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

Abstract

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 > or =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 > or =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.

• Authors: Olivier Rixe, Sandra X Franco, Denise A Yardley, Stephen R Johnston, Miguel Martin, Banu K Arun, Stephen P Letrent, Hope S Rugo
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 64 Issue 6 Pg. 1139-48 (Nov 2009) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19294387 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Morpholines
• Receptors, Estrogen
• Canertinib
• ERBB2 protein, human
• ERBB4 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Receptor, ErbB-3
• Receptor, ErbB-4

Topics

• Adult
• Aged
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Disease-Free Survival
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Humans
• Kaplan-Meier Estimate
• Middle Aged
• Morpholines (administration & dosage, adverse effects, therapeutic use)
• Neoplasm Metastasis (drug therapy)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Receptor, ErbB-3 (metabolism)
• Receptor, ErbB-4
• Receptors, Estrogen (metabolism)
• Treatment Outcome