Abstract P3-14-02: Phase 1 Dose-Escalation Study of the Heat Shock Protein 90 Inhibitor BIIB021 with Trastuzumab in HER2+ Metastatic Breast Cancer

Background: BIIB021 is an oral, fully synthetic heat shock protein 90 inhibitor (Hsp90i) that selectively and potently inhibits the molecular chaperone Hsp90, thereby preventing proper assembly of oncogenic proteins such as HER2. Methods: The safety and tolerability of escalating doses of BIIB021 taken by mouth twice weekly (BIW) in combination with fixed doses of trastuzumab (8 mg/kg loading dose, then 6 mg/kg IV every 3 weeks [Q3W]) were determined using a 3+3 dose escalation design with dose expansion at MTD in patients with advanced HER2+ metastatic breast cancer (MBC) refractory to trastuzumab-based therapy. Pharmacokinetics (PK), efficacy, and pharmacodynamics were also assessed. Results: Thirty patients received BIIB021 within 4 dose groups: 200 (n = 3), 400 (n = 5), 600 (n = 20), and 700 mg (n = 2) BIW plus trastuzumab Q3W. All patients were female and median age was 58 years. All patients had ≥1 prior systemic therapy (median 8) and ≥1 prior treatment with trastuzumab (median 4) for HER2+ MBC. Median time on study was 45 days (range 8-213). Twenty (67%) patients withdrew due to progressive disease, 4 (13%) withdrew consent, 3 (10%) withdrew due to adverse events (AEs), and 1 was withdrawn by the Investigator. The MTD for BIIB021 with trastuzumab is 600 mg BIW. Dose-limitingtoxicities were Grade (G) 3 diarrhea (2/20 patients at 600 mg) and G4 aphasia (1/2 patients at 700 mg). The event of aphasia was serious, drug-related, and considered by the Sponsor to be a complex partial seizure. An additional drug-related SAE was G3 hypopituitarism reported for 1 patient at 600 mg. All AEs regardless of relationship occurring in ≥20% of patients included nausea (70%), dizziness (63%), fatigue (63%), diarrhea (57%), vomiting (50%), headache (37%), rash (33%), constipation (30%), hot flush (27%), chills (23%), back pain (23%), UTI (23%), and dyspnea (20%). PK analyses indicated dose-dependent increases in BIIB021 plasma C max and AUC, consistent with previous studies. C max and AUC did not change from Day 1 to Day 22 for any dose group. Terminal half-life ranged from 1-2 hours and T max from 0.5-1.5 hours. Trastuzumab PK was consistent with the product label. Significant induction of Hsp70 (7.5-fold increase) in PBMCs and/or inhibition of serum HER2-ECD (20% decrease) were observed in 50% of evaluable patients (n = 25). A >50% decrease in total circulating tumor cells (CTC) and in HER2+ CTC was observed in patients with >5 CTC at baseline. Antitumor activity was observed in 2 patients (400 and 600 mg) who experienced confirmed partial response (PR) by RECIST. These 2 patients also had metabolic PR (>25% reduction in SUVmax by FDG-PET) and significant changes in Hsp70 and HER2-ECD biomarkers. One confirmed PR is ongoing (>6 months). Conclusions: BIIB021 was tolerated at doses ≥600 mg BIW plus trastuzumab Q3W without apparent alteration in the PK profile of either drug. Consistent with previous combination studies with other Hsp90i in trastuzumab-refractory HER2+ MBC, antitumor activity was observed (2 confirmed PRs) along with significant changes in biomarker levels. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-02.