title: Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors.
abstract: OBJECTIVE
  Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients.
  
  
  METHODS
  Weekly i.v. doses were administered on a 28-day cycle. Safety, immunogenicity, PK, efficacy, T-cell membrane-associated SEMA4D (cSEMA4D) expression and saturation, soluble SEMA4D (sSEMA4D) serum levels, and serum biomarker levels were evaluated.
  
  
  RESULTS
  Forty-two patients were enrolled into seven sequential cohorts and an expansion cohort (20 mg/kg). VX15/2503 was well tolerated. Treatment-related adverse events were primarily grade 1 or 2 and included nausea (14.3%) and fatigue (11.9%); arthralgia, decreased appetite, infusion-related reaction, and pyrexia were each 7.3%. One pancreatic cancer patient (15 mg/kg) experienced a Grade 3 dose-limiting toxicity; elevated γ-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥ 0.3 μg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusion number. Neutralizing anti-VX15/2503 antibodies led to treatment discontinuation for 1 patient. VX15/2503 Cmax and AUC generally increased with dose and dose number. One patient (20 mg/kg) experienced a partial response, 19 patients (45.2%) exhibited SD for ≥ 8 weeks, and 8 (19%) had SD for ≥ 16 weeks. Subjects with elevated B/T lymphocytes exhibited longer progression-free survival.
  
  
  CONCLUSIONS
  VX15/2503 was well tolerated and produced expected PD effects. The correlation between immune cell levels at baseline and progression-free survival is consistent with an immune-mediated mechanism of action. Future investigations will be in combination with immunomodulatory agents.
authors.affiliation: South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio, Texas.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Cancer Treatment Centers of America, Goodyear, Arizona.
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.affiliation: Vaccinex, Inc., Rochester, New York. jleonard@vaccinex.com.
authors.forename: John E
authors.initials: JE
authors.lastname: Leonard
authors.affiliation: South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio, Texas.
authors.forename: Drew Warren
authors.initials: DW
authors.lastname: Rasco
authors.affiliation: Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona.
authors.forename: Jasgit C
authors.initials: JC
authors.lastname: Sachdev
authors.affiliation: Vaccinex, Inc., Rochester, New York.
authors.forename: Terrence L
authors.initials: TL
authors.lastname: Fisher
authors.affiliation: Vaccinex, Inc., Rochester, New York.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Winter
authors.affiliation: Vaccinex, Inc., Rochester, New York.
authors.forename: Christine
authors.initials: C
authors.lastname: Reilly
authors.affiliation: Vaccinex, Inc., Rochester, New York.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Parker
authors.affiliation: South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio, Texas.
authors.forename: Danielle
authors.initials: D
authors.lastname: Mutz
authors.affiliation: Cancer Treatment Centers of America, Goodyear, Arizona.
authors.forename: Lisa
authors.initials: L
authors.lastname: Blaydorn
authors.affiliation: South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio, Texas.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Vaccinex, Inc., Rochester, New York.
authors.forename: Maurice
authors.initials: M
authors.lastname: Zauderer
authors.affiliation: Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D003110:Colonic Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000604277:VX15-2503 monoclonal antibody