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

NCT01132573 | Completed Phase 1

• 7 other identifiers: NCI-2011-01436CDR0000671796JHOC-MD017J091128298U01CA070095P30CA006973
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 4

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.

Conditions

Acute Leukemias of Ambiguous Lineage; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (2)

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

  The frequency of the observed toxicities will be tabulated by type and grade.

  Up to 360 days

• 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 Outcomes (3)

• Percentage change in phosphorylated H2A histone family, member X (H2AX), an indication of DNA damage

  From baseline to 360 days

• Percentage change in apoptosis

  From baseline to 360 days

• Percentage change in histone acetylation

  From baseline to 360 days

Study Arms (1)

Treatment (entinostat and clofarabine)

EXPERIMENTAL

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; Drug: clofarabine; Other: pharmacological study; Other: laboratory biomarker analysis

Interventions

entinostat DRUG

Given PO

Also known as: HDAC inhibitor SNDX-275, SNDX-275

Treatment (entinostat and clofarabine)

clofarabine DRUG

Given IV

Also known as: CAFdA, Clofarex, Clolar

Treatment (entinostat and clofarabine)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (entinostat and clofarabine)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (entinostat and clofarabine)

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

University of Colorado Anschutz Medical Campus

Aurora, Colorado, 80045, United States

Location

University of Colorado

Denver, Colorado, 80217-3364, United States

Location

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21287, United States

Location

Related Publications (1)

• Carraway HE, Sawalha Y, Gojo I, Lee MJ, Lee S, Tomita Y, Yuno A, Greer J, Smith BD, Pratz KW, Levis MJ, Gore SD, Ghosh N, Dezern A, Blackford AL, Baer MR, Gore L, Piekarz R, Trepel JB, Karp JE. Phase 1 study of the histone deacetylase inhibitor entinostat plus clofarabine for poor-risk Philadelphia chromosome-negative (newly diagnosed older adults or adults with relapsed refractory disease) acute lymphoblastic leukemia or biphenotypic leukemia. Leuk Res. 2021 Nov;110:106707. doi: 10.1016/j.leukres.2021.106707. Epub 2021 Sep 10.

  PMID: 34563945 DERIVED

MeSH Terms

Conditions

Leukemia, Biphenotypic, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

entinostat; Clofarabine

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides

Study Officials

• Ivana Gojo

  Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2010
• First Posted: May 28, 2010
• Study Start: April 1, 2010
• Primary Completion: June 1, 2014
• Last Updated: July 17, 2014

Record last verified: 2014-04

Locations

US (4)