To determine the doses and schedule appropriate for phase 2 study of sorafenib and vorinostat
with concurrent gemcitabine and radiation therapy (RT) as neoadjuvant treatment of pancreatic
cancer following chemotherapy. RP2Ds and schedule of sorafenib and vorinostat defined as the
doses and schedule that are the same as or less than the MTDs and schedule.
This is a dose-escalation trial employing a standard "3+3" schema of sorafenib and
vorinostat.
The sample size with a total of 5 proposed dose levels and starting at dose level 1B for dose
escalation, the number of patients evaluable for DLT ranges from 4-30. To account for about
20% patients anticipated to subsequently be found to be not evaluable for toxicity,
authorization for enrollment of 36 patients will be sought from regulatory authorities.
Likely scenarios probably involve 12-24 evaluable patients and therefore 15-30 patients will
be enrolled in the study.
After completion of study treatment, patients are followed up for 30 days and then every 2-3
months up to 2 years or until death.
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 60-100 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
