Abstract A218: Pharmacokinetic (PK) and pharmacodynamic (PD) data for MPC‐3100, a fully synthetic HSP90 inhibitor, in cancer patients

Purpose: MPC‐3100 is a fully synthetic, orally bioavailable, HSP90 inhibitor that recently entered Phase I clinical studies. We show updated xenograft data and preliminary PK/PD data in cancer patients.

Experimental Design: MPC‐3100 was dosed either daily or five out of every 7 days for a total of three weeks, as indicated, for most pre‐clinical studies. Following acute and 28‐day repeated dose toxicology studies in rats and cynomolgus monkeys, a human clinical study was initiated at a starting dose of 50 mg/m². MPC‐3100 is administered by mouth in tablet form for 21 consecutive days in a 28 day cycle to each enrolled subject.

For determination of drug levels in humans, plasma was collected prior to drug administration and 0.5 , 1, 2, 3, 4, 6, 8, and 24 hours post‐dosing on cycle 1 day 1, and cycle 1 day 21. Plasma was collected pre‐dose only for cycle 1 day 8. Peripheral blood mononuclear cells (PBMCs) were collected prior to drug administration, and 8 and 24 hours post‐dose on cycle 1 day 1 and cycle 1 day 21 in order to quantitate Hsp70 protein levels as an exploratory biomarker.

Results: Animals implanted with a large number of cancer cell types (MV‐4‐11, HT29, DU145, NCI‐H69, OVCAR‐3, BT‐474, NCI‐N87, and OPM‐2) as xenografts and dosed with 200 mg/kg of MPC‐3100 displayed activity that ranged between 68% tumor growth inhibition and 44% regression. Animals showed no significant weight loss.

We present preliminary PK and PD data from three patients with metastatic cancer who have been treated with MPC‐3100. Hsp70 levels in PBMCs showed an increase 8 hours after the first dose which was sustained on Day 8 and Day 21. There was a more than proportional increase in drug levels with increasing dose. Plasma C_max and AUC_(0‐24) in the patient dosed at 165 mg/m² (11789 ng/mL and 199,749 hr*ng/mL at day 21) are comparable in magnitude to those achieved in tumor bearing mice after a single dose of 200 mg/kg (21841 ng/mL and 135,779 hr*ng/mL, respectively). The drug level achieved in humans has demonstrated anti‐tumor activity in multiple mouse xenograft models. No dose limiting toxicities have been reported to date.

Conclusion: MPC‐3100 is orally bioavailable in cancer patients. The pharmacokinetic properties and drug concentration achieved in patients are similar to those observed in efficacious mouse experiments.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A218.