In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. A96-A96
Abstract:
Background: MPC-3100 is an orally-bioavailable, fully-synthetic inhibitor of the molecular chaperone HSP90. HSP90 is important for post-translational protein folding, stabilization, and function of so-called client proteins, many of which are necessary for growth and survival of cancer cells. In preclinical studies, MPC-3100 has demonstrated client protein modulation and antitumor activity against a broad range of tumor types. Methods: In this first-in-human, open label, dose escalating, 3+3 design with accelerated titration, multiple-dose study, the safety and tolerability of single agent MPC-3100 were assessed in subjects with recurrent or refractory cancer. Secondary objectives were to characterize the pharmacokinetic parameters (PK) of MPC-3100, assess antitumor activity, and evaluate pharmacodynamic (PD) biomarkers. Subjects received oral MPC-3100 once daily for 21 days followed by 7 days off at doses of 50, 100, 165, 245, or 340 mg/m2 (Cohorts 1–5, respectively) or for 28 days continuously at total daily doses of 480 mg or 640 mg administered as 240 mg or 320 mg Q12H (Cohorts 6 and 7, respectively) per 28-day cycle. Clinical examinations, blood draws for PK and PD, and tumor assessments were performed at pre-specified times during the study. Results: MPC-3100 was administered to 26 subjects [13 M, 13 F; median age 63.5 yr, range 45–85 yr; ECOG performance status 0 (n=13), 1 (n=11) and 2 (n=2) at screening; most-represented primary cancer types colon (n=6), prostate (6), and breast (3); median of 4 (range 0 to 16) prior chemotherapies]. The total number of cycles of MPC-3100 administered to all subjects was 44 (median 1, range & lt; 1 to 13). Twenty five subjects experienced at least one potentially drug-related adverse event (AE), the majority of which were Grade 1 and 2, most frequently diarrhea (56%), nausea (56%), vomiting (32%), fatigue (32%). Five potentially-related serious AEs (SAEs) were observed in four subjects: abdominal pain, supraventricular tachycardia, respiratory failure, enteritis, and renal failure. The single dose-limiting toxicity (DLT) in this study, Grade 3 supraventricular tachycardia, was observed at the 245 mg/m2 dose level. Total daily doses greater than 600 mg were not well tolerated secondary to Grade 1–3 gastrointestinal and Grade 1/2 visual adverse events that resolved following discontinuation of study drug. Hepatotoxicity was not observed in this study. Best clinical response was stable disease in 12/26 (46%) subjects with 6 subjects remaining on study for ≥ 3 cycles. PK analysis indicated that Cmax and AUC(0–12h) on Day 1 increased in a nearly dose-proportional manner. Terminal plasma half-life ranged from 4.8 to 21.4 hours (mean 11.2 hours). Day 21 exposures were 1.01 to 1.99 times those observed on Day1, indicating a modest degree of drug accumulation. Biomarker analysis demonstrated induction of HSP70 expression at 24 hours post-treatment, and an increase in the degree of HSP70 induction from Day 1 through Day 22, suggesting effective and persistent HSP90 inhibition by MPC-3100 in vivo. Conclusions: MPC-3100 appears to be safe and tolerable when administered orally at doses below 600 mg per day to subjects with recurrent or refractory cancer. Side-effects were generally manageable or reversible upon discontinuation of MPC-3100. Biomarker modulation indicates appropriate HSP90 inhibition. Nearly half of the subjects attained stable disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A96.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-11-A96
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2062135-8
SSG:
12
Permalink
