In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. B128-B128
Abstract:
Background: GSK1120212 (MEK) is a reversible, highly selective allosteric inhibitor of MEK1/MEK2. MEK was combined with everolimus (EVE), an mTOR inhibitor, to provide simultaneous inhibition of the MAPK and PI3K/mTOR pathways. This Phase I escalation study evaluated the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of MEK+EVE and assessed the recommended Phase II regimen (RP2R). Materials and Methods: Advanced solid tumor patients (pts) with adequate end-organ function received MEK (0.5–2mg) orally once daily (QD). EVE (5–7.5mg) was given orally with various schedules (QD, QOD, 5/7D, or 7/14D). Results: Sixty-seven pts (21 pancreatic, 14 colorectal, 6 melanoma, 4 breast, 3 neuroendocrine and 19 other cancers) received ≥ 1 dose of MEK + EVE. Cohorts 4A and 5 exceeded the maximum tolerated dose. Dose-limiting toxicities (DLTs) were G3 mucositisa (n=5), G4 thrombocytopenia (n=1), G3 acneiform rash/fatigue/dehydration (n=1) and G3 hypokalemia secondary to diarrhea. All DLTs were reversible. 2 pts had fatal serious adverse events (pneumonia, GI hemorrhage); both considered unrelated to study drugs. The most common adverse events (AEs) (≥ 25%) were mucositisa (67%), skin-related toxicities (66%), fatigue (60%), diarrhea (45%), nausea (40%), vomiting (37%), pyrexia (30%) and decreased appetite (28%). G3/G4 AEs included mucositisa (12% G3), AST elevation (10% G3) and hyperglycemia (7% G3). Mucositisa led to dose interruptions, reductions, and discontinuations in 27%, 9%, and 1% of pts, respectively. There was no PK interaction when MEK was coadministered with EVE, and PK results were consistent with previous reports when either agent was administered alone. There did not appear to be a relationship between EVE or MEK exposure and mucositisa incidence or severity. 62 pts had measurable disease at baseline and 5 achieved a partial response: 3 confirmed (1 adenoid cystic carcinoma, on-going & gt;13 months; 1 squamous cell lung, 6 months, withdrawn due to co-morbidity; 1 melanoma, 6 months), and 2 unconfirmed (1 laryngeal, 1 pancreatic cancer). 18 pts had stable disease with median duration on study treatment of 18.5 (range: 5.9–52.9) weeks. Conclusion: Despite evidence of clinical activity in this heavily pretreated patient population, the toxicity profiles limit the ability to give MEK+EVE. Although multiple dosing schedules were explored, an RP2R was not identified. 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 B128.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-11-B128
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2062135-8
SSG:
12
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