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A Phase I/II Study of Sorafenib (BAY 43-9006) in Combination With Low Dose ARA-C (CYTARABINE) in Elderly Patients With AML or High-Risk MDS

Phase 1/Phase 2
60 Years
Not Enrolling
Leukemia, Myelodysplastic Syndromes

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Trial Information

A Phase I/II Study of Sorafenib (BAY 43-9006) in Combination With Low Dose ARA-C (CYTARABINE) in Elderly Patients With AML or High-Risk MDS


- To determine the recommended dose of sorafenib tosylate and cytarabine when given in
combination to elderly patients with acute myeloid leukemia or high-risk
myelodysplastic syndromes who are not suitable for intensive chemotherapy. (Phase I)

- To determine the safety, tolerability, toxicity profile, and dose-limiting toxicities
in patients treated with this regimen. (Phase I)

- To estimate the efficacy (as measured by complete response rate) in patients treated
with this regimen. (Phase II)

- To describe the toxic effects and overall response rate (complete and partial) in
patients treated with this regimen. (Phase II)

- To evaluate potential correlates of response in translational research studies
including FLT-3 internal tandem duplications and point mutations in blasts. (Phase II)

OUTLINE: This is a multicenter study.

- Phase I: Patients receive oral sorafenib tosylate twice daily on days 2-28 and
cytarabine subcutaneously twice daily on days 1-10 at the dose level assigned at
registration. Doses of both drugs will be escalated and the recommended doses for the
combination will be determined. Treatment repeats every 28 days for up to 6 courses in
the absence of disease progression or unacceptable toxicity. Patients who respond to
treatment will receive 2 cycles after response criteria are met.

- Phase II: Patients receive sorafenib tosylate and cytarabine as in phase I at the
recommended doses for the combination determined in phase I.

Bone marrow (or blood) samples are collected at baseline and at the end of each course of
study treatment. Baseline samples are analyzed for mutational status of FLT-3 (i.e.,
internal tandem duplication [ITD] and point mutations).

After completion of study treatment, patients are followed at 4 weeks and then every 3
months thereafter until progression and toxicities resolve.

Inclusion Criteria


- Diagnosis of 1 of the following:

- Acute myeloid leukemia (AML) by FAB criteria (By morphology and routine
histochemistry and confirmed, when possible, by flow cytometric analysis of
surface immunophenotype; co-expression of lymphoid markers permitted)

- High-risk myelodysplastic syndromes defined as IPSS category of intermediate-2
or greater

- Must be considered unsuitable for intensive chemotherapy regimens

- No documented CNS involvement


- ECOG performance status 0-2

- AST and ALT ≤ 2 times upper limit of normal (ULN)

- Bilirubin normal

- Creatinine ≤ 1.2 times ULN OR creatinine clearance ≥ 50 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No history of other malignancies, except adequately treated nonmelanoma skin cancer,
curatively treated in situ carcinoma of the cervix, or other solid tumors curatively
treated with no evidence of disease for ≥ 5 years

- No upper gastrointestinal or other conditions that would preclude compliance with or
administration of oral medication

- No serious illness or medical condition that would not permit the patient to be
managed according to the protocol, including any of the following:

- History of significant neurologic or psychiatric disorder that would impair the
ability to obtain consent

- Active, uncontrolled, serious infections

- Active peptic ulcer disease

- Evidence of bleeding diathesis

- No myocardial infarction within the past 6 months

- No congestive heart failure

- No unstable angina

- No active cardiomyopathy or unstable ventricular arrhythmia

- No poorly controlled hypertension (e.g., systolic BP ≥ 150 mm Hg or diastolic BP ≥ 95
mm Hg)

- No known hypersensitivity to the study drugs or their components

- No preexisting hypothyroidism prior to enrollment unless patient is euthyroid on

- No neuropathy ≥ grade 2


- At least 2 days since prior hydroxyurea

- No other prior chemotherapy

- No concurrent therapeutic doses (≥ 2 mg/day) of anticoagulants (e.g., warfarin)

- Doses of up to 2 mg/day given for prophylaxis of thrombosis are accepted
provided INR is ≤ 1.5

- No other concurrent experimental drugs or anticancer therapy

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Recommended phase II dose of sorafenib tosylate when given in combination with cytarabine (Phase I)

Outcome Time Frame:

29 months

Safety Issue:


Principal Investigator

Brian Leber, MD, FRCPC

Investigator Role:

Study Chair

Investigator Affiliation:

McMaster Children's Hospital at Hamilton Health Sciences


Canada: Health Canada

Study ID:




Start Date:

July 2007

Completion Date:

January 2013

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndromes
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • untreated adult acute myeloid leukemia
  • secondary acute myeloid leukemia
  • de novo myelodysplastic syndromes
  • secondary myelodysplastic syndromes
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia