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Imatinib Mesylate to Treat Myeloproliferative Hypereosinophilic Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:
NCT00044304
First received: August 24, 2002
Last updated: June 17, 2014
Last verified: May 2014

August 24, 2002
June 17, 2014
August 2002
June 2018   (final data collection date for primary outcome measure)
reduction of absolute eosinophil count to& lt; 1500/mm3 [ Time Frame: 1, 3 6 9 and 12 month ] [ Designated as safety issue: Yes ]
Not Provided
Complete list of historical versions of study NCT00044304 on ClinicalTrials.gov Archive Site
  • Measures of eosinophil activation [ Time Frame: 1,3,6,9 and 12 months ] [ Designated as safety issue: No ]
  • Resolution of bone marrow abnormalities [ Time Frame: 4-8 weeks ] [ Designated as safety issue: No ]
  • Reduction or disappearance of FIP1L1/PDGFRAtranscript in applicable subjects [ Time Frame: 1,3,6,9 and 12 months ] [ Designated as safety issue: No ]
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Imatinib Mesylate to Treat Myeloproliferative Hypereosinophilic Syndrome
A Pilot Study of the Safety and Efficacy of Imatinib Mesylate in Reducing Eosinophilia in Patients With the Myeloproliferative Variant Hypereosinophilic Syndrome (HES) or Non-Myeloproliferative HES Refractory to Standard Therapy

The purpose of this study is to evaluate the safety and efficacy of the tyrosine kinase inhibitor, imatinib mesylate (Gleevec ) in reducing peripheral blood eosinophilia in patients with the myeloproliferative form of hypereosinophilic syndrome (HES). Patients with the hypereosinophilic syndrome who meet a set of criteria designed to select patients with the myeloproliferative form of the disease, as well as patients without myeloproliferative disease who are refractory to standard therapy for HES, will be admitted on this protocol. A thorough clinical evaluation will be performed with emphasis on potential sequelae of eosinophil-mediated tissue damage. A baseline bone marrow will be obtained to exclude leukemia or lymphoma and to assess the degree and nature of eosinophilopoiesis. Bone marrow, blood cells and/or serum will also be collected to test for the presence of a recently described mutation that is associated with imatinib-responsiveness in HES, and to provide reagents (such as DNA, RNA, and specific antibodies) and for use in the laboratory to address issues related to the mechanism of action of imatinib mesylate in HES. Imatinib mesylate will be initiated at a dose of 400 mg daily, the FDA-approved dose for the treatment of chronic myelogenous leukemia. In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100mg daily and then discontinued. In order to minimize bone marrow suppression, other myelosuppressive agents will be tapered and discontinued during the first week of therapy with imatinib mesylate. Complete blood counts will be performed weekly for the first month and biweekly thereafter. Clinical assessments will be performed every three months to assess progression of end organ damage.

In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100 mg daily and then discontinued. In the event of clinical, hematologic or molecular relapse during the taper, the imatinib dose will be increased to a maximum of 600 mg daily to achieve a second remission. Laboratory monitoring will be performed as above except for molecular monitoring which will be monitored monthly if drug is discontinued or molecular relapse occurs. Once a stable dosing regimen is achieved for greater than or equal to 6 months in subjects who have undergone dose descalation or greater than or equal to 2 years in subjects receiving 300-400 mg of imatinib daily who did not qualify for dose de-escalation, the frequency of NIH visits and end organ assessments will be decreased to 6 months, with molecular monitoring every 3 months and monthly routine laboratory assessments.

This study will evaluate the safety and effectiveness of imatinib mesylate in reducing the number of eosinophils (a type of white blood cell) in patients with hypereosinophilic syndrome (HES). Patients with HES have elevated counts of eosinophils in the blood and body tissues, which can cause damage to these tissues. Although HES can involve any tissues, the heart, nerves, and skin are most often affected. Several drugs, including steroids, interferon, and hydroxyurea can lower eosinophil counts; however, these drugs have drawbacks in that they do not work in all patients with HES, or they may work only temporarily, or patients may develop side effects that require stopping the drugs. Imatinib mesylate is a new drug approved to treat gastrointestinal tumors and chronic myelogenous leukemia. Some data suggest that imatinib mesylate may be useful in treating a subgroup of patients with HES.

Patients with HES who are 18 years of age and older may be eligible for this study. Candidates will be screened with a medical history, physical examination, blood tests, electrocardiogram (EKG), echocardiogram (ultrasound examination of the heart), pulmonary (lung) function tests, eye exam and a bone marrow examination to determine if they fall into the subgroup of patients likely to respond to this therapy. For the bone marrow procedure, an area of skin and bone is numbed and a very sharp needle is inserted into the bone to draw out a sample of bone marrow for evaluation under the microscope.

