Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17-Demethoxygeldanamycin in Patients With Advanced Malignancies

Abstract

A B S T R A C T PurposeTo study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17-demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials. Patients and MethodsThis was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated. ResultsThe highest dose level reached was 450 mg/m 2 /week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m 2 /week and two at 450 mg/m 2 /week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m 2 /week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r 2 ϭ .71) over the dose range 10 to 450 mg/m 2 /week, with peak plasma concentrations of 8,998 g/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre-and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m 2 /week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment. ConclusionIt has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m 2 /week. We recommend this dose for phase II clinical trials.

Hsp90 inhibitors deplete key anti‐apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin

“…In addition, levels of CDK4 were decreased in 8 of 9 patients' tumors. 14 Unfortunately, no tumor shrinkage was seen in these patients indicating that modulation of the individual Hsp90 client proteins studied was not predictive of anti-tumor effect. Similarly, in our in vitro experiments, the degree of modulation of levels of AKT and IGF1R did not necessarily predict cytotoxicity after exposure to Hsp90 inhibitors.…”

“…In light of these data, we hypothesize that in some tumors, Hsp90 inhibitors may be most useful in altering levels of apoptosis-related proteins and in sensitizing cells to the effects of cytotoxins. The Hsp90 inhibitor 17AAG has been associated with relatively modest toxicity in adults with leukemia and solid tumors, 3,13,14 making it likely that this drug could be integrated readily into multi-agent treatment regimens for childhood cancers. We evaluated the effects of an Hsp90 inhibitor in combination with another agent commonly used in the treatment of osteosar-FIGURE 5 -Increased TUNEL positivity after exposure to combined GA ϩ cisplatin.…”

“…Banerji et al 14 have reported that in 4 of 7 post-therapy tumor samples from adults enrolled on a Phase I study of 17AAG, depletion of c-RAF could be detected. In addition, levels of CDK4 were decreased in 8 of 9 patients' tumors.…”

“…These conditions were selected to approximate the range of clinically relevant drug exposure conditions for the GA derivative 17-AAG that have been defined in several adult Phase I trials. 11,13,14 Marked inhibition of cell survival/proliferation was seen in both neuroblastoma cell lines after exposure to sub-micromolar GA concentrations for just 4 hr, whereas substantially higher concentrations and exposure times were required to inhibit the osteosarcoma lines.…”

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

“…One of the hallmarks of Hsp90 inhibition, along with client protein degradation, is the subsequent up regulation of Hsp70. So universal is this response to Hsp90 inhibition that it is in use as a biomarker for many Hsp90 inhibitor clinical trials [20].…”