3087 Background: AT13387, a synthetic, non-ansamycin, small molecule inhibitor of HSP90 (Kd 0.71 nM), binds to the N-terminal ATP-binding site resulting in down-regulation of key oncoproteins (HER2 and ERK). In xenograft models AT13387 produced tumor growth inhibition on a QD x 2 dosing schedule. Objectives: To determine toxicity, MTD, PK, and pharmacodynamic (PD) effect of AT13387 given IV QD x 2, 3 weeks out of 4. Methods: Adult patients (pts) with advanced cancers progressing following standard therapy; ECOG ≤ 2; adequate organ function. One pt cohorts for first three dose levels (DLs, 20, 40, 80 mg/m2), planned 3+3 design at DL 4 (120 mg/m2). PK evaluations on C1D1 and C1D15. Mandatory tumor biopsies in expansion cohort at MTD for HER2+ tumors (baseline, C1D17) to evaluate HSP70 and HSP27 mRNA by RT-PCR; and client protein by IHC and immunoassay. HSP70 in PBMCs as a PD marker (pre-dose, D2, D15, D16) assessed by Western blot; serum markers of cell death, M30 and M65 (baseline and pre-dose C1D16), assessed by ELISA. Results: 12 pts treated up to DL 5 (160 mg/m2). Median age, 59; median # prior therapies, 3; diagnosis (# pts): colorectal (7); esophageal (2), liposarcoma (1); head and neck (1); synovial sarcoma (1). Drug-related toxicities (gr ≤ 2; # pts) in 9 evaluable pts: fatigue (5), rash (2), nausea (5), diarrhea (7), QTc prolongation (2), thrombocytopenia (5), AST (3) and ALT (2). Vision disorder (2 pts): gr 1, reversible, no objective findings on eye exams. DLT (1 pt, with liver metastases): DL 5, gr 3 AST/ALT. PK was dose proportional; T1/2 8 hrs. In one paired tumor biopsy (DL 3) an increase in HSP70 (> 1.5 fold) and HSP27 (2 fold) mRNA and a decrease in pERK was observed. M30 and M65 increased in 5/6 pts (p-value n.s.). Induction of HSP70 (1.48 - 5.01 fold) in PBMCs was noted at all time points following first dose (≥ DL 2). 3/9 pts had SD after 2 cycles. Conclusions: Preliminary data indicate that AT13387 QD x 2 is well tolerated and produces a sustained induction of HSP70 in PBMCs. Accrual is ongoing to establish the MTD and obtain further tumor biopsies for assessment of drug effect. Optional Indium-labeled trastuzumab scan will be used to evaluate drug effect on HER2 levels in pts with HER2 expressing tumors.