A Phase I Study of Sorafenib in Combination With the Histone Deacetylase Inhibitor, Entinostat in Patients With Advanced Cancers
Overview
- Phase
- Phase 1
- Intervention
- entinostat
- Conditions
- Adult Acute Basophilic Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 44
- Locations
- 1
- Primary Endpoint
- Safety as assessed by the NCI CTCAE version 4.0
- Status
- Terminated
- Last Updated
- 12 years ago
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). 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. TERTIARY OBJECTIVES (EXPLORATORY): 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.
Investigators
Eligibility Criteria
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
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
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
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
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
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)