Safety, pharmacokinetics, and pharmacodynamics of a humanized anti-semaphorin 4D antibody, in a first-in-human study of patients with advanced solid tumors

Amita Patnaik, Glen J. Weiss, John E. Leonard, Drewwarren Rasco, Jasgit C. Sachdev, Terrence L. Fisher, Laurie A. Winter, Christine Reilly, Robert B. Parker, Danielle Mutz, Lisa Blaydorn, Anthony W. Tolcher, Maurice Zauderer, Ramesk K Ramanathan

Research output: Contribution to journalArticle

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Abstract

Purpose: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients. Experimental Design: 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 g-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥0.3 mg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusionnumber. 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.

Original languageEnglish (US)
Pages (from-to)827-836
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number4
DOIs
StatePublished - Feb 15 2016
Externally publishedYes

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Pharmacokinetics
Safety
Antibodies
Neoplasms
Cell Membrane
Disease-Free Survival
Serum
T-Lymphocytes
Arthralgia
Appetite
Transferases
Pancreatic Neoplasms
Nausea
Area Under Curve
Fatigue
CD100 antigen
Research Design
Fever
Biomarkers
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Safety, pharmacokinetics, and pharmacodynamics of a humanized anti-semaphorin 4D antibody, in a first-in-human study of patients with advanced solid tumors. / Patnaik, Amita; Weiss, Glen J.; Leonard, John E.; Rasco, Drewwarren; Sachdev, Jasgit C.; Fisher, Terrence L.; Winter, Laurie A.; Reilly, Christine; Parker, Robert B.; Mutz, Danielle; Blaydorn, Lisa; Tolcher, Anthony W.; Zauderer, Maurice; Ramanathan, Ramesk K.

In: Clinical Cancer Research, Vol. 22, No. 4, 15.02.2016, p. 827-836.

Research output: Contribution to journalArticle

Patnaik, A, Weiss, GJ, Leonard, JE, Rasco, D, Sachdev, JC, Fisher, TL, Winter, LA, Reilly, C, Parker, RB, Mutz, D, Blaydorn, L, Tolcher, AW, Zauderer, M & Ramanathan, RK 2016, 'Safety, pharmacokinetics, and pharmacodynamics of a humanized anti-semaphorin 4D antibody, in a first-in-human study of patients with advanced solid tumors', Clinical Cancer Research, vol. 22, no. 4, pp. 827-836. https://doi.org/10.1158/1078-0432.CCR-15-0431
Patnaik, Amita ; Weiss, Glen J. ; Leonard, John E. ; Rasco, Drewwarren ; Sachdev, Jasgit C. ; Fisher, Terrence L. ; Winter, Laurie A. ; Reilly, Christine ; Parker, Robert B. ; Mutz, Danielle ; Blaydorn, Lisa ; Tolcher, Anthony W. ; Zauderer, Maurice ; Ramanathan, Ramesk K. / Safety, pharmacokinetics, and pharmacodynamics of a humanized anti-semaphorin 4D antibody, in a first-in-human study of patients with advanced solid tumors. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 4. pp. 827-836.
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abstract = "Purpose: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients. Experimental Design: 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 g-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥0.3 mg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusionnumber. 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.",
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AU - Weiss, Glen J.

AU - Leonard, John E.

AU - Rasco, Drewwarren

AU - Sachdev, Jasgit C.

AU - Fisher, Terrence L.

AU - Winter, Laurie A.

AU - Reilly, Christine

AU - Parker, Robert B.

AU - Mutz, Danielle

AU - Blaydorn, Lisa

AU - Tolcher, Anthony W.

AU - Zauderer, Maurice

AU - Ramanathan, Ramesk K

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