Phase I-II Study of Idarubicin, Cytarabine, and Sorafenib (BAY43-9006), an Oral Vascular Endothelial Growth Factor (VEGF), Rapidly Accelerated Fibrosarcoma (RAF) and FMS-like Tyrosine Kinase 3 (FLT3), in Patients With High-risk MDS and AML
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 78
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose (MTD)
Study Overview
Brief Summary
A primary goal of this clinical research study is to find the highest safe dose of sorafenib that can be given in combination with idarubicin and Ara-C for the treatment of acute myelogenous leukemia (AML) and high-risk, myelodysplastic syndrome (MDS).
Once the highest safe dose is found, researchers will then try to learn if this combination treatment can help control AML and high-risk MDS in newly diagnosed patients. The safety of this treatment combination will also be studied.
Detailed Description
The Study Drugs:
Sorafenib is designed to block the function of important proteins in cancer cells. When active, these proteins help cause abnormal growth and behavior of leukemia cells.
Idarubicin and Ara-C are both designed to insert themselves into DNA (the genetic material of cells) and to stop DNA from repairing itself.
Study Groups:
If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 15 Years to 60 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Diagnosis of 1) AML (World Health Organization classification definition of > 20% blasts), or 2) high risk MDS (defined as the presence of > 10% blasts).
- •Patients aged 15 to 60 years are eligible. Patients older than 60 who are deemed fit to receive intensive chemotherapy by the treating physician are eligible after discussion with the Principal Investigator (PI). For the Phase II portion of the study, patients must be chemo-naïve, i.e. not have received any prior chemotherapy (except hydrea) for AML or MDS. They could have received hypomethylator agents, transfusions, hematopoietic growth factors or vitamins. Temporary prior measures such as pheresis or hydrea are allowed. In the Phase I portion, patients with relapsed or refractory AML/MDS are also eligible.
- •Serum biochemical values with the following limits unless considered due to leukemia: 1) creatinine less than or equal to 2 mg/dl, 2) total bilirubin less than or equal to 2 mg/dL, unless increase is due to hemolysis or congenital disorder, and 3) transaminases (SG PT) less than or equal to 2.5 times upper limit of normal (ULN)
- •Ability to take oral medication.
- •Ability to understand and provide signed informed consent.
- •Baseline test of ejection fraction must be >/=50%.
- •Performance status < 3, unless directly related to the disease process as determined by the principal investigator.
Exclusion Criteria
- •Patients with Acute promyelocytic leukemia (APL).
- •Any coexisting medical condition that in the judgment of the treating physician is likely to interfere with study procedures or results.
- •Nursing women, women of childbearing potential with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (such as birth control pills, Intrauterine Device (IUD), diaphragm, abstinence, or condoms by their partner) over the entire course of the study.
- •Any significant, uncontrolled hypertension.
- •Cardiac disease: Congestive heart failure > class II The New York Heart Association (NYHA). Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
- •Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Sorafenib is contraindicated in patients with known severe hypersensitivity to sorafenib or any of the excipients.
- •Known human immunodeficiency virus (HIV) infection or active Hepatitis B or C.
- •Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
- •Pulmonary hemorrhage/bleeding event > or = to Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 within 4 weeks of first dose of study drug.
- •Any other hemorrhage/bleeding event > or = to CTCAE Grade 3 within 4 weeks of first dose of study drug.
- •Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.
- •Use of St. John's Wort or rifampin.
- •Known or suspected allergy to sorafenib or any agent given in the course of this trial.
- •Active clinically serious and uncontrolled infection > CTCAE Grade 2
- •Serious non-healing wound, ulcer, or bone fracture
Arms & Interventions
Sorafenib + Idarubicin + Ara-C
Sorafenib starting dose 400 mg orally for 7 days; Idarubicin 12 mg/m^2 intravenous (IV) daily (days 1-3); and Ara-C 1.5 g/m^2 IV over 24 hours daily (days 1-4)
Intervention: Idarubicin (Drug)
Sorafenib + Idarubicin + Ara-C
Sorafenib starting dose 400 mg orally for 7 days; Idarubicin 12 mg/m^2 intravenous (IV) daily (days 1-3); and Ara-C 1.5 g/m^2 IV over 24 hours daily (days 1-4)
Intervention: Sorafenib (Drug)
Sorafenib + Idarubicin + Ara-C
Sorafenib starting dose 400 mg orally for 7 days; Idarubicin 12 mg/m^2 intravenous (IV) daily (days 1-3); and Ara-C 1.5 g/m^2 IV over 24 hours daily (days 1-4)
Intervention: Ara-C (Drug)
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD)
Time Frame: Twice a week for first two 28 day cycles
MTD is dose level where grade 3-4 sorafenib-attributable toxicity in \<2 of 6 participants. Dose-Limiting Toxicity graded according to the NCI Common Toxicity Criteria version 3.0.
Secondary Outcomes
- Number of Participants With Complete Response(Baseline to 2 years or disease progression.)