Clinical Trial: Entinostat and Clofarabine in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Poor-Risk Acute Lymphoblastic Leukemia or Bilineage/Biphenotypic Leukemia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase I Study of the Histone Deacetylase Inhibitor Entinostat (SNDX-275, NSC 706995) Plus Clofarabine for Philadelphia Chromosome-Negative, Poor Risk Acute Lymphoblastic Leukemia or Bilineage/Biphen

Brief Summary: This phase I trial studies the side effects and best dose of entinostat when given together with clofarabine in treating patients with newly diagnosed, relapsed, or refractory poor-risk acute lymphoblastic leukemia or bilineage/biphenotypic leukemia. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as clofarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving entinostat with clofarabine may kill more cancer cells.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To determine the feasibility, tolerability, toxicities, and maximum tolerated dose (MTD) of entinostat plus clofarabine for: adult patients age 40 and over with newly diagnosed, poor-risk Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) or bilineage/biphenotypic leukemia (ABL) prior to traditional cyclical multi-agent chemotherapy, and adults age 21 and over with relapsed or refractory ALL/ABL.

II. To determine if entinostat plus clofarabine can induce clinical responses in adults with newly diagnosed, poor-risk ALL/ABL and in adults with relapsed/refractory ALL/ABL.

SECONDARY OBJECTIVES:

I. To determine pharmacokinetics (PK) of entinostat alone and in combination with clofarabine.

II. To obtain descriptive preliminary pharmacodynamic (PD) data regarding the effects of entinostat alone and in combination with clofarabine on histone acetylation and global and gene specific methylation in leukemic blasts.

III. To obtain descriptive preliminary data regarding the effects of entinostat alone and in combination with clofarabine on deoxyribonucleic acid (DNA) damage and apoptosis in leukemic blasts and residual disease monitored by 6-color flow cytometry.

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

Patients receive entinostat orally (PO) on days 1 and 8 and clofarabine intravenously (IV) over 2 hours on days 3-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity (only for patients at least 60 years of age with newly diagnosed ALL or A
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Frequency of the observed toxicities based on the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 360 days ]
    The frequency of the observed toxicities will be tabulated by type and grade.
  • MTD of entinostat followed by clofarabine, defined as the dose at which less than 2 of 3 patients experience dose limiting toxicity graded according to NCI CTCAE version 4.0 [ Time Frame: 21 days ]


Original Primary Outcome:

  • Feasibility and tolerability
  • Toxicities
  • Maximum-tolerated dose
  • Clinical responses


Current Secondary Outcome:

  • Percentage change in phosphorylated H2A histone family, member X (H2AX), an indication of DNA damage [ Time Frame: From baseline to 360 days ]
    Will be evaluated as a continuous variable. Will be estimated including the 95% confidence interval.
  • Percentage change in apoptosis [ Time Frame: From baseline to 360 days ]
    Will be estimated including the 95% confidence interval.
  • Percentage change in histone acetylation [ Time Frame: From baseline to 360 days ]
    Will be estimated including the 95% confidence interval.


Original Secondary Outcome:

  • Pharmacokinetics
  • Pharmacodynamics
  • Effects of entinostat alone and in combination with clofarabine on DNA damage and apoptosis in leukemic blasts and residual disease


Information By: National Cancer Institute (NCI)

Dates:
Date Received: May 26, 2010
Date Started: April 2010
Date Completion:
Last Updated: July 16, 2014
Last Verified: April 2014