Phase I clinical trial of an allosteric AKT inhibitor, MK-2206, using a once weekly (QW) dose regimen in patients with advanced solid tumors.

Biondo, Andrea; Yap, Tami; Yan, Libo; Patnaik, Amita; Fearen, Ivy; Baird, Richard D.; Papadopoulos, Kyriakos P.; Delgado, Liliana; Taylor, Adekemi; Lupinacci, L.; Blackman, Samuel C.; Decordova, Shaun; Tall, Matthew; Heaton, Simon P.; Garrett, May; Sullivan, Dan M.; Bono, Johann S. de; Tolcher, A. W.

doi:10.1200/jco.2011.29.15_suppl.3037

Cited by 18 publications

(17 citation statements)

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“…While initial clinical studies explored alternate dosing schedules (23), preclinical data indicated that weekly dosing would be at least as efficacious. Thus, later clinical studies investigated MK-2206 given once weekly (34). Building upon this experience, we administered MK-2006 at 200 mg weekly, the maximum tolerated dose established in patients with solid tumors (34).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, later clinical studies investigated MK-2206 given once weekly (34). Building upon this experience, we administered MK-2006 at 200 mg weekly, the maximum tolerated dose established in patients with solid tumors (34). …”

Section: Resultsmentioning

confidence: 99%

“…Treatment consisted of MK-2206 200 mg orally once weekly, the maximum tolerated dose in patients with solid tumors (34). The weekly dosing was recommended by CTEP based on Phase I data demonstrating pAKT suppression in platelet-rich plasma up to 96 hours post-dose (34).…”

Section: Methodsmentioning

confidence: 99%

“…The weekly dosing was recommended by CTEP based on Phase I data demonstrating pAKT suppression in platelet-rich plasma up to 96 hours post-dose (34). With the exception of hydroxyurea during the first month of therapy, concomitant cytotoxic medications were prohibited.…”

Section: Methodsmentioning

confidence: 99%

“…To begin testing this compound clinically, we then conducted a phase 1/2 trial in adults with poor-prognosis AML to determine the drug’s tolerability and obtain preliminary data on its efficacy of AKT inhibition. Weekly (34) rather than every-other-day (23) dosing of MK-2206 was explored following recommendations of the Cancer Therapy Evaluation Program at the National Cancer Institute (CTEP/NCI; see Treatment, Methods).…”

Section: Introductionmentioning

confidence: 99%

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Preclinical and Early Clinical Evaluation of the Oral AKT Inhibitor, MK-2206, for the Treatment of Acute Myelogenous Leukemia

Konopleva

Walter

Faderl

et al. 2014

Clinical Cancer Research

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Purpose Recent studies suggested that AKT activation might confer poor prognosis in acute myeloid leukemia (AML), providing the rationale for therapeutic targeting of this signaling pathway. We therefore explored the preclinical and clinical anti-AML activity of an oral AKT inhibitor, MK-2206. Experimental Methods We first studied the effects of MK-2206 in human AML cell lines and primary AML specimens in vitro. Subsequently, we conducted a phase 2 trial of MK-2206 (200 mg weekly) in adults requiring second salvage therapy for relapsed/refractory AML, and assessed target inhibition via reverse phase protein array (RPPA). Results In preclinical studies, MK-2206 dose-dependently inhibited growth and induced apoptosis in AML cell lines and primary AML blasts. We then treated 19 patients with MK-2206 but, among 18 evaluable participants, observed only 1 (95% CI: 0–17%) response (complete remission with incomplete platelet count recovery), leading to early study termination. The most common grade 3/4 drug-related toxicity was a pruritic rash in 6/18 patients. Nevertheless, despite the use of MK-2206 at maximum tolerated doses, RPPA analyses indicated only modest decreases in Ser473 AKT (median 28%; range, 12–45%) and limited inhibition of downstream targets. Conclusions While preclinical activity of MK-2206 can be demonstrated, this inhibitor has insufficient clinical anti-leukemia activity when given alone at tolerated doses, and alternative approaches to block AKT signaling should be explored.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%