Phase l study assessing a two-consecutive-day (QD x 2) dosing schedule of the HSP90 inhibitor, AT13387, in patients with advanced solid tumors.

Abstract

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.

Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer

“…The combination of the HSP90 inhibitor with AA appeared to be tolerated at onalespib doses below the single-agent MTD [220 mg/m 2 weekly vs. 260 mg/m 2 for the single-agent weekly regimen (10,29); 120 mg/m 2 versus 160 mg/m 2 for the twice weekly on 2 consecutive day regimen (11)] with gastrointestinal toxicity in this population, most notably diarrhea being dose limiting. AA/P has a 5% reported incidence of diarrhea, but despite the reported single-agent MTDs, many subjects were unable to complete 3 full dosing cycles due to either AEs, study withdrawal, or disease progression.…”

“…Onalespib is a synthetic, non-ansamycin, small molecule inhibitor of HSP90 (K d ¼ 0.71 nmol/L) identified by fragment screening and subsequent structure-based drug design (9)(10)(11)(12). HSP90 is required for the functional stabilization of numerous client proteins involved in cell growth and differentiation, including the AR-FL (13,14).…”