title: Phase I trial to evaluate the tumor and normal tissue uptake, radiation dosimetry and safety of (111)In-DTPA-human epidermal growth factor in patients with metastatic EGFR-positive breast cancer.
abstract: The safety, pharmacokinetics, biodistribution and radiation dosimetry of (111)In-DTPA-hEGF, an Auger electron-emitting radiopharmaceutical, were evaluated in a first-in-human trial. Dose escalation was performed in patients with EGFR-positive metastatic breast cancer who had received ≥2 prior courses of systemic treatment. (111)In-DTPA-hEGF (0.25 mg) was administered once intravenously (i.v.). Blood was collected for biochemistry/hematology testing and pharmacokinetic and immunogenicity analyses at selected times post injection (p.i.). Whole body planar images were acquired at 1, 4-6, 24 and 72 h p.i. and SPECT images at 24 and/or 72 h p.i. Macrodosimetry (MIRD) for the whole body and organs was estimated using OLINDA. Correlative radiological imaging was obtained at baseline, 1 and 3 months and then 6 monthly. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE)v2.0. Sixteen patients, median age 47 yr (range, 35-59), received (111)In-DTPA-hEGF as follows: 357-434 MBq (7), 754-805 MBq (3), 1,241-1,527 MBq (3) and 2,030-2,290 MBq (3). Fifteen were evaluable for toxicity. The commonest adverse events (AE) were flushing, chills, nausea, and vomiting occurring during or immediately p.i. One patient experienced Grade 3 thrombocytopenia (attributed to bone marrow infiltration by cancer). There were no other Grade 3 or 4 AEs. Maximum tolerated dose was not reached. Clear accumulation of radiopharmaceutical in at least one known site of disease was observed in 47% of patients. (111)In-DTPA-hEGF was cleared biexponentially from the blood with α-phase T½ of 0.16 ± 0.03 h and β-phase T½ of 9.41 ± 1.93 h. (111)In-DTPA-hEGF was not immunogenic. The mean radiation dose estimates in mGy/MBq for whole body, liver, kidneys, spleen and thyroid were 0.08, 0.86, 0.74, 0.37 and 0.30, respectively. No objective antitumor responses were observed at the doses studied. In summary, administered amounts of up to 2,290 MBq (0.25 mg) of (111)In-DTPA-hEGF were well tolerated as a single i.v. injection.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, University of Oxford Oxford, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Vallis
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto Toronto, Canada ; Toronto General Hospital Research Institute Toronto, Canada ; Medical Imaging, University of Toronto Toronto, Canada.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto Toronto, Canada.
authors.forename: Deborah
authors.initials: D
authors.lastname: Scollard
authors.affiliation: Radiation Medicine Program, Princess Margaret Hospital, University of Toronto Canada.
authors.forename: Pat
authors.initials: P
authors.lastname: Merante
authors.affiliation: Radiation Medicine Program, Princess Margaret Hospital, University of Toronto Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brade
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto Toronto, Canada.
authors.forename: Sobi
authors.initials: S
authors.lastname: Velauthapillai
authors.affiliation: Medical Imaging, University of Toronto Toronto, Canada ; Medical Physics, Sunnybrook Health Sciences Center Toronto, Canada.
authors.forename: Curtis
authors.initials: C
authors.lastname: Caldwell
authors.affiliation: Medical Imaging, University of Toronto Toronto, Canada.
authors.forename: Ida
authors.initials: I
authors.lastname: Chan
authors.affiliation: Medical Imaging, University of Toronto Toronto, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Freeman
authors.affiliation: Biostatistics, Princess Margaret Hospital Toronto, Canada.
authors.forename: Gina
authors.initials: G
authors.lastname: Lockwood
authors.affiliation: Pathology, University Health Network Toronto, Canada.
authors.forename: Naomi A
authors.initials: NA
authors.lastname: Miller
authors.affiliation: Gray Institute for Radiation Oncology and Biology, University of Oxford Oxford, UK.
authors.forename: Bart
authors.initials: B
authors.lastname: Cornelissen
authors.affiliation: Medical Oncology and Hematology, Princess Margaret Hospital Toronto, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Petronis
authors.affiliation: Biostatistics, Princess Margaret Hospital Toronto, Canada.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Sabate
keywords: 111In-DTPA-hEGF; Auger electron; Phase I trial; breast cancer
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