Dinaciclib And Akt Inhibitor MK2206 In Treating Patients With Pancreatic Cancer That Cannot Be Removed By Surgery

Study Overview

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.

Pancreatic Adenocarcinoma
Recurrent Pancreatic Carcinoma
Stage III Pancreatic Cancer AJCC v6 and v7
Stage IV Pancreatic Cancer AJCC v6 and v7
Unresectable Pancreatic Carcinoma

DRUG: Akt Inhibitor MK2206
DRUG: Dinaciclib
OTHER: Laboratory Biomarker Analysis
OTHER: Pharmacological Study

NCI-2013-00153
NCI-2013-00153 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
NA_00075037
J1269
9231 (OTHER Identifier) (OTHER: Johns Hopkins University/Sidney Kimmel Cancer Center)
9231 (OTHER Identifier) (OTHER: CTEP)
P30CA006973 (U.S. NIH Grant/Contract)
R21CA172997 (U.S. NIH Grant/Contract)
U01CA132123 (U.S. NIH Grant/Contract)
U01CA070095 (U.S. NIH Grant/Contract)
UM1CA186644 (U.S. NIH Grant/Contract)
UM1CA186688 (U.S. NIH Grant/Contract)
UM1CA186691 (U.S. NIH Grant/Contract)
UM1CA186716 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2013-01-31	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2017-08-21
First Submitted that Met QC Criteria 2013-01-31	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2017-08-22
First Posted (ACTUAL) 2013-02-04	Results First Posted N/A	Last Verified 2017-08

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm A (dinaciclib, Akt inhibitor MK2206) Patients receive dinaciclib IV over 2 hours 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 p	DRUG: Akt Inhibitor MK2206 Given PO DRUG: Dinaciclib Given IV OTHER: Laboratory Biomarker Analysis Correlative studies OTHER: Pharmacological Study Correlative studies
EXPERIMENTAL: Arm B (Akt inhibitor MK2206, dinaciclib) 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 prog	DRUG: Akt Inhibitor MK2206 Given PO DRUG: Dinaciclib Given IV OTHER: Laboratory Biomarker Analysis Correlative studies OTHER: Pharmacological Study Correlative studies

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Arm A (dinaciclib, Akt inhibitor MK2206)

Patients receive dinaciclib IV over 2 hours 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 p

DRUG: Akt Inhibitor MK2206

Given PO

DRUG: Dinaciclib

Given IV

OTHER: Laboratory Biomarker Analysis

Correlative studies

OTHER: Pharmacological Study

Correlative studies

EXPERIMENTAL: Arm B (Akt inhibitor MK2206, dinaciclib)

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 prog

DRUG: Akt Inhibitor MK2206

Given PO

DRUG: Dinaciclib

Given IV

OTHER: Laboratory Biomarker Analysis

Correlative studies

OTHER: Pharmacological Study

Correlative studies

Primary Outcome Measures	Measure Description	Time Frame
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.	28 days

Secondary Outcome Measures	Measure Description	Time Frame
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.	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.	Up to 1 year
Overall survival	Summarized using overall hazard rate estimates and 95% confidence intervals as well as Kaplan-Meier (KM) estimates.	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 from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Nilofer Azad, Johns Hopkins University/Sidney Kimmel Cancer Center

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Hu C, Dadon T, Chenna V, Yabuuchi S, Bannerji R, Booher R, Strack P, Azad N, Nelkin BD, Maitra A. Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models. Mol Cancer Ther. 2015 Jul;14(7):1532-9. doi: 10.1158/1535-7163.MCT-15-0028. Epub 2015 Apr 30.

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