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

NCT03247088 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 2016-0592NCI-2018-01607
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (MTD) as defined by toxicity (Phase I)

  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.

  From day -24 pre-transplant to day 30 post-transplant

• Progression-free survival (PFS) (Phase II)

  The method of Thall et al will be used to monitor PFS time. PFS will be estimated using the method of Kaplan and Meier. The relationship between patient prognostic covariates and PFS and overall survival (OS) time will be assessed by Bayesian survival time regression.

  Interval between day of transplant and day of death or disease progression, assessed up to 6 years

Secondary Outcomes (6)

• Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

  Up to 6 years

• OS

  Interval between day of transplant and day of death, assessed up to 6 years

• Non-relapse mortality rate

  Up to 6 years

• Relapse rate

  Up to 6 years

• Graft failure

  Up to 6 years

Study Arms (1)

Treatment (sorafenib, busulfan, fludarabine, HSCT)

EXPERIMENTAL

PRE-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.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Busulfan; Drug: Cyclophosphamide; Biological: Filgrastim; Drug: Fludarabine; Drug: Mycophenolate Mofetil; Drug: Sorafenib; Drug: Tacrolimus

Interventions

Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo allogeneic HSCT IV

Also known as: Allogeneic, Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT, Stem Cell Transplantation, Allogeneic

Treatment (sorafenib, busulfan, fludarabine, HSCT)

Busulfan DRUG

Given IV

Also known as: 1, 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-19508

Treatment (sorafenib, busulfan, fludarabine, HSCT)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-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, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Treatment (sorafenib, busulfan, fludarabine, HSCT)

Filgrastim BIOLOGICAL

Given SC

Also known as: Filgrastim-aafi, G-CSF, Neupogen, Nivestym, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim

Treatment (sorafenib, busulfan, fludarabine, HSCT)

Fludarabine DRUG

Given IV

Also known as: Fluradosa

Treatment (sorafenib, busulfan, fludarabine, HSCT)

Mycophenolate Mofetil DRUG

Given PO

Also known as: CellCept, MMF

Treatment (sorafenib, busulfan, fludarabine, HSCT)

Sorafenib DRUG

Given PO

Also known as: BA4 43 9006, BAY 43-9006, Bay-439006

Treatment (sorafenib, busulfan, fludarabine, HSCT)

Tacrolimus DRUG

Given PO

Also known as: FK 506, Fujimycin, Hecoria, Prograf, Protopic

Treatment (sorafenib, busulfan, fludarabine, HSCT)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>= 18 and =\< 70 years
• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Stem Cell Transplantation; Busulfan; Cyclophosphamide; Filgrastim; Granulocyte Colony-Stimulating Factor; fludarabine; Mycophenolic Acid; Sorafenib; Tacrolimus

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Macrolides; Lactones

Study Officials

• Uday R Popat

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: August 8, 2017
• First Posted: August 11, 2017
• Study Start: July 30, 2017
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: December 15, 2025

Record last verified: 2025-12

Locations

US (1)