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

This is an interventional treatment trial for Adult Acute Basophilic Leukemia Read More

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