Clinical Trials /

Sorafenib, Busulfan and Fludarabine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia Undergoing Donor Stem Cell Transplant

NCT03247088

Description:

This phase I/II trial studies the best dose of sorafenib when given together with busulfan and fludarabine in treating patients with acute myeloid leukemia that has come back or does not respond to treatment and who are undergoing donor stem cell transplant. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as busulfan and fludarabine, 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. Giving sorafenib with busulfan and fludarabine may work better in treating patients with recurrent or refractory acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sorafenib, Busulfan and Fludarabine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia Undergoing Donor Stem Cell Transplant
  • Official Title: Phase I/II Study of Sorafenib Added to Busulfan and Fludarabine Conditioning Regimen in Patients With Relapsed/Refractory AML Undergoing Stem Cell Transplantation

Clinical Trial IDs

  • ORG STUDY ID: 2016-0592
  • SECONDARY ID: NCI-2018-01607
  • SECONDARY ID: 2016-0592
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03247088

Conditions

  • Allogeneic Hematopoietic Stem Cell Transplant Recipient
  • Donor
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Busulfan1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508Treatment (sorafenib, busulfan, fludarabine, HSCT)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (sorafenib, busulfan, fludarabine, HSCT)
FilgrastimG-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, TevagrastimTreatment (sorafenib, busulfan, fludarabine, HSCT)
FludarabineFluradosaTreatment (sorafenib, busulfan, fludarabine, HSCT)
Mycophenolate MofetilCellcept, MMFTreatment (sorafenib, busulfan, fludarabine, HSCT)
SorafenibBA4 43 9006, BAY 43-9006, Bay-439006Treatment (sorafenib, busulfan, fludarabine, HSCT)
TacrolimusFK 506, Fujimycin, Hecoria, Prograf, ProtopicTreatment (sorafenib, busulfan, fludarabine, HSCT)

Purpose

This phase I/II trial studies the best dose of sorafenib when given together with busulfan and fludarabine in treating patients with acute myeloid leukemia that has come back or does not respond to treatment and who are undergoing donor stem cell transplant. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as busulfan and fludarabine, 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. Giving sorafenib with busulfan and fludarabine may work better in treating patients with recurrent or refractory acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To identify the maximum tolerated dose (MTD) of sorafenib when combined with busulfan and
      fludarabine conditioning regimen.

      II. To obtain preliminary evidence of efficacy.

      SECONDARY OBJECTIVES:

      I. To determine safety of this regimen as per National Cancer Institute (NCI) toxicity
      criteria.

      II. To determine time to neutrophil and platelet engraftment. III. To determine incidence of
      acute and chronic graft versus host disease (GVHD).

      IV. To determine relapse incidence. V. To determine non relapse mortality. VI. To determine
      overall survival.

      TERTIARY OBJECTIVES:

      I. To study chemotherapy resistance. II. To study deoxyribonucleic acid (DNA) damage. III. To
      study immune recovery and cytokines (both in plasma and cells).

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

      PRE-STEM CELL INFUSION: Patients receive sorafenib orally (PO) once daily (QD) or twice daily
      (BID) on days -24 to -5, busulfan intravenously (IV) over 3 hours on days -20 and -13 and -6
      and -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression
      or unacceptable toxicity.

      STEM CELL INFUSION: Patients receive allogeneic hematopoietic stem cell transplant (HSCT) IV
      in the absence of disease progression or unacceptable toxicity.

      POST-STEM CELL INFUSION: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4,
      tacrolimus PO BID beginning day 5 for about 50 days, filgrastim subcutaneously (SC) on day 7
      and sorafenib PO BID beginning between days +30 and +120 for up to 1 year in the absence of
      disease progression or unacceptable toxicity. Patients with matched unrelated donor receive
      mycophenolate mofetil PO thrice daily (TID) or IV over 2 hours TID beginning on day 5 for up
      to 90 days for longer.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (sorafenib, busulfan, fludarabine, HSCT)ExperimentalPRE-STEM CELL INFUSION: Patients receive sorafenib orally PO QD or BID on days -24 to -5, busulfan IV over 3 hours on days -20 and -13 and -6 and -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression or unacceptable toxicity. STEM CELL INFUSION: Patients receive allogeneic HSCT IV in the absence of disease progression or unacceptable toxicity. POST-STEM CELL INFUSION: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4, tacrolimus PO BID beginning day 5 for about 50 days, filgrastim SC on day 7 and sorafenib PO BID beginning between days +30 and +120 for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients with matched unrelated donor receive mycophenolate mofetil PO TID or IV over 2 hours TID beginning on day 5 for up to 90 days for longer.
  • Busulfan
  • Cyclophosphamide
  • Filgrastim
  • Fludarabine
  • Mycophenolate Mofetil
  • Sorafenib
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with acute myeloid leukemia both flt3 positive and negative

          -  Human leukocyte antigen (HLA)-identical sibling or 8/8 matched unrelated donor
             available

          -  Life expectancy of at least 12 weeks (3 months)

          -  Direct bilirubin =< 1 mg/dL

          -  Alanine transaminase (ALT) =< 3 x upper limit of normal

          -  Serum creatinine =< 1.5 x the upper limit of normal

          -  Creatinine clearance >= 50

          -  Diffusing capacity for carbon monoxide (DLCO) > 50% of predicted corrected for
             hemoglobin

