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Filgrastim, Cladribine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2016 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT02044796
First received: January 22, 2014
Last updated: September 26, 2016
Last verified: September 2016
  Purpose
This phase I/II trial studies the side effects and best dose of mitoxantrone hydrochloride when given together with filgrastim, cladribine, and cytarabine and to see how well they work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndromes that is newly diagnosed, has returned, or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Condition Intervention Phase
Acute Biphenotypic Leukemia
de Novo Myelodysplastic Syndrome
Previously Treated Myelodysplastic Syndrome
Recurrent Adult Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndrome
Untreated Adult Acute Myeloid Leukemia
Drug: Cladribine
Drug: Cytarabine
Biological: Filgrastim
Other: Laboratory Biomarker Analysis
Drug: Mitoxantrone Hydrochloride
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1/2 Trial of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndromes (MDS)

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Minimal residual disease negative CR rate in patients with newly diagnosed disease (Phase II) [ Time Frame: Up to day 45 after start of second course of induction chemotherapy ] [ Designated as safety issue: No ]
  • MTD of mitoxantrone hydrochloride, defined as the highest dose studied in which the incidence of dose-limiting toxicity is < 33%, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I) [ Time Frame: Up to day 45 after start of induction chemotherapy ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Overall survival (OS) rate (Phase II expansion cohort) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    In addition to the formal test of 12-month OS, the entire survival curve will be estimated using the Kaplan-Meier method. OS of this cohort will be compared to a historical cohort treated with standard of care using Cox regression methods.

  • Remission rate (CR and CRp) of this regimen in patients with relapsed/refractory disease (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 199
Study Start Date: January 2014
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (filgrastim, mitoxantrone, cladribine, cytarabine)

INDUCTION CHEMOTHERAPY (G-CLAM): Patients receive G-CLAM chemotherapy comprising filgrastim SC daily on days 0-5, mitoxantrone hydrochloride IV over 60 minutes on days 1-3, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Patients achieving CRi, partial remission, or persistent disease may receive a second course of induction chemotherapy. Patients achieving CR or CRp may continue on to Consolidation Chemotherapy.

CONSOLIDATION CHEMOTHERAPY (G-CLA): Beginning within 6 weeks of achieving CR/CRp/CRi, patients receive G-CLA comprising filgrastim SC on days 0-5, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Treatment continues for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Drug: Cladribine
Given IV
Other Names:
  • 2-CdA
  • 2CDA
  • CdA
  • Cladribina
  • Leustat
  • Leustatin
  • Leustatine
  • RWJ-26251
Drug: Cytarabine
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-Cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosar-U
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453
Biological: Filgrastim
Given SC
Other Names:
  • Filgrastim XM02
  • G-CSF
  • Neupogen
  • r-metHuG-CSF
  • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
  • rG-CSF
  • Tbo-filgrastim
  • Tevagrastim
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • Dihydroxyanthracenedione Dihydrochloride
  • Mitoxantrone Dihydrochloride
  • Mitoxantroni Hydrochloridum
  • Mitozantrone Hydrochloride
  • Mitroxone
  • Neotalem
  • Novantrone
  • Onkotrone
  • Pralifan

Detailed Description:

PRIMARY OBJECTIVES:

I. Estimate the maximum tolerated dose (MTD) of dose-intensified mitoxantrone (mitoxantrone hydrochloride) as part of the G-CSF (filgrastim), cladribine, cytarabine, mitoxantrone hydrochloride (G-CLAM) regimen separately for adults with newly diagnosed acute myeloid leukemia (AML) and those with relapsed/refractory AML receiving first or greater salvage therapy.

SECONDARY OBJECTIVES:

I. To determine, within the limits of a phase 1/2 study, disease response and duration of remission separately for patients with newly diagnosed and relapsed/refractory AML.

II. To describe, within the limits of a phase 1/2 study, the toxicity profile of the study regimen separately for patients with newly diagnosed and relapsed/refractory AML.

OUTLINE: This is a phase I, dose-escalation study of mitoxantrone hydrochloride followed by phase II study.

