Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Related Information
Registry Information

Alternate Title

Vatalanib in Treating Patients With Primary or Secondary Myelodysplastic Syndromes

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Closed	18 and over	NCI	CALGB-10105 NCT00072475

Objectives

Primary

1. 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.
2. Determine the time to transformation to acute myeloid leukemia (at least 20% blasts) or death in patients treated with this drug.

Secondary

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

Entry 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



• Must be registered on CALGB-8461 and CALGB-9665 
  • Patients who are inaspirable after 2 attempts allowed

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

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
• No other malignancy within the past year

Expected Enrollment

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

Outcomes

Response rate as measured by International Standardized Response Criteria for myelodysplastic syndromes (MDS) at 2 months, then every 4 months for 1 year, then every 6 months for 5 years
Time to transformation to acute myeloid leukemia (AML) as measured by WHO criteria for AML at 2 months, then every 4 months for 1 year, then every 6 months for 5 years

Safety as measured by Common Terminology Criteria for Adverse Events (CTCAE) monthly
Duration of response as measured by International Standardized Response Criteria for MDS at 2 months, then every 4 months for 1 year, then every 6 months for 5 years
Cytogenetic response as measured by karyotyping at 2 months, then every 4 months for 1 year, then every 6 months for 5 years
Overall survival as measured by CTCAE at 2 months, then every 4 months for 1 year, then every 6 months for 5 years
Progression-free survival as measured by International Standardized Response Criteria for MDS at 2 months, then every 4 months for 1 year, then every 6 months for 5 years
Incidence of infections or bleeding as measured by CTCAE monthly

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.

Gupta P, Miller AA, Owzar K, et al.: Pharmacokinetics of an oral VEGF receptor tyrosine kinase inhibitor (PTK787/ZK222584) in patients with myelodysplastic syndrome (MDS): Cancer and Leukemia Group B study 10105. [Abstract] J Clin Oncol 24 (Suppl 18): A-6573, 355s, 2006.

Gupta P, Sanford BL, Yu D, et al.: A phase II study of an oral VEGF receptor tyrosine kinase inhibitor (PTK787/ZK222584) in patients with myelodysplastic syndrome (MDS): Cancer and Leukemia Group B study 10105. [Abstract] Blood 108 (11): A-2665, 2006.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Pankaj Gupta, MD, Protocol chair		Ph: 612-467-4135; 866-414-5058 Email: gupta.pankaj@minneapolis.va.gov

Related Information

PDQ® clinical trial CALGB-8461
PDQ® clinical trial CALGB-9665

Registry Information
Official Title		A Phase II Study of an Oral VEGF Receptor Tyrosine Kinase Inhibitor (PTK787/ZK222584) (IND #66370, NSC #719335) in Myelodysplastic Syndrome (MDS)
Trial Start Date		2003-12-15
Trial Completion Date		2005-06-15 (estimated)
Registered in ClinicalTrials.gov		NCT00072475
Date Submitted to PDQ		2003-10-01
Information Last Verified		2009-01-20
NCI Grant/Contract Number		CA31946

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