          -  Left ventricular ejection fraction (LVEF) >= 50%

          -  Subjects must be able to understand and be willing to sign the written informed
             consent form. A signed informed consent form must be appropriately obtained prior to
             the conduct of any trial-specific procedure

          -  Women of childbearing potential must have a negative serum pregnancy test performed
             within 7 days prior to the start of study drug. Post-menopausal women (defined as no
             menses for at least 1 year) and surgically sterilized women are not required to
             undergo a pregnancy test

          -  Subjects (men and women) of childbearing potential must agree to use adequate
             contraception beginning at the signing of the informed consent form (ICF) until at
             least 30 days after the last dose of study drug. The definition of adequate
             contraception will be based on the judgment of the principal investigator or a
             designated associate

          -  Subject must be able to swallow and retain oral medication

        Exclusion Criteria:

          -  Acute myeloid leukemia in first complete molecular remission and favorable risk
             disease as defined by presence of t(8:21) or inv (16)

          -  Patients with a comorbidity score > 3. The principal investigator is the final arbiter
             of eligibility for comorbidity score > 3

          -  Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure > 90 mm
             Hg [NCI-Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0] on
             repeated measurement) despite optimal medical management

          -  Active or clinically significant cardiac disease including: Congestive heart failure -
             New York Heart Association (NYHA) > class II. Active coronary artery disease. Cardiac
             arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin.
             Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before
             randomization, or myocardial infarction within 6 months before randomization

          -  Evidence or history of bleeding diathesis or coagulopathy. Patients with bleeding due
             to prior thrombocytopenia are permitted

          -  Subject with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v. 4.0 grade 2 or
             higher within 4 weeks before randomization; any other hemorrhage/bleeding event of
             NCI-CTCAE v. 4.0 grade 3 or higher within 4 weeks before randomization

          -  Subjects with thrombotic, embolic, venous, or arterial cerebrovascular event
             (including transient ischemic attacks) within 6 months of informed consent

          -  Subjects who have used strong CYP3A4 inducers (e.g., phenytoin, carbamazepine,
             phenobarbital, St. John's wort [Hypericum perforatum], dexamethasone at a dose of
             greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days
             before randomization

          -  Subjects with any previously untreated or concurrent cancer except cervical cancer
             in-situ, treated basal cell carcinoma, or superficial bladder tumor. Subjects
             surviving a cancer that was curatively treated and without evidence of disease for
             more than 3 years before randomization are allowed. All cancer treatments must be
             completed at least 3 years prior to study entry (i.e., signature date of the informed
             consent form)

          -  Presence of a non-healing wound, non-healing ulcer, or bone fracture

          -  History of organ allograft (including corneal transplant)

          -  Known or suspected allergy or hypersensitivity to any of the study drugs, study drug
             classes, or excipients of the formulations given during the course of this trial

          -  Any malabsorption condition

          -  Women who are pregnant or breast-feeding

          -  Inability to comply with the protocol and/or not willing or not available for
             follow-up assessments

          -  Any medical, psychological, or psychosocial condition which, in the investigator's
             opinion, makes the subject unsuitable for trial participation

          -  Major surgery within 30 days prior to start of study drug

          -  Patients who received inotuzumab and/or gemtuzumab in the past

          -  Therapeutic anticoagulation with vitamin-K antagonists (e.g., warfarin) or with
             heparins and heparinoids. However, prophylactic anticoagulation as described below is
             allowed: Low dose warfarin (1 mg orally, once daily) with prothrombin time
             international normalized ratio (PT-INR). =< 1.5 x upper limit of normal (ULN) is
             permitted. Infrequent bleeding or elevations in PT-INR have been reported in some
             subjects taking warfarin while on sorafenib or capecitabine therapy. Therefore,
             subjects taking concomitant warfarin should be monitored regularly for changes in PT,
             PT-INR or clinical bleeding episodes. Low dose aspirin (=< 100 mg daily). Prophylactic
             doses of heparin or low molecular weight heparin
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) as defined by toxicity (Phase I)
Time Frame:From day -24 pre-transplant to day 30 post-transplant
Safety Issue:
Description:Toxicity is defined as grade 3 or higher regimen-related non-hematologic, non-infectious, and non-graft versus host disease (GVHD) toxicity occurring during the period from day -5 to pre-transplant to day 30 post-transplant. Dose-finding will be done using the Bayesian Model Averaging Continual Reassessment (BMA-CRM) method.

Secondary Outcome Measures

Measure:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 4 years
Safety Issue:
Description:
Measure:OS
Time Frame:Up to 4 years
Safety Issue:
Description:OS will be estimated using the method of Kaplan and Meier. Categorical variables will be tabulated. The relationship between patient prognostic covariates and PFS and OS time will be assessed by Bayesian survival time regression.
Measure:Non-relapse mortality rate
Time Frame:Up to 4 years
Safety Issue:
Description:These events will be tabulated.
Measure:Relapse rate
Time Frame:Up to 4 years
Safety Issue:
Description:These events will be tabulated.
Measure:Graft failure
Time Frame:Up to 4 years
Safety Issue:
Description:These events will be tabulated.
Measure:Incidence of acute and chronic graft versus host disease graded according to National Cancer Institute CTCAE version 4.0
Time Frame:Up to 4 years
Safety Issue:
Description:These events will be tabulated.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 18, 2019