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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT01132573

Collaborator

(none)

Enrollment

Locations

Arm

6.8

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Leukemias of Ambiguous Lineage Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia Recurrent Adult Acute Lymphoblastic Leukemia Untreated Adult Acute Lymphoblastic Leukemia	Drug: entinostat Drug: clofarabine Other: pharmacological study Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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.
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:

To determine pharmacokinetics (PK) of entinostat alone and in combination with clofarabine.
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.
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 ABL who are unable or unwilling to tolerate standard multi-agent chemotherapy and patients with relapsed or refractory ALL or ABL).

Patients 40-59 years of age with newly diagnosed ALL receive standard multi-agent induction chemotherapy beginning on day 11. Patients at least 21 years of age in their first relapse with sensitive disease begin initiation of allogeneic transplant after one course of entinostat and clofarabine.

After completion of study treatment, patients are followed up at 30, 60, 90, 180, and 360 days.

Study Design

Study Type:

Interventional

Actual Enrollment :

27 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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/Biphenotypic Leukemia in Newly Diagnosed Older Adults or in Adults With Relapsed and Refractory Disease

Study Start Date :

Apr 1, 2010

Actual Primary Completion Date :

Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (entinostat and clofarabine) Patients receive entinostat PO on days 1 and 8 and clofarabine 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 >= 60 years of age with newly diagnosed ALL or ABL who are unable or unwilling to tolerate standard multi-agent chemotherapy and patients with relapsed or refractory ALL or ABL). Patients 40-59 years of age with newly diagnosed ALL receive standard multi-agent induction chemotherapy beginning on day 11. Patients >= 21 years of age in their first relapse with sensitive disease begin initiation of allogeneic transplant after one course of entinostat and clofarabine.	Drug: entinostat Given PO Other Names: HDAC inhibitor SNDX-275 SNDX-275 Drug: clofarabine Given IV Other Names: CAFdA Clofarex Clolar Other: pharmacological study Correlative studies Other Names: pharmacological studies Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (entinostat and clofarabine)

Patients receive entinostat PO on days 1 and 8 and clofarabine 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 >= 60 years of age with newly diagnosed ALL or ABL who are unable or unwilling to tolerate standard multi-agent chemotherapy and patients with relapsed or refractory ALL or ABL). Patients 40-59 years of age with newly diagnosed ALL receive standard multi-agent induction chemotherapy beginning on day 11. Patients >= 21 years of age in their first relapse with sensitive disease begin initiation of allogeneic transplant after one course of entinostat and clofarabine.

Drug: entinostat

Given PO

Other Names:

HDAC inhibitor SNDX-275

SNDX-275

Drug: clofarabine

Given IV

Other Names:

CAFdA

Clofarex

Clolar

Other: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Frequency of the observed toxicities based on the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [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 [21 days]

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adults age >= 40 years with the established, pathologically-confirmed diagnoses of newly diagnosed ALL or ABL are eligible for study; adults with relapsed and refractory ALL or ABL who are >= 21 years of age and who have progressive disease following their last therapy are eligible for study; the additional following criteria must be met:
For adults with relapsed/refractory ALL, no more than 5 previous regimens
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
Patients must be able to give informed consent
Female patients of childbearing age must have negative pregnancy test
Total white blood cell count (WBC) =< 150,000 with no evidence for ongoing or impending leukostasis
Total bilirubin =< 2.0 mg/dL unless elevated due to Gilbert's disease, hemolysis or leukemic infiltration
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 × upper limit of normal (ULN) unless due to leukemic infiltration
Serum creatinine =< 2.0 mg/dL
Left ventricular ejection fraction (LVEF) >= 45% as measured by echocardiogram (ECHO) or multi gated acquisition (MUGA) scan
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 30 days after study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are >= 4 weeks from stem cell infusion, have no active graft-vs-host disease (GVHD), and meet other eligibility criteria
Patients who fail primary induction therapy or relapse after achieving complete remission (CR) are eligible if they have undergone no more than 5 prior cytotoxic regimen, >= 14 days off cytotoxic chemotherapy, and >= 2 weeks radiation therapy; patients must be off biologic therapies >= 7 days, must be off hematopoietic growth factors >= 3 days; if using hydroxyurea steroids, imatinib, arsenic, interferon, or other non-cytotoxics for blast count control, patient must be off for >= 24 hrs before starting entinostat plus clofarabine

Exclusion Criteria:

Philadelphia chromosome positive ALL
Patients may not have received previous treatment with entinostat or other histone deacetylase (HDAC) inhibitors (including valproic acid) or clofarabine within the previous 6 months
Concomitant chemotherapy, radiation therapy, or immunotherapy
Hyperleukocytosis with >= 150,000 blasts/uL (if using hydroxyurea, steroids, maintenance doses of 6-mercaptopurine and/or methotrexate, arsenic, interferon or leukapheresis for blast count control, patient must be off those agents for 24 hours prior to beginning entinostat plus clofarabine)
Active disseminated intravascular coagulation (DIC)
Active central nervous system (CNS) leukemia; patients with known previous CNS leukemia may continue to receive intrathecal therapy with cytarabine (ara-C), methotrexate, and/or thiotepa plus steroids as prophylaxis against reactivation of active CNS disease
Use of investigational cytotoxic agents within 30 days or any anticancer therapy within 14 days before study entry, except for hydroxyurea and steroids, both of which must be discontinued at least 24 hours before study entry; the patient must have recovered from all acute toxicities from any previous therapy; the patient must have recovered from all acute toxicities from any previous therapy
Patients must have discontinued all growth factors at least 3 days before study
History of severe coronary artery disease, including myocardial infarction within the previous 3 months, arrhythmias other than atrial flutter or fibrillation requiring medication, or uncontrolled congestive heart failure
Dyspnea at rest or with minimal exertion
Active uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible
Patients with active >= grade 2 graft versus host disease (GVHD)
Presence of other life-threatening illness
Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol
Pregnant or nursing women; breastfeeding should be discontinued if the mother is treated with entinostat
Male and female patients who are fertile who do not agree to use an effective barrier method of birth control (i.e., hormonal or barrier method of birth control; abstinence) to avoid pregnancy during the study and for a minimum of 30 days after study treatment
Previous history of or current seizure disorder
Human immunodeficiency virus (HIV) infected patients who have cluster of differentiation (CD4) cell count =< 350/mm^3 or a history of acquired immunodeficiency syndrome (AIDS)-defining conditions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Anschutz Medical Campus	Aurora	Colorado	United States	80045
2	University of Colorado	Denver	Colorado	United States	80217-3364
3	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
4	Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287