Vatalanib in Treating Patients With Primary or Secondary Myelodysplastic Syndromes

Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00072475
• Other study ID #: CALGB-10105
• Secondary ID: U10CA031946CALGB
• Status: Completed
• Phase: Phase 2
• First received: November 4, 2003
• Last updated: November 23, 2015
• Start date: December 2003
• Est. completion date: June 2014

Study information

• Verified date: November 2015
• Source: Alliance for Clinical Trials in Oncology
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 155
• Est. completion date: June 2014
• Est. primary completion date: November 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasms
• Myeloproliferative Disorders
• Preleukemia
• Syndrome

Intervention

Drug:
• vatalanib
Pts registered before 1/15/05 1250 mg/day PO After 1/15/05: Start w/ 750 mg/day PO; escalate q 4 wks in absence of Grade 2 or > tox (1st increase=1000mg/day; 2nd increase 1250 mg/day)

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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-6

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.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Response	Response was measured by International Standardized Response Criteria for MDS; Complete Response: Bone marrow showing < 5% myeloblasts with normal maturation of all cell lines; Hgb > 11 g/dL (untransfused), ANC =1.5 K/L, PLT = 100 K/L, No blasts, no dysplasia; Partial remission: All of the CR criteria (if abnormal at baseline), except BM evaluation. Blasts decreased by = 50% over baseline. Cellularity and morphology are not relevant.; Hematologic improvement: Erythroid (HI-E): For participants with baseline HGB < 11g/dL, Major: > 2g/dL increase, transfusion independence. Minor: 1-2g/dL increase, = 50% decrease in transfusion requirements; Platelet (HI-P): For participants with baseline PLT < 100 K/L: Major: absolute increase of > 30 K/L, transfusion independence. Minor: = 50% increase (net increase of >10 K/L); Neutrophil (HI-N): For participants with baseline ANC < 1.5 K/L, Major: > 100% increase (net increase > 0.5 K/L). Minor: > 100% increase (absolute increase < 0.5 K/L)	Duration of study (up to 5 years)	No
Primary	Time to Transformation to AML	Time to transformation to AML is defined as the time from registration to the transformation of MDS to AML or death of any cause. Participants not meeting these criteria were censored at the date of last follow-up. This outcome was estimated using the Kaplan Meier method.	Duration of study (up to 5 years)	No
Secondary	Duration of Response	Duration of response (DOR) was defined as the time from response (complete remission, partial remission or hematologic improvement) to progression or death of any cause. Responding and alive patients were censored at the date of last follow-up. The median DOR with 95% CI was estimated using the Kaplan Meier method.; Response was measured by International Standardized Response Criteria for MDS (described in above outcome measure).	5 yrs	No
Secondary	Overall Survival	Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method.	Duration of study (up to 5 years)	No
Secondary	Progression-free Survival	Progression free survival (PFS) was defined as the time from registration to progression or death of any cause. Progression free and alive patients were censored at the date of last clinical assessment. The median PFS with 95% CI was estimated using the Kaplan Meier method.; Progression is defined as; For patients with <5% bone marrow blasts: =50% increase in blasts to >5% blasts; For patients with 5-10% bone marrow blasts: =50% increase to >10% blasts; For patients with 10-19% bone marrow blasts: increase to =20% blasts; One or more of the following: 50% or greater decrement from maximum remission/response levels in ANC < 1.5 K/L or PLT< 100 K/L, or reduction in HGB by at least 2 g/dL or becoming transfusion dependent; Progression after HI: Includes one or more of the following; Decrement of 50% or greater from maximum response levels in ANC < 1.5 K/L or PLT < 100 K/L; Reduction in HGB concentration by at least 2 g/dL; Becoming transfusion dependent	Duration of study (up to 5 years)	No