| Eligibility |
Inclusion Criteria:
- Adenocarcinoma of the pancreas
- Prior therapy with = 1 prior systemic therapy over a period of at least 2 months (eg,
at least two 4-week cycles of a regimen such as gemcitabine and nab-paclitaxel; or at
least four 2-week cycles of a regimen such as FOLFOX, FOLFIRINOX, or FOLFIRI)
-Candidate for additional therapy consisting of radiation with gemcitabine-
radiosensitization.
- Able to initiate study treatment no later than 9 weeks from last dose of any
antineoplastic component of prior therapy regimen.
- Recovery from = grade 2 toxicities of prior therapy regimen to grade 1 or baseline,
with the exception of anemia and lymphopenia and chronic residual toxicities that in
the opinion of the investigator are not clinically relevant given the known
safety/toxicity profiles of gemicitabine, sorafenib, and vorinostat (eg, alopecia,
changes in pigmentation, stable endocrinopathies). Patients with = grade 2 peripheral
sensory or motor neuropathy are eligible..
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 3 x upper limit
of normal (ULN) for the laboratory
- Total bilirubin <= 1.5 x ULN for the laboratory at the time of enrollment, all forms
of biliary stents allowed
- Creatinine clearance >= 45 mL/min as calculated by the standard Cockcroft-Gault
equation using age, actual weight, creatinine and gender
- International normalized ratio (INR) <= 1.5
- Absolute neutrophil count (ANC) >= 1,500/mm^3
- Platelets >= 100,000/mm^3 (may not be transfused to meet this level for enrollment)
- Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) (version [v]1.1
- Ability to understand and the willingness to sign a written informed consent document
- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of treatment
- Women of childbearing potential and men must agree to use a medically accepted form of
birth control during the treatment and for 2 months following completion of study
treatment
Exclusion Criteria:
- Prior radiotherapy for pancreatic cancer
- Prior surgical resection of pancreatic cancer
- Evidence of metastatic disease
- Any investigational agent within 4 weeks of study treatment initiation
- Diagnosis or treatment for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, any in situ malignancy, or low-risk prostate cancer after curative therapy
- Intolerance of protocol agents as follows:
- Known or presumed intolerance of gemcitabine, vorinostat or sorafenib
- Experienced any of the following toxicities with prior gemcitabine adminstration
(if given): capillary leak syndrome, posterior reversible encephalopathy,
hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, unexplained
dyspnea or other evidence of severe pulmonary toxicity, or severe hepatic
toxicity
- Unable to swallow medication
- Suspected malabsorption or obstruction; note: use of pancreatic enzyme supplements is
allowed to control malabsorption
- Contraindication to antiangiogenic agents, including:
- Bronchopulmonary hemorrhage/bleeding event >= grade 2 (Common Terminology
Criteria for Adverse Events [CTCAE] v4.0) within 12 weeks prior to of treatment
- Any other hemorrhage/bleeding event >= grade 3 (CTCAE v4.0) within 12 weeks prior
to initiation of treatment
- Serious non-healing wound, ulcer, or bone fracture
- Arterial thrombotic or embolic events such as a myocardial infarction or
cerebrovascular accident (including transient ischemic attacks) within the 6 months
prior to initiation of treatment. Incidental clinically insignificant embolic
phenomena that do not require anti-coagulants are not excluded. Also,tumor-associated
thrombus of locally-involved vessels does not count as an exclusion criterion.
- Clinically significant cardiac disease, including major cardiac dysfunction, such as
uncontrolled angina, clinical congestive heart failure with New York Heart Association
(NYHA) class III or IV, ventricular arrhythmias requiring anti-arrhythmic therapy,
recent (within 6 months) myocardial infarction or unstable coronary artery disease
- Concomitant use of other histone deacetylase (HDAC) inhibitors
- Planned ongoing administration of STRONG cytochrome P450, family 3, subfamily A,
polypeptide 4 (CYP3A4) inducers. Examples of clinical inducers and classifications of
strong, moderate, and weak interactions are available through the FDA website (Table
3-3 of website):
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm
- Persistent heart rate (HR) < 50 or > 120 beats per minute (bpm).
- QT(c) = 481 ms (>= grade 2) on electrocardiogram (ECG) prior to initiation of
treatment
- If baseline QTc on screening ECG meets exclusion criteria:
- Check potassium and magnesium serum levels
- Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to
confirm exclusion of patient due to QTc
- For patients with HR >60 of >100 beats per minute (bpm), no manual read of QTc is
required
- For patients with baseline HR < 60 or > 100 bpm, manual read of QT by
cardiologist is required, with Fridericia correction applied to determine QTc
- Planned ongoing treatment with other drugs thought to potentially adversely interact
with study drugs; if such medications have been used, patients must be off of these
agents for >= 2 weeks prior to initiation of treatment:
- Anticoagulants at therapeutic doses
- Immunosuppressants such as tacrolimus, leflunomide or tofacitinib, roflumilast,
pimecrolimus
- Serious uncontrolled infection > grade 2 (CTCAE v4.0)
- Medical, psychological, or social conditions that, in the opinion of the investigator,
may increase the patient's risk or interfere with the patient's participation in the
study or hinder evaluation of the study results
|
