Vatalanib in Treating Patients With Primary or Secondary Myelodysplastic Syndromes

RATIONALE: Vatalanib may be effective in preventing the development of leukemia in patients who have myelodysplastic syndromes.

PURPOSE: This phase II trial is studying vatalanib to see how well it works in treating patients with primary or secondary myelodysplastic syndromes.

OBJECTIVES:

Primary

* Determine the response rate, in terms of hematologic improvement and complete and partial remission, in patients with primary or secondary (therapy-related) myelodysplastic syndromes treated with vatalanib.
* Determine the time to transformation to acute myeloid leukemia (at least 20% blasts) or death in patients treated with this drug.

Secondary

* Determine the safety of this drug in these patients.
* Determine the duration of response in patients treated with this drug.
* Determine the cytogenetic response rate in patients treated with this drug.
* Determine the overall and progression-free survival of patients treated with this drug.
* Determine the incidence of infections requiring antibiotics or hospitalization or bleeding requiring red blood cell transfusions in patients treated with this drug.

OUTLINE: This is a multicenter study. Patients are stratified\* according to risk group (low grade \[refractory anemia with or without ringed sideroblasts, refractory anemia with excess blasts-1, refractory cytopenia with multilineage dysplasia with or without ringed sideroblasts, myelodysplastic syndromes-unclassified, or chronic myelomonocytic leukemia-1\] vs high grade \[refractory anemia with excess blasts-2 or chronic myelomonocytic leukemia-2\]).

NOTE: \*Stratification according to risk (low vs high) does not occur after 11/30/06.

Patients receive oral vatalanib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with a complete response (CR) receive 6 additional courses after documentation of a CR.

Patients are followed periodically for up to 5 years from study entry.

PROJECTED ACCRUAL: Approximately 144 patients will be accrued for this study within 2.5 years.

Eligibility Criteria:
DISEASE CHARACTERISTICS:

* Diagnosis of primary or secondary (therapy-related) myelodysplastic syndromes\* (MDS), including the following cellular types:

  * Refractory anemia (RA)\*\*
  * RA with excess blasts (RAEB)-1
  * RA with ringed sideroblasts\*\*
  * Refractory cytopenia with multilineage dysplasia
  * Refractory cytopenia with multilineage dysplasia with ringed sideroblasts\*
  * MDS-unclassified\*\*
  * MDS associated with isolated del (5q)\*\*
  * Chronic myelomonocytic leukemia (CMML)-1 NOTE: \*High-risk MDS (i.e., RAEB-2 or CMML-2) is closed to accrual as of 11/30/06

NOTE: \*\*Accompanied with at least 1 of the following laboratory values: hemoglobin less than 10 g/dL, platelet count less than 50,000/mm3, or absolute neutrophil count less than 1,000/mm3

* No prior leukemia (i.e., 20% or greater blasts)
* No prior primary or metastatic brain tumor or carcinomatous meningitis

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* WHO 0-2

Life expectancy

* Not specified

Hematopoietic

* See Disease Characteristics

Hepatic

* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* AST no greater than 2.5 times ULN
* APTT no greater than 1.5 times ULN
* INR no greater than 1.5

Renal

* Creatinine no greater than 1.5 times ULN
* Urine protein negative by urinalysis

  * Protein 1+ by dipstick allowed provided total urine protein no greater than 500 mg AND creatinine clearance at least 50 mL/min by 24-hour urine collection

Cardiovascular

* No significant cardiac or vascular events within the past 6 months, including any of the following:

  * Acute myocardial infarction
  * Unstable angina
  * Uncontrolled hypertension
  * Severe peripheral vascular disease (e.g., ischemic pain at rest or nonhealing ulcers or wounds)
  * New York Heart Association class II-IV congestive heart failure
  * Cardiac arrhythmia
  * Disseminated intravascular coagulation or other coagulopathies
  * Deep vein or arterial thrombosis
* No history of congenital long QTc syndrome or elongated QTc (\> 450 msec for males or 470 for females)

Pulmonary

* No pulmonary embolism within the past 6 months

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective barrier contraception during and for at least 3 months after study participation
* No need for full anticoagulation within the past 6 months
* No significant hemorrhage (e.g., visceral, gastrointestinal, genitourinary, or gynecological) requiring red blood cell transfusion within the past month
* No known cerebral aneurysms, other cerebrovascular malformations, or CNS bleeding
* No unhealed fractures, wounds, or ulcers

PRIOR CONCURRENT THERAPY:

Biologic therapy

* More than 12 months since prior autologous stem cell or allogeneic transplantation
* More than 6 months since prior antiangiogenic agents
* More than 1 month since prior interferon for MDS
* More than 1 month since prior hematopoietic growth factors for MDS
* More than 1 month since prior epoetin alfa (EPO) for MDS
* More than 1 month since prior thalidomide for MDS
* More than 1 month since prior immunotherapy for MDS
* No concurrent prophylactic growth factors or cytokines (e.g., filgrastim \[G-CSF\], sargramostim \[GM-CSF\], EPO or EPO-derivatives, or interleukin-11)

Chemotherapy

* No prior low-dose antimetabolites for MDS (e.g., hydroxyurea, azacitidine, or low-dose cytarabine)
* More than 12 months since prior chemotherapy for another disease\* NOTE: \*Not MDS or leukemia

Endocrine therapy

* More than 1 month since prior corticosteroids for MDS
* More than 1 month since prior androgens for MDS

Radiotherapy

* More than 12 months since prior radiotherapy for another disease\* NOTE: \*Not MDS or leukemia

Surgery

* More than 1 month since prior surgery, including needle biopsy of visceral organs and recovered

  * Bone marrow biopsy allowed
* More than 2 weeks since prior placement of a subcutaneous or tunneled venous access device (e.g., PortaCath or Hickman's catheter) and adequately healed

Other

* No prior cytotoxic therapy for MDS
* More than 1 month since prior administration of any of the following medications for MDS:

  * Danazol
  * Retinoids
  * Amifostine
  * Investigational agents
* No concurrent administration of any of the following medications:

  * Warfarin
  * Heparin
  * Derivatives of heparin
  * Other anticoagulants
* No concurrent grapefruit or grapefruit juice