A Phase II Study of an Oral VEGF Receptor Tyrosine Kinase Inhibitor (PTK787/ZK222584) (IND #66370, NSC #719335) in Myelodysplastic Syndrome (MDS)

Inclusion 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