A phase 1 study of ABT-806 in subjects with advanced solid tumors

James M. Cleary, David A. Reardon, Nilofer Azad, Leena Gandhi, Geoffrey I. Shapiro, Jorge Chaves, Michelle Pedersen, Peter Ansell, William Ames, Hao Xiong, Wijith Munasinghe, Matt Dudley, Edward B. Reilly, Kyle Holen, Rod Humerickhouse

Research output: Contribution to journalArticle

Abstract

Purpose: ABTa-806, a humanized recombinant monoclonal antibody, binds a unique epidermal growth factor receptor (EGFR) epitope exposed in the EGFRde2-7 (EGFRvIII) deletion mutant and other EGFR proteins in the activated state. This phase I study evaluated the safety, pharmacokinetics, and recommended phase two dose (RP2D) of ABT-806 in patients with solid tumors that commonly overexpress activated EGFR or EGFRvlll. Methods: Patients with advanced solid tumors, including glioblastoma, were eligible. Following a dose escalation phase, expanded safety cohorts of patients with solid tumors or EGFR-amplified glioblastoma were enrolled. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events v4.0; tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. EGFR protein expression was quantified by immunohistochemistry. Results: 49 patients were treated. Frequent AEs (≥10 %) possibly/probably related to ABT-806 were fatigue (18 %), nausea (16 %), dermatitis acneiform (12 %), and vomiting (10 %). Only one dose-limiting toxicity (grade three morbilliform rash) occurred. The RP2D was the pre-specified highest dose (24 mg/kg). Systemic exposures were dose proportional between 2 and 24 mg/kg. Median time to progression was 55 days (95 % confidence interval, 53-57) in all patients and 43 days (22-57) for glioblastoma patients. No objective responses occurred; however, two patients had prolonged stable disease. An EGFR-amplified penile cancer patient has stable disease lasting over 2.5 years. Conclusions: ABT-806 has unique pharmacokinetic and safety profiles. Toxicities were infrequent and typically low grade at the RP2D. Linear ABT-806 pharmacokinetics suggest lack of significant binding to wild-type EGFR in normal tissues.

Original languageEnglish (US)
Pages (from-to)671-678
Number of pages8
JournalInvestigational New Drugs
Volume33
Issue number3
DOIs
StatePublished - Apr 17 2015

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Epidermal Growth Factor Receptor
Glioblastoma
Neoplasms
Pharmacokinetics
Penile Neoplasms
Safety
Antibodies, Monoclonal, Humanized
National Cancer Institute (U.S.)
Dermatitis
Patient Safety
ABT-806
Exanthema
Terminology
Nausea
Vomiting
Fatigue
Epitopes
Proteins
Immunohistochemistry
Confidence Intervals

Keywords

  • EGFR
  • EGFRvIII
  • Glioblastoma
  • Solid tumors

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Cleary, J. M., Reardon, D. A., Azad, N., Gandhi, L., Shapiro, G. I., Chaves, J., ... Humerickhouse, R. (2015). A phase 1 study of ABT-806 in subjects with advanced solid tumors. Investigational New Drugs, 33(3), 671-678. https://doi.org/10.1007/s10637-015-0234-6

A phase 1 study of ABT-806 in subjects with advanced solid tumors. / Cleary, James M.; Reardon, David A.; Azad, Nilofer; Gandhi, Leena; Shapiro, Geoffrey I.; Chaves, Jorge; Pedersen, Michelle; Ansell, Peter; Ames, William; Xiong, Hao; Munasinghe, Wijith; Dudley, Matt; Reilly, Edward B.; Holen, Kyle; Humerickhouse, Rod.

In: Investigational New Drugs, Vol. 33, No. 3, 17.04.2015, p. 671-678.

Research output: Contribution to journalArticle

Cleary, JM, Reardon, DA, Azad, N, Gandhi, L, Shapiro, GI, Chaves, J, Pedersen, M, Ansell, P, Ames, W, Xiong, H, Munasinghe, W, Dudley, M, Reilly, EB, Holen, K & Humerickhouse, R 2015, 'A phase 1 study of ABT-806 in subjects with advanced solid tumors', Investigational New Drugs, vol. 33, no. 3, pp. 671-678. https://doi.org/10.1007/s10637-015-0234-6
Cleary, James M. ; Reardon, David A. ; Azad, Nilofer ; Gandhi, Leena ; Shapiro, Geoffrey I. ; Chaves, Jorge ; Pedersen, Michelle ; Ansell, Peter ; Ames, William ; Xiong, Hao ; Munasinghe, Wijith ; Dudley, Matt ; Reilly, Edward B. ; Holen, Kyle ; Humerickhouse, Rod. / A phase 1 study of ABT-806 in subjects with advanced solid tumors. In: Investigational New Drugs. 2015 ; Vol. 33, No. 3. pp. 671-678.
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AU - Chaves, Jorge

AU - Pedersen, Michelle

AU - Ansell, Peter

AU - Ames, William

AU - Xiong, Hao

AU - Munasinghe, Wijith

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