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