Clinical Trials /

Filgrastim, Cladribine, Cytarabine, and Mitoxantrone With Sorafenib in Treating Patients With Newly-Diagnosed, Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

NCT02728050

Description:

This phase I/II trial studies the side effects and best dose of filgrastim (granulocyte colony-stimulating factor [G-CSF]), cladribine, cytarabine, and mitoxantrone, when given together with sorafenib and to see how well they work in treating patients with newly-diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome (likely to be more aggressive). Drugs used in chemotherapy, such as cladribine, cytarabine, and mitoxantrone 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. Colony-stimulating factors, such as filgrastim, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving filgrastim, cladribine, cytarabine, and mitoxantrone together with sorafenib may kill more cancer cells.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Filgrastim, Cladribine, Cytarabine, and Mitoxantrone With Sorafenib in Treating Patients With Newly-Diagnosed, Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
  • Official Title: Addition of Sorafenib to G-CSF, Cladribine, Cytarabine and Mitoxantrone (G-CLAM) in Adults With Newly-Diagnosed Acute Myeloid Leukemia (AML) Independent of FLT3-ITD Status: A Phase 1/2 Study

Clinical Trial IDs

  • ORG STUDY ID: 9510
  • SECONDARY ID: NCI-2016-00286
  • SECONDARY ID: 9510
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG1016000
  • NCT ID: NCT02728050

Conditions

  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
  • de Novo Myelodysplastic Syndrome
  • Myelodysplastic Syndrome
  • Myeloproliferative Neoplasm

Interventions

DrugSynonymsArms
Cladribine2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251Treatment (sorafenib, G-CLAM)
Cytarabine.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, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (sorafenib, G-CLAM)
FilgrastimFILGRASTIM, LICENSE HOLDER UNSPECIFIED, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim, Nivestym, Filgrastim-aafiTreatment (sorafenib, G-CLAM)
MitoxantroneDihydroxyanthracenedione, MitozantroneTreatment (sorafenib, G-CLAM)
Sorafenib284461-73-0, BAY 43-9006, Bay-439006Treatment (sorafenib, G-CLAM)

Purpose

This phase I/II trial studies the side effects and best dose of filgrastim (granulocyte colony-stimulating factor [G-CSF]), cladribine, cytarabine, and mitoxantrone, when given together with sorafenib and to see how well they work in treating patients with newly-diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome (likely to be more aggressive). Drugs used in chemotherapy, such as cladribine, cytarabine, and mitoxantrone 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. Colony-stimulating factors, such as filgrastim, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving filgrastim, cladribine, cytarabine, and mitoxantrone together with sorafenib may kill more cancer cells.

Detailed Description

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

      INDUCTION: Patients receive mitoxantrone intravenously (IV) over 60 minutes on days 1-3 and
      sorafenib orally (PO) twice daily (BID) on days 10-19 in the absence of disease progression
      or unacceptable toxicity. Patients also receive filgrastim subcutaneously (SC) once daily
      (QD) on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine IV QD over 2
      hours on days 1-5 in the absence of disease progression or unacceptable toxicity. Patients
      achieving partial remission (including MRD positive [pos] CR, CR with incomplete platelet
      recovery [CRp], and CR with incomplete count recovery [CRi]) or persistent AML may receive up
      to 2 cycles of induction therapy per the discretion of the treating physician.

      POST-REMISSION: Patients receive sorafenib PO BID on days 8-27 or 3 days prior to next cycle
      of treatment, whichever occurs first. Patients also receive filgrastim subcutaneously SC QD
      on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine IV QD over 2 hours on
      days 1-5 in the absence of disease progression or unacceptable toxicity. Patients achieving
      MRDneg CR may receive up to 4 cycles of post-remission therapy. Patients achieving disease
      response (MRDpos CR, CRi/CRp, or persistent disease) may receive up to two induction cycles
      and 1 cycle of post-remission therapy with mitoxantrone omitted in cycle 3. If they then
      enter MRDneg CR, they can proceed with up to a total of 4 cycles of post-remission therapy.

