Phase II trial of KOS-862 (epothilone D) in anthracycline and taxane pretreated metastatic breast cancer

Abstract

778 Background: KOS-862 (K) is genetically-produced epothilone D, a naturally occurring macrolide. K has preclinical activity in multiple breast cancer models, including taxane-resistant cell lines. A phase II trial was implemented to determine antitumor activity of K in women with anthracycline (A) and taxane (T) pretreated metastatic breast cancer (MBC). Methods: Pts with MBC + A & T treatment failure are eligible. Treatment failure is defined as disease progression after receipt of both A and T (adjuvant or metastatic setting) or inability to tolerate these agents (toxicity). All pts are ECOG 0–1. Pts with baseline neuropathy > gr 1 or CNS metastases are excluded. K administered as 100 mg/m2 iv over 90 min wkly x 3 Q 4 wks. H1 + H2 antagonists & corticosteroids are given 30–60 min before K as infusion reaction prophylaxis. PK sampling for K + its seco-metabolite collected up to 48 hr post C1D1. Results: 12 women (10 evaluable) have received K. Mean number of K cycles 2.6 (1–6). Three pts had > 4 K cycles. Two pts have had confirmed PR, including 1 pt with hepatic-metastases who had > 50% tumor reduction & normalization of CA 27–29. This pt’s prior treatments include adjuvant AC+T and 6 mo. docetaxel for metastatic disease shortly before trial entry. K-related toxicities (event/grade-#pts) include: peripheral neuropathy (1–2, 2–4, 3–1), paresthesia/hypoesthesia (1–4, 2–1), ataxia (2–1, 3–1), cognitive disorder (2–1), dizziness (1–2), diarrhea (1–4), nausea (1–2), anorexia (2–1), flushing (1–1, 2–1), & fatigue (1–4). Several pts with neurotoxicity (including responders) have been successfully retreated with K dose reduction (75 mg/m2). PK: mean KOS-862 Cmax 4.6±3.0 μg/mL, AUCinf 26 ± 31 h•μg/mL, Vz 196 ± 137 L and T1/2 12 ± 5 hr. Seco-metabolite 39±25% of K. Conclusions: Initial phase II results demonstrate encouraging antitumor activity for K (2 of 10 eval pts) in A & T pretreated MBC. Pts with K toxicities have been successfully retreated with 25% dose reduction. Accrual is anticipated to 53 evaluable pts in order to determine the antitumor activity of K in MBC. Updated response & PK data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Hoffmann-La Roche