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

This study has been terminated.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
First received: July 8, 2010
Last updated: September 18, 2013
Last verified: September 2013
This phase I trial is studying the side effects and the best dose of entinostat when given together with sorafenib tosylate in treating patients with advanced or metastatic solid tumors or refractory or relapsed acute myeloid leukemia. Entinostat and sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition Intervention Phase
Adult Acute Basophilic Leukemia
Adult Acute Eosinophilic Leukemia
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Blastic Phase Chronic Myelogenous Leukemia
Recurrent Adult Acute Myeloid Leukemia
Unspecified Adult Solid Tumor, Protocol Specific
Drug: entinostat
Drug: sorafenib tosylate
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Sorafenib in Combination With the Histone Deacetylase Inhibitor, Entinostat in Patients With Advanced Cancers

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum-tolerated dose as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Safety as assessed by the NCI CTCAE version 4.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacokinetic profile of sorafenib tosylate [ Time Frame: At baseline, and at days 15, 16, and 28 of course 1, and day 1 of course 2 ] [ Designated as safety issue: No ]
  • Pharmacokinetic profile of entinostat [ Time Frame: At baseline and at days 1, 8, 15, 16, and 22 ] [ Designated as safety issue: No ]
  • Objective response rate (ORR) based on the best overall response recorded for each patients or according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    For ORR the 95% confidence interval will be estimated. The 95% confidence interval for percent of patients in each RECIST response category (i.e., CR, PR, SD, and PD) and disease control rate will also be estimated.

Enrollment: 44
Study Start Date: June 2010
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (entinostat, sorafenib tosylate)
Patients receive oral entinostat once daily on days 1 and 15 and oral sorafenib tosylate twice daily on days 1-28 (days 15-28 only of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: entinostat
Given orally (PO)
Other Names:
  • HDAC inhibitor SNDX-275
  • SNDX-275
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:


I. To determine the maximum-tolerated dose of entinostat in combination with sorafenib tosylate in patients with advanced, inoperable, or metastatic solid tumors.

II. To determine the safety and tolerability of this regimen in these patients.


I. To determine the pharmacokinetic profile of this regimen in patients with refractory/relapsed acute myeloid leukemia (AML).

II. To assess the preliminary anti-tumor activity of this regimen in patients with advanced, inoperable, or metastatic solid tumors or refractory/relapsed AML.

III. To evaluate histone deacetylase (HDAC) inhibition of histone acetylation in leukemia blast cells.


I. To evaluate the expression of downstream markers of drug activity such as p38, MCL-1, FLT-3, and VEGFR-2 in leukemia blast cells.

II. To evaluate SNDX-induced expression of p21^WAF1/CIP1 in leukemia blast cells.

OUTLINE: This is a multicenter, dose-escalation study of entinostat.

Patients receive oral entinostat once daily on days 1 and 15 and oral sorafenib tosylate twice daily on days 1-28 (days 15-28 only of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients in the expansion cohort undergo blood, bone marrow aspiration, or biopsy for pharmacokinetic studies and biomarker analysis.

After completion of study therapy, patients are followed up for up to 24 months.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01159301

United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Alex Adjei Roswell Park Cancer Institute
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01159301     History of Changes
Other Study ID Numbers: NCI-2011-01435  NCI-2011-01435  CDR0000675600  I-165409  8272 
Study First Received: July 8, 2010
Last Updated: September 18, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Blast Crisis
Hypereosinophilic Syndrome
Leukemia, Basophilic, Acute
Leukemia, Eosinophilic, Acute
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Bone Marrow Diseases
Cell Transformation, Neoplastic
Hematologic Diseases
Leukocyte Disorders
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Histone Deacetylase Inhibitors
Antineoplastic Agents

ClinicalTrials.gov processed this record on May 26, 2016