Patients enrolled in the study will take imatinib mesylate daily. Any other drugs they may be taking for HES, as well as other drugs they are taking that may interact with imatinib mesylate, will be tapered and stopped. If it is not possible to stop taking certain drugs for other conditions, their dosages may be adjusted. Patients will be monitored weekly with laboratory testing during the first month of treatment and whenever neutrophil counts drop below 1500/mm3 or platelets fall below 100,000/mm3. If blood counts remain high enough, monitoring will be reduced to every 2 weeks for 3 months and once a month after that. Patients will have a clinic visit at NIH 1 month after beginning the drug for a clinical and laboratory evaluation, including a repeat bone marrow examination. Patients whose eosinophil counts are not lowered after 4 weeks of treatment will leave the study. Those who respond to therapy will return to NIH every 3 months for a history and physical examination, laboratory tests, EKG, echocardiogram, and pulmonary function testing to determine how treatment is affecting disease progression. In some participants with stable disease where an optimal dose of imatinib mesylate has been identified, visits may be extended to every six months. In addition, the following procedures will be done solely for research purposes:

  • Blood tests to determine the effects of imatinib mesylate on immune cells, including eosinophils.
  • Leukapheresis to study the effects of imatinib mesylate on eosinophils: For this procedure, whole blood is collected through a needle in an arm vein, similar to donating blood. The blood circulates through a machine that separates it into its components, and the white cells are removed. The rest of the blood is returned to the body, either through the same needle or through another needle in the other arm.
  • Bone marrow examinations will be done during the screening tests and again 1 month after starting treatment to look at newly developing cells in the bone marrow.
  • Genetic testing to determine how imatinib mesylate is able to lower eosinophil counts in patients with HES.
Interventional
Phase 2
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Hypereosinophilic Syndrome
Drug: Imatinib Mesylate
Imatinib is a tyrosine kinase inhibitor that selectively inhibits bcr-abl, c-kit and the plateletderived growth factor receptor tyrosine kinases. Imatinib mesylate was approved by the FDA for use in patients with advanced phase CML and in patients in chronic phase failing first line interferon therapy and in as well as for the treatment of gastrointestinal stromal tumors. Drugs used to treat CML have historically been of benefit in the treatment of HES.
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
50
June 2018
June 2018   (final data collection date for primary outcome measure)
  • INCLUSION CRITERIA:

All subjects must meet the established diagnostic criteria for hypereosinophilic syndrome: eosinophilia greater than 1,500/mm(3) on two occasions, no secondary etiology for the eosinophilia despite careful clinical evaluation, and evidence of end organ damage (histologic evidence of tissue infiltration by eosinophils and/or objective evidence of clinical pathology in any organ system that is temporally associated with eosinophilia and not clearly attributable to another cause).

All subjects must fit one of the following three categories:

  1. refractory to or intolerant of steroids
  2. presence of FIP1L1/PDGFRA by RT-PCR
  3. presence of greater than or equal to 4 of the following laboratory criteria suggestive of a myeloproliferative disorder:

i. dysplastic eosinophils on peripheral smear

ii. serum B12 level greater than or equal to 1000 pg/ml

iii. serum tryptase level greater than or equal to 12

iv. anemia and/or thrombocytopenia

v. bone marrow cellularity greater than 80% with left shift in maturation

vi. dysplastic (spindle-shaped) mast cells on bone marrow biopsy

vii. evidence of fibrosis on bone marrow biopsy

viii. dysplastic megakaryocytes on bone marrow biopsy

3. All subjects must be at least 2 years of age.

4. Negative serum beta-hCG within 24 hours prior to drug administration for women of childbearing potential to exclude early pregnancy.

5. All subjects (men and women) must agree to practice abstinence or effective contraception during administration of imatinib mesylate and for 6 months after discontinuation of drug.

Of note, failure of the standard chemotherapeutic agents (steroids, hydroxyurea, and interferon alpha) will not be a prerequisite for participation in this protocol for the following reasons. 1) There is no approved therapy for HES. 2) Steroid therapy in the myeloproliferative subset of HES patients is generally ineffective. 3) Although hydroxyurea and interferon alpha are initially effective in most cases, a majority of patients become refractory to or intolerant of these agents within a relatively short period of time (less than 1 year). 4) Data from other myeloproliferative disorders, including CML, suggest that interferon and imatinib mesylate, but not hydroxyurea, are associated with cytogenetic remission. 5) The reported incidence and severity of side effects from imatinib mesylate in patients with CML appears comparable to (or less than) those associated with interferon alpha.

Although a private physician is not required for inclusion in the study, it is strongly recommended that all subjects have a physician outside the NIH for routine medical care and emergencies.

EXCLUSION CRITERIA:

  1. Pregnancy or nursing women
  2. HIV positivity or other known immunodeficiency
  3. D816V KIT-positive systemic mastocytosis
  4. Absolute neutrophil count less than 1000/mm(3) or platelet count less than 10,000/mm(3) or less than 50,000/m(3) with clinical evidence of bleeding.
  5. Elevated transaminases (greater than 5 times the upper limit of normal) or elevated bilirubin (greater than 3 times the upper limit of normal)
  6. Any condition that, in the investigator s opinion, places the patient at undue risk by participating in the study
Both
2 Years and older
No
Contact: Nicole C Holland-Thomas, R.N. (301) 402-5969 hollandnc@mail.nih.gov
Contact: Amy D Klion, M.D. (301) 435-8903 aklion@niaid.nih.gov
United States
 
NCT00044304
020286, 02-I-0286
Not Provided
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
National Institute of Allergy and Infectious Diseases (NIAID)
Not Provided
Principal Investigator: Amy D Klion, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health Clinical Center (CC)
May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP