Abstract A218: Pharmacokinetic (PK) and pharmacodynamic (PD) data for MPC-3100, a fully synthetic HSP90 inhibitor, in cancer patients
Authors: Yu Margaret K. , Baichwal Vijay , Brown Brita , Wettstein Daniel , Dowd Brian , Mather Gary 
Published: June 2012

Abstract
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 Cmax 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.
Dose (mg/m2)/Total daily dose (mg) Cycle 1 Timepoints T ½ (hr)/ Cmax (ng/mL)/Cmin (ng/mL)/AUC (0–24) (hr*ng/mL) Hsp70* 50/100 day 1 8.5/1903.5/0.0/20636.0 104 50/100 day 8 N/A/N/A/162.0/N/A 85 50/100 day 21 13.4/1700.5/456.6/21992.0 63 100/160 day 1 9.8/2984.8/0.0/30230.0 16 100/160 day 8 N/A/N/A/914.3/N/A 53 100/160 day 21 11.2/3182.1/818.1/49805.0 −25 165/300 day 1 11.5/6869.2/0.0/91824 43 165/300 day 8 N/A/N/A/2086.3/N/A 34 165/300 day 21 14.0/11789.0/4874.4/199749.0 72 Single dose N-87 tumor bearing mice 200 mg/kg 4.8/21841.0/N/A/135779.8 N/A * Hsp70 induction (ng/ mg of total protein)
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A218.