INDUCTION CHEMOTHERAPY (G-CLAM): Patients receive G-CLAM chemotherapy comprising filgrastim subcutaneously (SC) daily on days 0-5, mitoxantrone hydrochloride intravenously (IV) over 60 minutes on days 1-3, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Patients achieving complete remission with incomplete peripheral blood count recovery (CRi), partial remission, or persistent disease may receive a second course of induction chemotherapy. Patients achieving complete remission (CR) or CR with incomplete platelet count recovery (CRp) may continue on to Consolidation Chemotherapy.

CONSOLIDATION CHEMOTHERAPY (G-CLA): Beginning within 6 weeks of achieving CR/CRp/CRi, patients receive G-CLA comprising filgrastim SC on days 0-5, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Treatment continues for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 5 years.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • For patients with newly diagnosed disease: diagnosis of "high-risk" myelodysplastic syndrome (MDS) (>= 10% blasts) or AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2008 World Health Organization (WHO) classification; for patients with relapsed/refractory disease: prior diagnosis of "high-risk" MDS or non-APL AML, with relapsed/refractory disease according to standard criteria requiring first or subsequent salvage therapy; patients with biphenotypic AML are eligible
  • Outside diagnostic material is acceptable as long as peripheral blood and/or bone marrow slides are reviewed at the study institution; flow cytometric analysis of peripheral blood and/or bone marrow should be performed according to institutional practice guidelines
  • For patients with relapsed/refractory disease: patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT) for MDS/AML are eligible if relapse occurs provided symptoms of graft-versus host disease are well controlled with stable use of immunosuppressive agents
  • Treatment-related mortality (TRM) score =< 6.9 as calculated with simplified model
  • The use of hydroxyurea prior to study registration is allowed; patients with symptoms/signs of hyperleukocytosis or white blood cell (WBC) > 100,000/uL can be treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500 mg/m^2/dose) prior to enrollment
  • For patients with relapsed/refractory disease: patients may have previously received chemotherapy with a mitoxantrone- or cladribine-based regimen for MDS or AML; if that patient has received G-CLAM before and has been sensitive to this regimen, eligibility will be determined on a case-by-case basis by the study principal investigator (PI)
  • Should be off any active systemic therapy for AML with the exception of hydroxyurea for at least 14 days prior to study registration unless patient has rapidly progressive disease, and all grade 2-4 non-hematologic toxicities should have resolved
  • Bilirubin < 2.5 x institutional upper limit of normal (IULN) unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (assessed within 14 days prior to study day 0)
  • Serum creatinine =< 2.0 mg/dL (assessed within 14 days prior to study day 0)
  • Left ventricular ejection fraction >= 45%, assessed within 3 months prior to study day 0, e.g. by multi gated acquisition scan (MUGA) scan or echocardiography, or other appropriate diagnostic modality and no clinical evidence of congestive heart failure; if the patient had anthracycline-based therapy since the most recent cardiac assessment, cardiac evaluation should be repeated if there is clinical or radiographic suspicion of cardiac dysfunction, or if the previous cardiac assessment was abnormal
  • Women of childbearing potential and men must agree to use adequate contraception
  • Provide written informed consent

Exclusion Criteria:

  • Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not considered candidate for tyrosine kinase inhibitor treatment
  • Concomitant illness associated with a likely survival of < 1 year
  • Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with anti-microbials and/or controlled or stable (e.g. if specific, effective therapy is not available/feasible or desired [e.g. chronic viral hepatitis, human immunodeficiency virus (HIV)]); patient needs to be clinically stable as defined as being afebrile and hemodynamically stable for 24 hours; patients with fever thought to be likely secondary to leukemia are eligible
  • Known hypersensitivity to any study drug
  • Pregnancy or lactation
  • Treatment with any other investigational agent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02044796

Locations
United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Roland B. Walter    206-667-3599    rwalter@fredhutch.org   
Principal Investigator: Roland B. Walter         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Roland Walter Fred Hutch/University of Washington Cancer Consortium
  More Information

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT02044796     History of Changes
Other Study ID Numbers: 2734.00  NCI-2013-02465  2734.00  P30CA015704 
Study First Received: January 22, 2014
Last Updated: September 26, 2016
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Leukemia
Syndrome
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasm Metastasis
Leukemia, Biphenotypic, Acute
Neoplasms by Histologic Type
Neoplasms
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplastic Processes
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Cladribine
Mitoxantrone
Lenograstim
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents

ClinicalTrials.gov processed this record on December 07, 2016