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