression-free survival (PFS) using RECIST 1.1 [ Time Frame: Up to one (1) year ] [ Designated as safety issue: No ]

The purpose of this study is to evaluate the safety and tolerability of IV administration of VX15/2503 in patients with advanced solid tumors. The escalation part of the study will determine the maximum tolerated dose (MTD).

VX15/2503-01 is a dose-escalation, open label study to evaluate the safety and tolerability of IV administered VX15/2503 in patients with advanced solid tumors. This will be accomplished by using a dose escalation procedure starting at low doses of VX15/2503 and will continue based on predefined parameters until the maximum tolerated dose is identified.

The study drug, VX15/2503, is a monoclonal antibody that binds to the semaphorin 4D (SEMA4D; CD100) antigen. Semaphorins have been shown to play an important role in certain physiological processes such as vascular growth, tumor progression and immune cell regulation. Experimental evidence suggests that SEMA4D has two mechanisms of action that result in angiogenesis and tumor proliferation and invasion. Antibody neutralization of SEMA4D thus may represent a new therapeutic strategy for cancer treatment.

Main Inclusion Criteria:

• Patients 18 yrs or older with confirmed histological or cytological advanced solid tumors, relapsed or refractory to standard treatment for which no curative therapy is available
• Has disease activity that can be monitored by imaging or tumor biomarker measurement
• Life expectancy of at least 3 months (per investigator assessment)
• ECOG performance status of 0-2
• Adequate bone marrow, renal and liver function
• Recovered from any significant prior toxicity of previous anti-neoplastic therapy
• For patients of reproductive potential, is willing to use a medically acceptable form of contraception throughout the study period and for at least 4 weeks after the last dose of VX15/2503

Main Exclusion Criteria:

• Treatment with anti-neoplastic agents (chemotherapy, immunotherapy, radiotherapy or endocrine therapy) within 3 weeks prior to start of study treatment
• Treatment with an investigational agent within 4 weeks prior to start of study treatment
• Is on concurrent anti-neoplastic therapy with the exception of continuing luteinizing hormone-releasing hormone agonist/antagonist therapy for patients with castrate-resistant prostate cancer
• Treatment with oral or parenteral corticosteroids in excess of 10mg/day of prednisolone or equivalent for more than 5 days within 4 weeks prior to start of study treatment or a requirement for systemic immunosuppressive therapy for any reason
• Untreated brain Mets or CNS tumor involvement
• Any other intercurrent illness or condition which could impact patient compliance or ability to complete the study
• Sensitivity to VX15/2503 or the ingredients or excipients of VX15/2503
• Pregnant or breast-feeding women (women of child-bearing potential must have negative serum pregnancy test within 3 days prior to receiving the first dose of VX15/2503)