This phase I trial is studying the side effects, best way to give, and best dose of Akt inhibitor MK2206 (MK2206) in treating patients with recurrent or refractory solid tumors or leukemia. MK2206 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: l. To estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose of MK-2206 (Akt inhibitor MK2206) administered orally every other day (schedule 1) or once weekly (schedule 2) to children with refractory or recurrent solid malignancies, including central nervous system (CNS) tumors or lymphomas. II. To define and describe the toxicities of MK-2206 in children with refractory solid malignancies administered on this schedule. III. To assess the tolerability of MK-2206 at the solid tumor MTD in patients with recurrent or refractory leukemia. IV. To characterize the pharmacokinetics of MK-2206 in children with recurrent or refractory cancer. (exploratory) SECONDARY OBJECTIVES: I. To preliminarily define the antitumor activity of MK-2206 within the confines of a phase 1 study.(exploratory) II. To evaluate biological activity of MK-2206 by measuring phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling in tumor and peripheral blood mononuclear cells and measure the expression of biomarkers related to AKT activation phenotypes. (exploratory) OUTLINE: This is a dose-escalation study (part A) followed by treatment at the maximum-tolerated dose (part B). Patients receive Akt inhibitor MK2206 orally (PO) every other day (schedule 1) OR once weekly (schedule 2) on days 1-28. Treatment repeats every 28 days for up 12 courses (1 year) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
45
Given PO
Correlative studies
Correlative studies
University of Alabama at Birmingham
Birmingham, Alabama, United States
Childrens Hospital of Orange County
Orange, California, United States
University of California San Francisco Medical Center-Parnassus
San Francisco, California, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia, United States
MTD and/or recommended phase 2 dose of Akt inhibitor MK2206 determined according to incidence of dose-limiting toxicities (DLTs) graded using CTCAE v4.0 (Part A)
The MTD will be the maximum dose at which fewer than one-third of patients experience DLT during course 1 of therapy.
Time frame: 28 days
Pharmacokinetic (PK) parameters of Akt inhibitor MK-2206
Summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Time frame: Baseline, 0.5, 1.5, 3, 6-8, 24, 48 hours day 1 course 1; pre-dose and 6-8 hours post-dose (optional) day 15 (Schedule 1); baseline, 0.5, 1.5, 3, 6-8, 24, 48 hours day 1 course 1; pre-dose days 8 and 15; 6-8 hours post-dose day 15 (optional) (Schedule 2)
Antitumor activity assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1
Time frame: Up to 30 days
Levels of activation of downstream signaling molecules
Summarized using descriptive statistics at each timepoint. The Wilcoxon signed-rank test or Friedman's test may be used as a preliminary test of change in activity over two or more timepoints.
Time frame: Up to day 15 of course 1
Mutations or amplification of upstream signaling molecules
Summarized using descriptive statistics at each timepoint. The Wilcoxon signed-rank test or Friedman's test may be used as a preliminary test of change in activity over two or more timepoints.
Time frame: Baseline
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Chicago, Illinois, United States
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