This randomized phase I trial studies the side effects and best dose of dinaciclib and Akt inhibitor MK2206 in treating patients with pancreatic cancer that cannot be removed by surgery. Dinaciclib and Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD), safety, and toxicity of the combination of MK-2206 (Akt inhibitor MK2206) and dinaciclib in patients with advanced pancreatic adenocarcinoma (Level 2.5, determined August 2015: Dinaciclib 9 mg/m2 intravenously \[IV\]; MK-2206 135 mg orally \[PO\]). SECONDARY OBJECTIVES: I. Assess the preliminary efficacy of the combination of MK-2206 and dinaciclib in metastatic pancreatic cancer patients as determined by disease control rate in an expansion cohort of patients at the MTD. II. Characterize the pharmacokinetic (PK) profile of the combination of MK-2206 and dinaciclib. III. Analyze pre-treatment tumor specimens for activation of retrovirus-associated deoxyribonucleic acid (DNA) sequence (RAS) downstream pathway signaling as potential predictors of treatment benefit. IV. Correlate post-treatment pharmacodynamic (PD) changes in phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated-v-akt murine thymoma viral oncogene homolog 1 (p-AKT), p-ribosomal protein S6 kinase (S6), phosphorylated DNA-directed ribonucleic acid (RNA) polymerase II subunit RPB1 (pPOLR2), phosphorylated retinoblastoma protein (pRB), proliferation-related Ki-67 antigen (Ki-67), and cleaved caspase-3 in tumor biopsies and peripheral blood mononuclear cells with MK-2206 and dinaciclib exposure and treatment response to demonstrate proof-of-concept and assess for post-treatment predictive biomarkers. V. To assess the effect of polymorphic variations in candidate genes (cytochrome P450 3A4/5 \[CYP3A4/5\], ATP-binding cassette, sub-family B \[MDR/TAP\], member 1 \[ABCB1\]) and other genetic alterations that may be discovered during the conduct of the study, on MK-2206 and dinaciclib disposition, toxicity, and efficacy. OUTLINE: This is a dose-escalation study. Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive dinaciclib IV over 2 hours on day 1 of course 1. ARM B: Patients receive Akt inhibitor MK2206 PO on day 1 of course 1. After day 1, all patients receive Akt inhibitor MK2206 PO on days 1, 8, and 15 and dinaciclib IV over 2 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
42
University of Colorado Cancer Center - Anschutz Cancer Pavilion
Aurora, Colorado, United States
University of Colorado
Denver, Colorado, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada
MTD of dinaciclib in combination with Akt inhibitor MK2206 defined as the highest dose at which 0 or 1 dose-limiting toxicities are observed in six patients
The proportion of dose-limiting toxicities at each dose level will be reported with exact binomial proportions and 95% confidence intervals.
Time frame: 28 days
Disease control rate: complete response, partial response and stable disease evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1
Calculated with exact 95% confidence intervals. The exact Cochran-Armitage trend test will be used to test if the probability of controlled disease at four months is increased with combinations of greater baseline activation of Ras and greater inhibition of Ras downstream pathway signaling. Logistic regression will be used to assess the effects of multiple covariates on the probability of controlled disease at 4 months.
Time frame: 4 months
Incidence of adverse events of the combination of dinaciclib and Akt inhibitor MK-2206, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
The proportion of toxicities by type and grade will be reported with exact binomial proportions and 95% confidence intervals. Adverse events will be summarized by dose level for all doses.
Time frame: Up to 1 year
Overall survival
Summarized using overall hazard rate estimates and 95% confidence intervals as well as Kaplan-Meier (KM) estimates.
Time frame: Up to 1 year
Progression-free survival
Summarized using overall hazard rate estimates and 95% confidence intervals as well as KM estimates. The median PFS and median survival will be reported. Cox proportional hazards models will be used to evaluate the impact of key covariates on PFS and survival.
Time frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year
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