randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer

• Published in: Cancer chemotherapy and pharmacology 2009-11, Vol.64 (6), p.1139-1148
• Main Authors: Rixe, Olivier, Franco, Sandra X, Yardley, Denise A, Johnston, Stephen R, Martin, Miguel, Arun, Banu K, Letrent, Stephen P, Rugo, Hope S
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer Research; Disease-Free Survival; Female; Gynecology. Andrology. Obstetrics; Humans; Kaplan-Meier Estimate; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Morpholines - administration & dosage; Morpholines - adverse effects; Morpholines - therapeutic use; Neoplasm Metastasis - drug therapy; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Receptor, ErbB-3 - metabolism; Receptor, ErbB-4; Receptors, Estrogen - metabolism; Treatment Outcome; Tumors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-009-0975-z

Purpose To evaluate the efficacy and safety of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in metastatic breast cancer (MBC). Experimental design Patients with measurable, progressive, or recurrent MBC whose primary tumor expressed >=1 ErbB receptor were randomized to the following CI-1033 regimens: 50 mg (arm A) or 150 mg (arm B) daily without rest period, or 450 mg/day x 14 days every 21 days (arm C). The primary endpoint was 1-year progression-free survival (PFS). Results Overall, 194 patients were treated. One-year PFS estimates were 3.8, 2.0, and 4.6%; median PFS was 61, 56, and 58 days; and investigator-assessed overall response rates were 1.5, 1.5, and 7.3%, in arms A, B, and C, respectively. Response duration was 110-419 days. In arm C, response (18.8 vs. 2.6%) and 1-year overall survival rates (86.7 vs. 47.5%) were greater in patients with HER2-positive versus HER2-negative tumors. The incidence of grade 3/4 adverse events (AEs) was dose-dependent, affecting 10.3, 48.6, and 80.4% of patients in arms A, B and C, respectively. The most common grade 3/4, treatment-related AEs were diarrhea, asthenia, and stomatitis. Arm C enrollment was prematurely discontinued due to a high frequency of grade 3/4 AEs. Conclusion Single-agent CI-1033 did not show clinically meaningful activity in heavily pretreated patients with MBC expressing >=1 ErbB receptor. Antitumor activity was observed in arm C patients with HER2-positive tumors. However, only the 50 mg dose was well tolerated, and the highest dose reached unacceptable levels of toxicity.