First-in-human trial of Hsp90-targeted PET imaging

Objectives To study the pharmacokinetics (PK), metabolism, biodistribution, and radiation dosimetry of I-124 PUH71, a radiolabeled heat shock protein 90 (Hsp90) inhibitor, in patients with active solid malignancy and/or lymphoma.

Methods Trial performed under IRB-approved protocol and US FDA-approved exploratory IND. Main eligibility criteria: >21 years; evaluable tumors on clinical imaging; serum liver and renal indices within specified range; no hyperthyroidism. Patients took SSKI oral solution for 2 weeks, started 1 day before tracer. 5.5 mCi I-124 PUH71 tracer dose (<100 µg) injected peripheral IV. PET-CT scans obtained at 0, 4, and 24 h; and optionally at 48-72 h and 7-8 days, post-injection. Serial blood sampling over 24h for activity and metabolite assays. MIRD formalism and OLINDA software used for dosimetry analyses of PET-derived and blood time-activity data.

Results 14 patients to-date, with breast (n=8), lymphoma (NHL; n=3), neuroblastoma (n=2), and fallopian tube (n=1) cancers. Cancerous tumors evident on PUH71 PET imaging (Figure), after rapid blood clearance and sustained tumor PUH71 concentration. Dosimetry ongoing. No adverse events due to PUH71 tracer.

Conclusions This is the first human trial of an Hsp90-targeted imaging agent to our knowledge. Our results with I-124 PUH71 demonstrate the feasibility of detecting cancerous tumors in human subjects by PET imaging with an Hsp90-targeted tracer. Preliminary PK, metabolism, biodistribution and dosimetry data encourage further development of I-124 PUH71 as a first-of-its-kind Hsp90-targeted imaging agent.

Research Support Clinical trial supported by MSKCC Breast Cancer Research Fund 3. Preclinical development supported by ICMIC P50 CA 086438; SAIRP grant R24 CA83084; and the Cyclotron-Radiochemistry Core of MSKCC