Joleen M Hubbard1, George Kim2, Mitesh J Borad3, Elizabeth Johnson4, Rui Qin5, Janet Lensing6, Suneetha Puttabasavaiah6, John Wright7, Charles Erlichman6, Axel Grothey6. 1. Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA. hubbard.joleen@mayo.edu. 2. University of Florida Health Oncology, Jacksonville, FL, USA. 3. Mayo Clinic Scottsdale, Scottsdale, AZ, USA. 4. Mayo Clinic Jacksonville, Jacksonville, FL, USA. 5. Regeneron Pharmaceuticals, Basking Ridge, NJ, USA. 6. Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA. 7. Investigational Drug Branch of the Cancer Therapy Evaluation Program, Bethesda, MD, USA.
Abstract
BACKGROUND: A previous phase II trial in patients with chemorefractory metastatic colorectal cancer demonstrated a 63 % disease control rate with a combination of bevacizumab and sorafenib. This phase I trial sought to determine the maximum tolerable dose (MTD) of bevacizumab and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. METHODS: A standard 3 + 3 trial design utilized 3 escalating sorafenib dose levels: (1) 200 mg daily, days 3-7, 10-14; (2) 200 mg twice daily, days 3-6, 10-13; and (3) 200 mg twice daily, days 3-7, 10-14 combined with standard dose FOLFIRI (5-fluouracil, leucovorin, and irinotecan) and bevacizumab (5 mg/kg), repeated every 14 days. RESULTS: Fifteen patients were evaluable for safety and response assessment. There were no dose limiting toxicities (DLTs) at dose level 1 or 2. At dose level 3, two patients experienced DLTs (asymptomatic grade 3 hypophosphatemia, grade 3 dehydration and diarrhea). The MTD was determined to be dose level 2: sorafenib 200 mg twice daily, days 3-6, 10-13 combined with FOLFIRI and bevacizumab at standard doses. Four patients had a partial response and 8 had stable disease as best response (disease control rate of 80 %). Three patients with CRC had disease control >12 months. CONCLUSIONS: The MTD of this regimen is sorafenib 200 mg twice daily, days 3-6, 10-13 combined with standard doses of FOLFIRI and bevacizumab. Dual antiangiogenic treatment combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies.
BACKGROUND: A previous phase II trial in patients with chemorefractory metastatic colorectal cancer demonstrated a 63 % disease control rate with a combination of bevacizumab and sorafenib. This phase I trial sought to determine the maximum tolerable dose (MTD) of bevacizumab and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. METHODS: A standard 3 + 3 trial design utilized 3 escalating sorafenib dose levels: (1) 200 mg daily, days 3-7, 10-14; (2) 200 mg twice daily, days 3-6, 10-13; and (3) 200 mg twice daily, days 3-7, 10-14 combined with standard dose FOLFIRI (5-fluouracil, leucovorin, and irinotecan) and bevacizumab (5 mg/kg), repeated every 14 days. RESULTS: Fifteen patients were evaluable for safety and response assessment. There were no dose limiting toxicities (DLTs) at dose level 1 or 2. At dose level 3, two patients experienced DLTs (asymptomatic grade 3 hypophosphatemia, grade 3 dehydration and diarrhea). The MTD was determined to be dose level 2: sorafenib 200 mg twice daily, days 3-6, 10-13 combined with FOLFIRI and bevacizumab at standard doses. Four patients had a partial response and 8 had stable disease as best response (disease control rate of 80 %). Three patients with CRC had disease control >12 months. CONCLUSIONS: The MTD of this regimen is sorafenib 200 mg twice daily, days 3-6, 10-13 combined with standard doses of FOLFIRI and bevacizumab. Dual antiangiogenic treatment combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies.
Authors: M Relf; S LeJeune; P A Scott; S Fox; K Smith; R Leek; A Moghaddam; R Whitehouse; R Bicknell; A L Harris Journal: Cancer Res Date: 1997-03-01 Impact factor: 12.701
Authors: L B Saltz; J V Cox; C Blanke; L S Rosen; L Fehrenbacher; M J Moore; J A Maroun; S P Ackland; P K Locker; N Pirotta; G L Elfring; L L Miller Journal: N Engl J Med Date: 2000-09-28 Impact factor: 91.245
Authors: Herbert Hurwitz; Louis Fehrenbacher; William Novotny; Thomas Cartwright; John Hainsworth; William Heim; Jordan Berlin; Ari Baron; Susan Griffing; Eric Holmgren; Napoleone Ferrara; Gwen Fyfe; Beth Rogers; Robert Ross; Fairooz Kabbinavar Journal: N Engl J Med Date: 2004-06-03 Impact factor: 91.245
Authors: Bruce J Giantonio; Paul J Catalano; Neal J Meropol; Peter J O'Dwyer; Edith P Mitchell; Steven R Alberts; Michael A Schwartz; Al B Benson Journal: J Clin Oncol Date: 2007-04-20 Impact factor: 44.544
Authors: A Awada; A Hendlisz; T Gil; S Bartholomeus; M Mano; D de Valeriola; D Strumberg; E Brendel; C G Haase; B Schwartz; M Piccart Journal: Br J Cancer Date: 2005-05-23 Impact factor: 7.640
Authors: Nilofer S Azad; Edwin M Posadas; Virginia E Kwitkowski; Seth M Steinberg; Lokesh Jain; Christina M Annunziata; Lori Minasian; Gisele Sarosy; Herbert L Kotz; Ahalya Premkumar; Liang Cao; Deborah McNally; Catherine Chow; Helen X Chen; John J Wright; William D Figg; Elise C Kohn Journal: J Clin Oncol Date: 2008-08-01 Impact factor: 50.717