Clinical Trials /

Filgrastim, Cladribine, Cytarabine, and Mitoxantrone With Sorafenib Tosylate 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 hydrochloride, when given together with sorafenib tosylate 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 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. Sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride together with sorafenib tosylate 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 Tosylate 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
  • NCT ID: NCT02728050

Conditions

  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
  • de Novo Myelodysplastic Syndrome
  • High Risk 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, TevagrastimTreatment (sorafenib, G-CLAM)
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanTreatment (sorafenib, G-CLAM)
Sorafenib TosylateBAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenibTreatment (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 hydrochloride, when given together with sorafenib tosylate 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 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. Sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride together with sorafenib tosylate may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the maximum tolerated dose (MTD) of sorafenib (sorafenib tosylate) used in
      combination with dose-intensified mitoxantrone (mitoxantrone hydrochloride) as part of the
      G-CSF, cladribine, cytarabine and mitoxantrone hydrochloride (G-CLAM) regimen in adults with
      newly-diagnosed acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes (MDS).
      (Phase 1) II. To determine if the addition of sorafenib to G-CLAM improves the rate of
      minimal residual disease negative (MRDneg) complete response (CR) compared with our center's
      historical control of G-CLAM alone in adults with newly-diagnosed AML/high-risk MDS. (Phase
      2)

      SECONDARY OBJECTIVES:

      I. To estimate rates of CR, overall response rate (ORR), overall survival (OS), event-free
      survival (EFS), and relapse-free survival (RFS) after the addition of sorafenib to G-CLAM in
      patients with newly-diagnosed AML/high-risk MDS.

      II. To describe the toxicity profile and safety (rate of adverse events) of sorafenib in
      combination with G-CLAM.

      III. To assess the feasibility of incorporating quality of life (QOL), cost and healthcare
      resource utilization endpoints in to a phase 1/2 clinical trial for newly diagnosed AML.

      IV. To investigate, within the limits of a phase 1/2 trial, the impact of study treatment and
      response on quality of life, cost, and healthcare resource utilization for patients with AML
      undergoing intensive chemotherapy.

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

      INDUCTION: Patients receive mitoxantrone hydrochloride intravenously (IV) over 60 minutes on
      days 1-3 and sorafenib tosylate 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 courses of induction therapy per the discretion of the
      treating physician.

      POST-REMISSION: Patients receive sorafenib tosylate PO BID on days 8-27 or 3 days prior to
      next course 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 courses of post-remission therapy.
      Patients achieving disease response (MRDpos CR, CRi/CRp, or persistent disease) may receive
      up to two induction courses and 1 course of post-remission therapy with mitoxantrone
      hydrochloride omitted in course 3. If they then enter MRDneg CR, they can proceed with up to
      a total of 4 courses of post-remission therapy.

      MAINTENANCE THERAPY: Patients achieving MRDneg CR may receive maintenance therapy of
      sorafenib tosylate 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
  • Mitoxantrone Hydrochloride
  • Sorafenib Tosylate

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 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
      
Maximum Eligible Age:60 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD), 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 (Phase I)
Time Frame:28 days
Safety Issue:
Description:

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 using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Quality of life (QOL) scores, assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30
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: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

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