A Phase I Study of Sorafenib in Combination With the Histone Deacetylase Inhibitor, Entinostat in Patients With Advanced Cancers
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Enrollment
- 44
- Locations
- 1
- Primary Endpoint
- Safety as assessed by the NCI CTCAE version 4.0
Study Overview
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.
Detailed Description
PRIMARY OBJECTIVES:
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.
SECONDARY OBJECTIVES:
I. To determine the pharmacokinetic profile of this regimen in patients with refractory/relapsed acute myeloid leukemia (AML).
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- 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
- +15 more not shown
Exclusion Criteria
- Not provided
Arms & Interventions
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.
Intervention: entinostat (Drug)
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.
Intervention: sorafenib tosylate (Drug)
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.
Intervention: pharmacological study (Other)
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.
Intervention: laboratory biomarker analysis (Other)
Outcomes
Primary Outcomes
Safety as assessed by the NCI CTCAE version 4.0
Time Frame: Up to 30 days
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
Secondary Outcomes
- Pharmacokinetic profile of sorafenib tosylate(At baseline, and at days 15, 16, and 28 of course 1, and day 1 of course 2)
- Pharmacokinetic profile of entinostat(At baseline and at days 1, 8, 15, 16, and 22)
- 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(Up to 30 days)