Clinical trial NCT00072475: Vatalanib in Treating Patients With Primary or Secondary Myelodysplastic Syndromes
Official title: A Phase II Study of an Oral VEGF Receptor Tyrosine Kinase Inhibitor (PTK787/ZK222584) (IND #66370, NSC #719335) in Myelodysplastic Syndrome (MDS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Keywords: refractory anemia with excess blasts
refractory anemia with ringed sideroblasts
refractory cytopenia with multilineage dysplasia
chronic myelomonocytic leukemia
de novo myelodysplastic syndromes
secondary myelodysplastic syndromes
myelodysplastic/myeloproliferative neoplasm, unclassifiable
refractory anemia
previously treated myelodysplastic syndromes
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-11-06
Enrollment: 155
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Primary outcomes:
measure: Number of Participants With Response
timeFrame: Duration of study (up to 5 years)
measure: Time to Transformation to AML
timeFrame: Duration of study (up to 5 years)
Secondary outcomes:
measure: Duration of Response
timeFrame: 5 yrs
measure: Overall Survival
timeFrame: Duration of study (up to 5 years)
measure: Progression-free Survival
timeFrame: Duration of study (up to 5 years)
Other outcomes:
Locations:
city: Lewes
country: United States
facility: Tunnell Cancer Center at Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Fort Lauderdale
country: United States
facility: Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital
state: Florida
city: Jupiter
country: United States
facility: Ella Milbank Foshay Cancer Center at Jupiter Medical Center
state: Florida
city: Miami Beach
country: United States
facility: CCOP - Mount Sinai Medical Center
state: Florida
city: Canton
country: United States
facility: Graham Hospital
state: Illinois
city: Carthage
country: United States
facility: Memorial Hospital
state: Illinois
city: Eureka
country: United States
facility: Eureka Community Hospital
state: Illinois
city: Evanston
country: United States
facility: Evanston Northwestern Healthcare - Evanston Hospital
state: Illinois
city: Galesburg
country: United States
facility: Galesburg Clinic, PC
state: Illinois
city: Galesburg
country: United States
facility: Galesburg Cottage Hospital
state: Illinois
city: Havana
country: United States
facility: Mason District Hospital
state: Illinois
city: Hopedale
country: United States
facility: Hopedale Medical Complex
state: Illinois
city: Macomb
country: United States
facility: McDonough District Hospital
state: Illinois
city: Normal
country: United States
facility: BroMenn Regional Medical Center
state: Illinois
city: Normal
country: United States
facility: Community Cancer Center
state: Illinois
city: Ottawa
country: United States
facility: Community Hospital of Ottawa
state: Illinois
city: Ottawa
country: United States
facility: Oncology Hematology Associates of Central Illinois, PC - Ottawa
state: Illinois
city: Pekin
country: United States
facility: Cancer Treatment Center at Pekin Hospital
state: Illinois
city: Peoria
country: United States
facility: Proctor Hospital
state: Illinois
city: Peoria
country: United States
facility: CCOP - Illinois Oncology Research Association
state: Illinois
city: Peoria
country: United States
facility: Oncology Hematology Associates of Central Illinois, PC - Peoria
state: Illinois
city: Peoria
country: United States
facility: Methodist Medical Center of Illinois
state: Illinois
city: Peru
country: United States
facility: Illinois Valley Community Hospital
state: Illinois
city: Princeton
country: United States
facility: Perry Memorial Hospital
state: Illinois
city: Rockford
country: United States
facility: Center for Cancer Care at OSF Saint Anthony Medical Center
state: Illinois
city: Spring Valley
country: United States
facility: St. Margaret's Hospital
state: Illinois
city: Elkhart
country: United States
facility: Elkhart General Hospital
state: Indiana
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology
state: Indiana
city: South Bend
country: United States
facility: CCOP - Northern Indiana CR Consortium
state: Indiana
city: South Bend
country: United States
facility: Memorial Hospital of South Bend
state: Indiana
city: Lewiston
country: United States
facility: Central Maine Comprehensive Cancer Center at Central Maine Medical Center
state: Maine
city: Elkton MD
country: United States
facility: Union Hospital Cancer Program at Union Hospital
state: Maryland
city: St. Joseph
country: United States
facility: Lakeland Regional Cancer Care Center - St. Joseph
state: Michigan
city: Minneapolis
country: United States
facility: Veterans Affairs Medical Center - Minneapolis
state: Minnesota
city: Columbia
country: United States
facility: Ellis Fischel Cancer Center at University of Missouri - Columbia
state: Missouri
city: Kansas City
country: United States
facility: CCOP - Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
state: Missouri
city: North Platte
country: United States
facility: Callahan Cancer Center at Great Plains Regional Medical Center
state: Nebraska
city: Omaha
country: United States
facility: CCOP - Missouri Valley Cancer Consortium
state: Nebraska
city: Omaha
country: United States
facility: Methodist Estabrook Cancer Center
state: Nebraska
city: Omaha
country: United States
facility: Immanuel Medical Center
state: Nebraska
city: Omaha
country: United States
facility: Alegant Health Cancer Center at Bergan Mercy Medical Center
state: Nebraska
city: Omaha
country: United States
facility: Creighton University Medical Center
state: Nebraska
city: Omaha
country: United States
facility: UNMC Eppley Cancer Center at the University of Nebraska Medical Center
state: Nebraska
city: Voorhees
country: United States
facility: Cancer Institute of New Jersey at Cooper - Voorhees
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Manhasset
country: United States
facility: Don Monti Comprehensive Cancer Center at North Shore University Hospital
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Syracuse
country: United States
facility: Veterans Affairs Medical Center - Syracuse
state: New York
city: Utica
country: United States
facility: Faxton Regional Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Presbyterian Cancer Center at Presbyterian Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital, Incorporated
state: North Carolina
city: Hendersonville
country: United States
facility: Pardee Memorial Hospital
state: North Carolina
city: Kinston
country: United States
facility: Kinston Medical Specialists
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
city: Oklahoma City
country: United States
facility: Oklahoma University Cancer Institute
state: Oklahoma
city: Oklahoma City
country: United States
facility: Cancer Care Associates - Mercy Campus
state: Oklahoma
city: Pittsburgh
country: United States
facility: Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital Comprehensive Cancer Center
state: Rhode Island
city: Providence
country: United States
facility: Miriam Hospital
state: Rhode Island
city: Berlin
country: United States
facility: Mountainview Medical
state: Vermont
city: Burlington
country: United States
facility: Fletcher Allen Health Care - University Health Center Campus
state: Vermont
city: Danville
country: United States
facility: Danville Regional Medical Center
state: Virginia
Study officials:
affiliation: Veterans Affairs Medical Center - Minneapolis
name: Pankaj Gupta, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.