Pancreatic Adenocarcinoma Clinical Trial
Official title:
A Phase I Trial of Dinaciclib (SCH727965) and MK-2206 in Metastatic Pancreatic Cancer With an Expansion Cohort in Advanced Pancreatic Cancer
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.
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