416O - A phase 1 study evaluating ABT-414 with concurrent radiotherapy (RT) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM)

Date 27 September 2014
Event ESMO 2014
Session CNS tumours
Topics Anti-Cancer Agents & Biologic Therapy
Central Nervous System Malignancies
Surgery and/or Radiotherapy of Cancer
Presenter Hui Gan
Citation Annals of Oncology (2014) 25 (suppl_4): iv137-iv145. 10.1093/annonc/mdu330
Authors H.K. Gan1, L. Fichtel2, A. Lassman3, R. Merrell4, M.J. van den Bent5, P. Kumthekar6, A. Scott1, M. Pedersen7, E. Gomez7, J. Fischer8, W. Ames9, H. Xiong10, M. Dudley11, L. Roberts-Rapp12, P.J. Ansell9, K. Holen8, D.A. Reardon13
  • 1Ludwig Institute For Cancer Research (licr), Austin Health, 3084 - Heidelberg/AU
  • 2Oncology, South Texas Oncology and Hematology, San Antonio/US
  • 3Neuro Oncology, Columbia University Medical Center and Herbert Irving Comprehensive Cancer Center, New York/US
  • 4Kellog Cancer Center, Northshore University Health System, Evanston/US
  • 5Neuro-oncology, Erasmus MC Daniel den Hoed Cancer Center, 3075 EA - Rotterdam/NL
  • 6Neurology, Northwestern University, Chicago/US
  • 7R477, AbbVie, 60063 - North Chicago/US
  • 8Oncology, AbbVie, 60063 - North Chicago/US
  • 9Oncology, AbbVie, North Chicago/US
  • 10R4pk, AbbVie, North Chicago/US
  • 11R436, AbbVie, 60063 - North Chicago/US
  • 12R460, AbbVie, 60063 - North Chicago/US
  • 13Neuro-oncology Department, Dana-Farber Cancer Insitute, 02215 - Boston/US

Abstract

Aim

Despite standard therapy for GBM, median survival is 1-2 years. Abnormal epidermal growth factor receptor (EGFR) expression and signaling are common in GBM. ABT-414 is a unique antibody-drug conjugate, with a toxic payload (monomethylauristatin F) targeted to active EGFR or mutant EGFRvIII, that has demonstrated high antitumor activity in preclinical GBM tumor models.

Methods

Objectives were to evaluate the safety, pharmacokinetics (PK), and the maximum tolerated dose (MTD) of ABT-414 when administered every 14 days with concurrent RT and TMZ in newly diagnosed GBM. Adverse events, PK parameters, objective response (RANO), and tumor tissue EGFR biomarkers were assessed. Dose escalation was determined by the exposure-adjusted continual reassessment method (EACRM).

Results

As of April 9, 2014, 22 pts were treated (13/9 Male/Female, median age 58 years, range 34-79). Common treatment-emergent adverse events (TEAEs, ≥ 5 pts) included fatigue (n= 11); blurred vision (n = 10); thrombocytopenia (n = 8); AST increase (n = 9); ALT increase (n = 8); nausea (n = 7); eye pain (n = 6); lacrimation increase (n = 6); dry eye, headache, and constipation (n = 5 each). Grade 3/4 TEAEs (≥ 2 pts) included lymphopenia (n = 3); eye toxicity (n = 3); brain edema, ALT, AST (n = 2 each). Doses from 0.5 - 3.2 mg/kg have been explored. Dose limiting toxicities primarily affecting the eye (keratitis) and liver occurred at the 2, 2.6, 3.0, and 3.2 mg/kg doses. The EACRM has predicted 2.4 mg/kg as the MTD. Confirmatory safety data are being collected. PK data from 9 subjects in the dose range of 0.5 - 3 mg/kg indicate that exposure (Cmax and AUC) of ABT‐414 appeared to be dose proportional with a half‐life of approximately 11 days. Efficacy endpoints are not yet mature. Patient samples are being evaluated for EGFR expression, amplification and EGFRvIII status to determine which marker best associates with clinical benefit.

Conclusions

PK and safety data support a dose of 2.4 mg/kg as the predicted MTD. Preliminary safety data demonstrate increased liver and eye toxicities in addition to common RT + TMZ toxicities. Further follow-up may demonstrate whether ABT-414 improves outcome.

Disclosure

H.K. Gan: employee of Ludwig Institute for Cancer Research, which has licensed ABT-806; A. Lassman: Consultancy: Amgen, Celgene, Genentech, Sigma-Tau, Agenus, Roche, Stemline, Synapse, RadMD, Venture Inflections, Novartis, Kyowa Hakko Kirin, Abbott, Scientia Advisors, MSD, GSK, Able Assoc, Defined Health, Easton Assoc.; M.J. van den Bent: Consultancy: Roche, ABBVIE, Actelion, Celldex, AMGEN. Research support: Roche, ABBVIE. Speakers bureau: MSD; A. Scott: employee of Ludwig Institute for Cancer Research, which has licensed ABT-806; Consultancy and stock ownership - Life Science Pharmaceuticals; M. Pedersen, E. Gomez, J. Fischer, W. Ames, H. Xiong, M. Dudley, L. Roberts-Rapp, P.J. Ansell and K. Holen: is an AbbVie employee and may own stock; D.A. Reardon: Speaker's Bureau – Merck/Schering and Genentech/Roche; Advisory Board – Novartis; Amgen; Roche/Genentech; EMD Serono; Stemline Therapeutics; Momenta Pharmaceuticals. All other authors have declared no conflicts of interest.