Faculty Collaboration Database

Phase I study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors. Clin Cancer Res 2013 Sep 01;19(17):4824-31

Date

07/23/2013

Pubmed ID

23873691

Pubmed Central ID

PMC3935614

DOI

10.1158/1078-0432.CCR-13-0477

Scopus ID

2-s2.0-84883474830 (requires institutional sign-in at Scopus site)   19 Citations

Abstract

PURPOSE: Heat shot protein 90 (Hsp90) is a ubiquitous molecular chaperone involved in protein folding, activation, and assembly, including key mediators of signal transduction, cell-cycle control, and transcriptional regulation. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of BIIB028, a prodrug designed to inhibit Hsp90 activity.

EXPERIMENTAL DESIGN: Patients with advanced solid tumors were enrolled and received escalating doses of BIIB028 intravenously twice a week in 21-day cycles (3+3 design). Response was evaluated after two cycles.

RESULTS: Forty-one patients received doses of 6 to 192 mg/m2. The maximum tolerated dose was 144 mg/m2. Dose-limiting toxicities were syncope (n=1) and fatigue (n=1). Common toxicities at least possibly related to drug were grades 1 to 2, including fatigue (46%), diarrhea (44%), nausea (44%), vomiting (29%), hot flushes (29%), and abnormal dreams (17%). The concentration-time curves for day 1 and day 18 for both prodrug and active metabolite (CF2772) showed a negligible difference. There was a dose-dependent increase in plasma exposure for BIIB028 (CF3647) and CF2772 with plasma half-life of 0.5 and 2.1 hours, respectively. Pharmacodynamic analyses showed significant increases in Hsp70 in peripheral blood mononuclear cells and significantly decreased circulating human EGF receptor-2 extracellular domain in all patients who received BIIB028 at dose levels of 48 mg/m2 or more. Stable disease for at least eight cycles (24 weeks) was achieved in 5 (12%) patients (for durations of 6, 6, 8, 12.5, and 19 months).

CONCLUSION: BIIB028 is a well-tolerated molecule that showed target impact and was associated with prolonged stable disease in two patients.

Author List

Hong D, Said R, Falchook G, Naing A, Moulder S, Tsimberidou AM, Galluppi G, Dakappagari N, Storgard C, Kurzrock R, Rosen LS

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Agents
Dose-Response Relationship, Drug
Drug-Related Side Effects and Adverse Reactions
Female
HSP90 Heat-Shock Proteins
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasm Recurrence, Local
Neoplasms
Organophosphates
Receptor, ErbB-2