First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma.
There are limited treatment options for patients with recurrent glioblastoma (GBM). The EnGeneIC delivery vehicle (EDV) is a novel nanocellular (minicell) compound which packages theoretically effective concentrations of chemotherapeutic drugs that are designed to target tumors via minicell-surface attached bispecific proteins (EnGeneIC, Lane Cove West, NSW, Australia). Epidermal growth factor receptor (EGFR) is overexpressed in 40-50% of patients with GBM and is a promising target for new therapeutics. (V)EDVDox contains doxorubicin (Dox) within the minicells and targets EGFR through Vectibix (V; Amgen Biologicals, Thousand Oaks, CA, USA). We conducted a first in human Phase I study of (V)EDVDox in adults with recurrent GBM expressing EGFR on immunohistochemistry, following standard therapy including radiation and temozolomide, to establish a safe maximum tolerated dose and determine a recommended Phase II dose (RPTD). (V)EDVDox was administered weekly in an 8week cycle, with dose escalation in successive cohorts of patients using a standard 3+3 design. In total, 14 patients were treated at three dose levels, and the RPTD was identified as 5×10(9)(V)EDVDox. Overall (V)EDVDox was well tolerated, with no dose limiting toxicity and no withdrawals from the study due to adverse events. The most common adverse events were nausea, fever, and chills or rigors, experienced in seven, five and five patients, respectively. Transient uncomplicated hypophosphatemia was seen in seven patients and was not dose-related. Our results demonstrate that (V)EDVDox, up to a dose of 5×10(9)(V)EDVDox weekly, is well tolerated in patients with recurrent GBM.
Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville, VIC 3050, Australia. Electronic address: jim.whittle@mh.org.au.
James R
JR
Whittle
Monash Cancer Centre, East Bentleigh, VIC, Australia.
Jason D
JD
Lickliter
Olivia Newton John Cancer and Wellness Centre, Austin Hospital, Heidelberg, VIC, Australia; Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, VIC, Australia.
Hui K
HK
Gan
Olivia Newton John Cancer and Wellness Centre, Austin Hospital, Heidelberg, VIC, Australia; Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, VIC, Australia.
Andrew M
AM
Scott
Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia.
John
J
Simes
Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
Benjamin J
BJ
Solomon
EnGeneIC Ltd, Lane Cove West, NSW, Australia.
Jennifer A
JA
MacDiarmid
EnGeneIC Ltd, Lane Cove West, NSW, Australia.
Himanshu
H
Brahmbhatt
Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville, VIC 3050, Australia.
Mark A
MA
Rosenthal
D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001315:Australia; D001932:Brain Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy / Q000009:adverse effects / Q000379:methods*; D036103:Nanotechnology / Q000379:methods*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D000077544:Panitumumab
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077544:Panitumumab; D004317:Doxorubicin; C512478:EGFR protein, human; D066246:ErbB Receptors
Doxorubicin; Epidermal growth factor receptor; First in human; Glioblastoma; Phase I trial