Entinostat and Sorafenib Tosylate in Treating Patients With Advanced or Metastatic Solid Tumors or Refractory or Relapsed Acute Myeloid Leukemia

Inclusion Criteria

• •Must meet 1 of the following criteria:
• •* Histologically or cytologically confirmed solid tumors (dose-escalation only)
• •* Locally advanced, inoperable, or metastatic disease
• •* Evaluable or measurable disease
• •* Diagnosis of acute myeloid leukemia (AML) for which no other standard therapy, including stem cell transplantation, is expected to result in meaningful clinical response (expansion cohort only)
• •* Refractory or relapsed disease
• •* Chronic myelogenous leukemia in blast crisis allowed
• •* No acute promyelocytic leukemia with t(15;17)
• •* Must consent to have fresh tumor, bone marrow aspirate, and biopsy obtained
• •No untreated, symptomatic, or unstable brain metastases
• •No active CNS involvement for patients with AML
• •ECOG performance status 0-1
• •ANC ≥ 1,500/mm³ (dose-escalation only)
• •Platelet count ≥ 100,000/mm³ (dose-escalation only)
• •Hemoglobin ≥ 10 g/dL (dose-escalation only)
• •Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• •ALT and AST ≤ 3 times ULN (≤ 5 times ULN for liver metastasis)
• •Creatinine clearance ≥ 40 mL/min
• •Albumin \> 3.0 g/dL
• •Plasma phosphorus \> lower limit of normal (with supplementation)
• •INR ≤ 1.5
• •APTT ≤ 1.5 times ULN (if not on anticoagulants)
• •Able to swallow oral medications
• •≥ 16 years old (expanded cohort patients recruited at the University of Colorado site)
• •Must have tolerated prior sorafenib tosylate (dose: 400 mg twice daily), if applicable
• •Not pregnant or nursing
• •Negative pregnancy test
• •Fertile patients must use effective double-barrier contraception during the study and for 90 days after completion of study therapy
• •No history of cardiac disease, including any of the following:
• •* NYHA class II-IV congestive heart failure
• •* Active coronary artery disease
• •* Prior diagnosis of bradycardia or other cardiac arrhythmia defined as ≥ grade 2 or uncontrolled hypertension
• •* Myocardial infarction (MI) within the past 6 months
• •* Persistent tachycardia
• •* LVEF \< 40% by MUGA
• •* Second- or third-degree heart block
• •* QTc \> 490 msec
• •* ST-T wave changes consistent with acute MI or acute ischemia
• •No clinically active serious infections defined as ≥ grade 2
• •No substance abuse, medical, psychological, or social conditions that may, in the opinion of the Investigator, interfere with the patient's participation or evaluation of the study results
• •No condition that is unstable or that could jeopardize the safety of the patient and his/her study compliance
• •No known HIV infection
• •No significant gastrointestinal disorder that, in the opinion of the Investigator, could interfere with the absorption of entinostat and/or sorafenib tosylate including any of the following:
• •* Significant, uncontrolled inflammatory bowel disease
• •* Abdominal fistula or gastrointestinal perforation within the past 6 months
• •* Extensive small bowel resection
• •* Requiring tube feeding or parenteral hydration and/or nutrition
• •No concurrent immunosuppressive therapies, including high-dose systemic corticosteroids (\> 0.5 mg/kg/day prednisone or equivalent) unless used intermittently or as a tapered course for ≤ 4 weeks
• •Concurrent hydroxyurea and/or anagrelide allowed
• •Concurrent warfarin allowed provided the dose has been stable for the past 2 months and INR has been between 2 and 3
• •More than 4 weeks since prior chemotherapy, immunotherapy, or investigational agents (=\< 2 weeks for leukemia patients in expansion cohort)
• •More than 2 weeks since prior palliative radiotherapy
• •More than 4 weeks since major surgery
• •More than 2 weeks since minor surgery (e.g., talc pleurodesis, excisional biopsy, etc.)
• •Concurrent hormonal therapies (e.g., LHRH antagonists, megestrol, octreotide, calcitonin, etc.) allowed
• •No concurrent strong CYP3A4 inducers or inhibitors, including, but not limited to, any of the following:
• •* Valproic acid
• •* Rifampin
• •* Phenobarbital
• •* Phenytoin
• •* Carbamazepine
• •* Ketoconazole
• •* Erythromycin
• •* Grapefruit
• •No other concurrent anticancer therapy including chemotherapy, radiotherapy (including palliative), or immunotherapy (except hydroxyurea in leukemia patients during course 1)
• •No other concurrent investigational agents