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

NCT01783171 | Completed Phase 1

• 12 other identifiers: NCI-2013-00153NA_00075037J12699231P30CA006973R21CA172997U01CA132123U01CA070095UM1CA186644UM1CA186688UM1CA186691UM1CA186716
• Study Type: interventional
• Target: 42
• Locations: 2 countries
• Sites: 5

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Disease control rate: complete response, partial response and stable disease evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1

  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

  Up to 1 year

• Overall survival

  Up to 1 year

• Progression-free survival

  Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

Other Outcomes (6)

• Change in protein expression in serum after treatment with a single drug, and after treatment with both drugs as a measure of the drug specific effects on pathway markers

  Baseline up to day 3 of course 2

• Change in protein expression in the tumor tissue before and after treatment using semi-quantitative immunohistochemical (IHC) analysis as a measure of response to therapy

  Baseline up to day 3 of course 2

• Inhibition and concordance of cyclin-dependent kinase (CDK)/Ral and phosphatidylinositol 3 kinase (PI3K)/pAkt pathways as measured in serum and tissue samples

  Up to day 3 of course 2

Study Arms (2)

Arm A (dinaciclib, Akt inhibitor MK2206)

EXPERIMENTAL

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 progression or unacceptable toxicity.

Drug: Akt Inhibitor MK2206; Drug: Dinaciclib; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study

Arm B (Akt inhibitor MK2206, dinaciclib)

EXPERIMENTAL

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.

Drug: Akt Inhibitor MK2206; Drug: Dinaciclib; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study

Interventions

Akt Inhibitor MK2206 DRUG

Given PO

Arm A (dinaciclib, Akt inhibitor MK2206); Arm B (Akt inhibitor MK2206, dinaciclib)

Dinaciclib DRUG

Given IV

Arm A (dinaciclib, Akt inhibitor MK2206); Arm B (Akt inhibitor MK2206, dinaciclib)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm A (dinaciclib, Akt inhibitor MK2206); Arm B (Akt inhibitor MK2206, dinaciclib)

Pharmacological Study OTHER

Correlative studies

Arm A (dinaciclib, Akt inhibitor MK2206); Arm B (Akt inhibitor MK2206, dinaciclib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (5)

University of Colorado Cancer Center - Anschutz Cancer Pavilion

Aurora, Colorado, 80045, United States

Location

University of Colorado

Denver, Colorado, 80217-3364, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

University Health Network-Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (1)

• 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.

  PMID: 25931518 DERIVED

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

MK 2206; dinaciclib

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• Nilofer Azad

  Johns Hopkins University/Sidney Kimmel Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2013
• First Posted: February 4, 2013
• Study Start: January 15, 2013
• Primary Completion: July 12, 2016
• Study Completion: July 12, 2016
• Last Updated: August 22, 2017

Record last verified: 2017-08

Locations

US (4); CA (1)