      MAINTENANCE THERAPY: Patients achieving MRDneg CR may receive maintenance therapy of
      sorafenib PO BID for up to 1 year.

      After completion of study treatment, patients are followed up every 3 months for up to 5
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (sorafenib, G-CLAM)ExperimentalSee Detailed Description.
  • Cladribine
  • Cytarabine
  • Filgrastim
  • Mitoxantrone
  • Sorafenib

Eligibility Criteria

        Inclusion Criteria:

          -  Newly diagnosed disease with either a diagnosis of "high-risk" MDS (>= 10% blasts in
             marrow or blood), high-risk myeloproliferative neoplasm (MPN; >= 10% blasts in blood
             or bone marrow), 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; patients with biphenotypic AML are eligible; such "high-risk" MDS or
             MPN have natural history much closer to AML than to lower risk MDS or MPN and have
             responded similarly to "AML-type" therapy

          -  Outside diagnostic material is acceptable as long as peripheral blood and/or bone
             marrow slides are reviewed at the study institution by appropriate clinical staff;
             flow cytometric analysis of peripheral blood and/or bone marrow should be performed
             according to institutional practice guidelines

          -  Treatment-related mortality (TRM) score =< 13.1 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, or acute
             symptoms can be treated with leukapheresis or may receive up to 2 doses of cytarabine
             (up to 500 mg/m^2/dose) prior to study day 0 enrollment

          -  Bilirubin =< 2 times institutional upper limit of normal unless elevation is thought
             to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (assessed
             within 10 days prior to study day 0)

          -  Serum creatinine =< 2.0 mg/dL (assessed within 10 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

          -  Women of childbearing potential and men must agree to use adequate contraception
             beginning at the signing of the consent until at least 3 months after the last dose of
             study drug

          -  Provide written informed consent (or legal representative)

        Exclusion Criteria:

          -  Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not
             considered candidate for CML-directed tyrosine kinase inhibitor treatment (excluding
             sorafenib)

          -  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 24-48 hours prior to study day 0,
             unless fever is thought to be secondary to the underlying hematologic disease

          -  Active or clinically significant (or symptomatic) cardiac disease, including active
             coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other
             than beta blockers or digoxin within the last 3 months, unstable angina (anginal
             symptoms at rest), new-onset angina within 3 months before randomization, or
             myocardial infarction within 6 months before study day 0

          -  Previous receipt of azacitidine, decitabine, anthracyclines, cytarabine, or other
             nucleoside analogues for treatment of AML or MPN/MDS other than as noted for
             cytarabine

          -  Pregnancy or lactation

          -  Concurrent treatment with any other investigational agent that has anti-leukemia
             activity or another drug with anti-AML-activity
      
Maximum Eligible Age:60 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) (Phase I)
Time Frame:28 days
Safety Issue:
Description:Will be defined as the highest dose studied in which the incidence of dose-limiting toxicity is < 33% assuming at least 6 patients have been treated at this dose.

Secondary Outcome Measures

Measure:Complete response (CR)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Overall response rate (ORR)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Event-free survival (EFS)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Relapse-free survival (RFS)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Incidence of toxicity
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Measure:Quality of life (QOL) scores
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. Will be recorded and summarized using descriptive methods including boxplots, histograms, and statistical summary measures (medians, means, standard deviation, N, and proportions).
Measure:Costs, obtained by cost records
Time Frame:Up to 5 years
Safety Issue:
Description:Will be recorded and summarized using descriptive methods including boxplots, histograms, and statistical summary measures (medians, means, standard deviation, N, and proportions).
Measure:Number of days in hospital
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Number of hospital admissions
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Mean duration of hospital stays
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Number of days in the intensive care unit
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Number of blood product transfusions received
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Number of episodes of febrile neutropenia
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Number of days requiring antibiotic use
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Number of visits to the emergency department
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Number of clinic visits
Time Frame:Up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Washington

Last Updated

June 29, 2021