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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01159301
Recruitment Status : Terminated
First Posted : July 9, 2010
Last Update Posted : September 19, 2013
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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 or disease Intervention/treatment 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

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : June 2010
Actual Primary Completion Date : September 2013

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. 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 ]
  2. Safety as assessed by the NCI CTCAE version 4.0 [ Time Frame: Up to 30 days ]

Secondary Outcome Measures :
  1. 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 ]
  2. Pharmacokinetic profile of entinostat [ Time Frame: At baseline and at days 1, 8, 15, 16, and 22 ]
  3. 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 ]
    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01159301

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

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Responsible Party: National Cancer Institute (NCI) Identifier: NCT01159301     History of Changes
Other Study ID Numbers: NCI-2011-01435
NCI-2011-01435 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I-165409 ( Other Identifier: Roswell Park Cancer Institute )
8272 ( Other Identifier: CTEP )
First Posted: July 9, 2010    Key Record Dates
Last Update Posted: September 19, 2013
Last Verified: September 2013

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