Dinaciclib and Akt Inhibitor MK2206 in Treating Patients With Pancreatic Cancer That Cannot Be Removed by Surgery
Dinaciclib and Akt Inhibitor MK2206 in Treating Patients With Pancreatic Cancer That Cannot Be Removed by Surgery
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.
Inclusion Criteria:

 -  Patients must have a histologically confirmed, unresectable pancreatic adenocarcinoma

 -  Patients must have already received or refused 1st-line treatment

 -  Measurable disease will be required; biopsiable disease will be required

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1

 -  Life expectancy of greater than 16 weeks

 -  Leukocytes >= 3,000/mcL

 -  Absolute neutrophil count >= 1,500/mcL

 -  Platelets >= 100,000/mcL

 -  Total bilirubin =< 1.5 institutional upper limit of normal (IULN)

 -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
 =< 2.5 X IULN if no liver metastasis or =< 5 X IULN if liver metastases are present

 -  Creatinine not to be above IULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for
 patients with creatinine levels above institutional normal

 -  Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry and for
 the duration of study participation; should a woman become pregnant or suspect she is
 pregnant while she or her partner is participating in this study, she should inform
 her treating physician immediately; men treated or enrolled on this protocol must also
 agree to use adequate contraception prior to the study, for the duration of study
 participation, and 4 months after completion of MK-2206 and dinaciclib administration

 -  Patients must be able to swallow whole tablets (for MK-2206); nasogastric or
 gastrostomy (G) tube administration is not allowed; tablets must not be crushed or
 chewed

 -  Ability to understand and the willingness to sign a written informed consent document

 Exclusion Criteria:

 -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
 nitrosoureas or mitomycin C) prior to entering the study or those who have not
 recovered to =< grade 1 (or =< tolerable grade 2 for neuropathy) adverse events due to
 agents administered more than 4 weeks earlier

 -  Patients who are receiving any other investigational agents

 -  Patients with known brain metastases should be excluded from this clinical trial

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to dinaciclib or to MK-2206

 -  Patients receiving any medications or substances that are strong inhibitors/inducers,
 sensitive substrates, or substrates with a narrow therapeutic index of cytochrome
 P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or permeability glycoprotein
 (P-gp) are ineligible; caution should be exercised when dosing dinaciclib and/or
 MK-2206 concurrently with CYP3A4 or P-gp substrates, inhibitors/inducers; if subjects
 are taken off a forbidden medicine, a one-week washout is required for inhibitors and
 two weeks for inducers; subjects on Coumadin are eligible but more frequent monitoring
 of the international normalized ratio (INR) (weekly during the first cycle, then at
 least each cycle thereafter) is recommended; as part of the enrollment/informed
 consent procedures, the patient will be counseled on the risk of interactions with
 other agents, and what to do if new medications need to be prescribed or if the
 patient is considering a new over-the-counter medicine or herbal product

 -  Patients with diabetes or in risk for hyperglycemia should not be excluded from trials
 with MK-2206, but the hyperglycemia should be well controlled before the patient
 enters the trial (glycosylated hemoglobin [Hba1c] < 7.5)

 -  Concurrent medications associated with a risk of corrected QT (QTc) prolongation
 and/or torsades de pointes are not allowed; those medications listed as reported but
 lacking substantial evidence for causing QTc prolongation and torsades de pointes will
 be allowed, although if an alternative medication can be substituted, that would be
 preferable; for this study, a baseline electrocardiogram (EKG) will be performed and
 will be repeated during cycle 1 and then every 3 cycles while on treatment

 -  Patients with current evidence of significant cardiovascular disease (New York Heart
 Association class III or IV cardiac disease), symptomatic congestive heart failure,
 dilated/hypertrophic or restrictive cardiomyopathy, myocardial infarction (within the
 past 6 months), unstable angina, unstable arrhythmia or a need for anti-arrhythmic
 therapy (use of medications for rate control for atrial fibrillation is allowed such
 as calcium channel blockers and beta-blockers, if stable medication for at least last
 month prior to initiation of MK-2206 treatment and medication not listed as causing
 torsades de pointes), or evidence of acute ischemia on electrocardiogram (ECG); marked
 baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc
 interval > 450 msec*; long QT syndrome; the required use of concomitant medication
 that may cause torsades de pointes or may cause a significant prolongation of the QTc

 -  Note: Due to difficulties assessing QTc in patients with heart block, they may be
 eligible if deemed safe by a cardiologist

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
 the mother is treated with MK-2206 and/or dinaciclib

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are ineligible

 -  Clinically significant ascites