Vatalanib in Treating Patients With Primary or Secondary Myelodysplastic Syndromes
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.
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