J1269: A Phase I Trial of Dinaciclib (SCH727965) and MK2206 in Metastatic Pancreatic Cancer with an Expansion Cohort in Advanced Pancreatic Cancer
The purpose of this study is to find the maximum tolerated dose and test the safety and toxicity of the combination of the investigational drugs dinaciclib and MK-2206 in patients with advanced pancreatic cancer. We will also be looking at the effectiveness of this combination of study drugs in patients with this type of cancer.
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 equal to less than 1 Life expectancy of greater than 16 weeks Leukocytes greater than equal to 3,000/mcL Absolute neutrophil count greater than equal to 1,500/mcL Platelets greater than equal to 100,000/mcL Total bilirubin equal to less than 1.5 institutional upper limit of normal (IULN) Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) equal to less than 2.5 X IULN if no liver metastasis or equal to less than 5 X IULN if liver metastases are present Creatinine within normal institutional limits OR creatinine clearance greater than equal to 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 product 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] less than 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 Points), or evidence of acute ischemia on ECG; marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval greater than 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
Patients will receive MK-2206 orally each week and dinaciclib as an intravenous infusion each week. A cycle is defined as 28 days with 3 weeks on treatment and 1 week off treatment. MK-2206 and dinaciclib will be escalated sequentially in Part 1, and after the maximum tolerated dose is determined, Part 2 will be enrolled for assessment of translational endpoints Patients will be evaluated for toxicity in clinic every week and every 8 weeks for response using RECIST criteria 1.1 Tumor biopsies will be obtained from patients in Part 2 (the expansion cohort) before treatment (cycle 1) and after treatment (cycle 2). Serum samples will be obtained at time points during cycle 1 and cycle 2 and will reflect pre-treatment, single-agent treatment, and combination therapy. A minimum of 18 and maximum of 48 patients will be enrolled.
04/16/2014 04:02 AM