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A Phase I Trial of Dinaciclib (SCH727965) and MK-2206 in Metastatic Pancreatic Cancer With an Expansion Cohort in Advanced Pancreatic Cancer

Phase 1
18 Years
Open (Enrolling)
Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer

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Trial Information

A Phase I Trial of Dinaciclib (SCH727965) and MK-2206 in Metastatic Pancreatic Cancer With an Expansion Cohort in Advanced Pancreatic Cancer


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


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

III. Analyze pre-treatment tumor specimens for activation of 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), p-AKT, p-S6, phosphorylated deoxyribonucleic acid
(DNA)-directed ribonucleic acid (RNA) polymerase II subunit RPB1 (pPOLR2), phosphorylated
retinoblastoma protein (pRB), 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 of dinaciclib and Akt inhibitor MK2206. Patients
are randomized to 1 of 2 treatment arms.

ARM A: Patients receive dinaciclib intravenously (IV) over 2 hours on day 1 of course 1.

ARM B: Patients receive Akt inhibitor MK2206 orally (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 in the
expansion cohort in which biopsies will be conducted

- 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 within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- The effects of MK-2206 and dinaciclib on the developing human fetus are unknown; for
this reason, 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 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 from 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
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- 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
CYP3A4 or 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

- Preclinical studies demonstrated the potential of MK-2206 for induction of
hyperglycemia in all preclinical species tested; 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 because MK-2206 and dinaciclib are agents
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with MK-2206 and/or dinaciclib 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 because of the potential for pharmacokinetic interactions with
MK-2206 and dinaciclib; in addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy; appropriate studies will be
undertaken in patients receiving combination antiretroviral therapy when indicated

- Clinically significant ascites

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerable dose (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

Outcome Description:

The proportion of dose-limiting toxicities at each dose level will be reported with exact binomial proportions and 95% confidence intervals.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Nilofer Azad

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Food and Drug Administration

Study ID:




Start Date:

January 2013

Completion Date:

Related Keywords:

  • Acinar Cell Adenocarcinoma of the Pancreas
  • Duct Cell Adenocarcinoma of the Pancreas
  • Recurrent Pancreatic Cancer
  • Stage III Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms
  • Carcinoma, Acinar Cell



Johns Hopkins University Baltimore, Maryland  21205
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
University of Colorado Denver, Colorado  80217