In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4716-4716
Kurzfassung:
Background: The RAS/RAF/MEK/ERK signaling pathway, which is deregulated in a variety of tumor types, plays a major role in mediating cell growth and differentiation. GDC-0973 is a potent, selective, orally bioavailable MEK1/2 inhibitor which has shown antitumor activity in preclinical models. Methods: A phase I dose-escalation study using a 3+3 design was initiated in patients (pts) with solid tumors to evaluate the safety and pharmacokinetic (PK) characteristics of GDC-0973. FDG-PET was evaluated as a pharmacodynamic (PD) marker. Pts were treated QD with oral GDC-0973 on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) dosing schedule. Serial plasma samples for GDC-0973 pharmacokinetic (PK) analysis were collected following first dose (Day 1) and last dose (Day 21 or Day 14, respectively) in Cycle 1. At expansion stages, pts with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule, and underwent serial FDG-PET scans (baseline, C1D10-14 (steady state) and C1D26-28 (trough). Results: In the 21/7 dose escalation, 36 pts enrolled in eight successive cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) reported were Grade 4 hepatic encephalopathy (40 mg), Grade 3 diarrhea (80 mg) and Grade 3 rash (60 mg and 80 mg). On a 21/7 dosing schedule, the MTD was 60 mg, and the most frequent adverse events (AE) attributed to GDC-0973 by the investigator were diarrhea, rash, nausea, fatigue, dry skin, and edema. In the 14/14 dose escalation, 16 pts enrolled in four successive cohorts (60-125 mg). The DLTs reported were Grade 3 rash (125 mg) and Grade 3 blurred vision associated with presence of reversible subretinal fluid (125 mg). On a 14/14 dosing schedule, the MTD was 100 mg, and the most frequent AEs attributed to GDC-0973 by the investigator were diarrhea, rash, pruritus, nausea, vomiting, blurred and impaired vision, fatigue, and abdominal pain. Preliminary GDC-0973 PK data showed dose-proportional increases in Cmax and AUC, and a mean elimination half-life of approximately 40 hours. With daily oral dosing, there was approximately 2.5-fold accumulation, consistent with the GDC-0973 half-life and dosing interval. Of 17 patients in the 21/7 cohort with PET scans read to date, 9 (53%) had a partial metabolic response ( & gt; 20% decrease in mean SUVmax from baseline) in at least one timepoint. Of 6 patients in the 14/14 cohort with PET scans read to date, 5 (83%) had a partial metabolic response in at least one timepoint. Confirmed partial responses were observed in 3 melanoma patients, of which two had BRAFV600E mutation. Six pts with prolonged stable disease (≥ 5 mo) were observed to date. Conclusion: GDC-0973 is generally well tolerated and has signs of antitumor activity. Preliminary analysis indicates GDC-0973 has linear PK with a half-life that allows once daily dosing. Updated data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4716. doi:10.1158/1538-7445.AM2011-4716
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-4716
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2011
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
