Phase I trial of bortezomib and concurrent external beam radiation in patients with advanced solid malignancies.
OBJECTIVE
To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy.


METHODS
An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m(2), 1.3 mg/m(2), and 1.6 mg/m(2)/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, defined as any grade 4 hematologic toxicity, any grade ≥3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for ≥2 weeks.


RESULTS
A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m(2). One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients).


CONCLUSIONS
The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m(2) is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m(2).
Pugh
Thomas J
TJ
Department of Radiation Oncology, University of Colorado Denver and Health Science Center, Aurora, USA.
Chen
Changhu
C
Rabinovitch
Rachel
R
Eckhardt
S Gail
SG
Rusthoven
Kyle E
KE
Swing
Robyn
R
Raben
David
D
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D000069286:Bortezomib; D003120:Colorado; D003131:Combined Modality Therapy / Q000379:methods; D003967:Diarrhea / Q000209:etiology; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000209:etiology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008231:Lymphopenia / Q000209:etiology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000209:etiology; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000532:radiotherapy*; D009503:Neutropenia / Q000209:etiology; D010166:Palliative Care / Q000379:methods; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects*; D011859:Radiography
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib