Imatinib in KIT-negative Systemic Mastocytosis

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
LUIS ESCRIBANO, Hospital Virgen de la Salud
ClinicalTrials.gov Identifier:
NCT01297777
First received: February 16, 2011
Last updated: April 21, 2015
Last verified: April 2015
  Purpose
The aim of this study is to evaluate the efficacy in terms of clinical and biological response rates of Imatinib Mesylate therapy in patients with systemic mastocytosis lacking KIT mutations.

Condition Intervention Phase
Systemic Mastocytosis
Drug: Imatinib Mesylate
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Imatinib Mesylate Therapy in Systemic Mastocytosis Patients Lacking KIT Mutations

Resource links provided by NLM:


Further study details as provided by Hospital Virgen de la Salud:

Primary Outcome Measures:
  • To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    The grade of bone marrow infiltration is evaluated before and after 6 months of therapy by bone marrow histology and cytology, and flow cytometry performed on highly-purified bone marrow mast cells from patients with B or C findings

  • To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    The grade of bone marrow infiltration is evaluated before and after 6 months of therapy by bone marrow histology and cytology, and flow cytometry performed on highly-purified bone marrow mast cells from patients without B or C findings, and from those with B or C findings who show response at the intermediate check-point (after 6 months of therapy)


Secondary Outcome Measures:
  • To evaluate the effect of Imatinib Mesylate on mastocytosis skin lesions. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Skin lesions are evaluated before and after therapy by macroscopic examination and skin biopsy.

  • To evaluate the effect of Imatinib Mesylate on mastocytosis mast-cell related symptoms. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Clinical symptoms such as pruritus, flushing, gastrointestinal symptoms and anaphylaxis are assessed before and after therapy using a clinical questionnaire that includes the type, frequency and severity of each symptom.

  • To evaluate the effect of Imatinib Mesylate on mastocytosis-related megalies. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Organomegalies and adenomegalies are assessed before and after therapy by abdominal ultrasound.

  • To evaluate the effect of Imatinib Mesylate on mastocytosis-related bone alterations. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Bone alterations are assessed before and after therapy by X-ray survey.

  • To investigate changes after Imatinib Mesilate therapy in mast cell clonality. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Genetic abnormalities are assessed before and after therapy by sequencyng analysis of the c-kit gene and the HUMARA assay.

  • To determine the effect of Imatinib Mesylate therapy on serum tryptase levels. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Serum tryptase is measured before and after therapy.

  • To determine the effect of Imatinib Mesylate therapy in the psychological impact of the disease and the quality of life. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    The psychological impact of the disease and the quality of life of patients are evaluated before and after therapy by the Dermatology Life Quality Index.


Estimated Enrollment: 10
Study Start Date: January 2011
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Imatinib mesylate
Imatinib mesylate 300 or 400 mg daily for 12 months.
Drug: Imatinib Mesylate
  • In patients without B or C findings and without biological progression: 300 mg/24 h p.o during one year or until progression/unacceptable toxicity.
  • In patients with B or C findings or biological progression: 300 mg/24 h p.o for two weeks and then 400 mg/24 h p.o for a total of one year of therapy, or until progression/unacceptable toxicity.
Other Names:
  • Gleevec
  • STI571

Detailed Description:

In vitro studies have proven that imatinib inhibits wild type Kit (wtKit) and suppresses proliferation of the HMC-1V560G cell line, while it is ineffective on inhibiting the growth of HMC-1V560G, D816V cells. Apart from wtKit, Kit molecules carrying mutations in the extracellular, transmembrane and juxtamembrane domains, such as V560G, F522C and K509I, remain sensitive to imatinib. In contrast, several experiments have provided compelling evidence regarding the resistance against the growth-inhibitory effects of imatinib on cells carrying the D816V KIT mutation. As a consequence, sensitive and specific methods should be used in order to avoid "false" KIT mutation-negative cases and, for that purpose, mainly in cases with low bone marrow mast cell numbers, mutational studies should be performed using highly purified bone marrow mast cells by means of Facs sorting systems better than whole bone marrow, unsorted mononuclear cell fraction or mononuclear cell fraction pre-enriched using magnetic beads conjugated with anti-CD25 monoclonal antibody. In the present study mutational studies were performed in all cases in purified bone marrow mast cells (purity > 97%) using a FACSaria system (Becton-Dickinson Biosciences) as previously described.

Patients without B or C findings according to the World Health Organization, and without features of biological progression of the disease receive oral Imatinib Mesylate 300 mg daily for up to 12 months or until clinical progression/unacceptable toxicity. Patients with B or C findings or biological progression initially receive oral Imatinib Mesylate 300 mg daily for two weeks; then, dose is increased up to 400 mg/day except in patients who develop hematological or any other dose-limiting toxicity.

Biological progression is defined as the presence of at least one of the following features: i) increased serum tryptase levels > 200 ng/mL, ii) diffuse bone sclerosis, iii) patchy sclerosis with osteolysis and increased risk of bone fracture or significant bone pain, and, iv) organomegalies or lymph node enlargement due to mastocytosis.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age older than 18 years.
  • Diagnosis of systemic mastocytosis in the absence of c-kit mutation.
  • ECOG ≤ 3.
  • Signed informed consent.

Exclusion Criteria:

  • Previous therapy with a tyrosin kinase inhibitor.
  • Positive antibodies against HIV or active viral hepatitis.
  • Impaired liver function (total bilirubin ≥ 2.0 mg/dl, AST or ALT > 3 x upper limit of normal).
  • Impaired renal function (≥ 2.0 mg/dL).
  • Grade III-IV cytopenias not related to mastocytosis.
  • Severe cardiopathy (grade III/IV of NYHA, or left ventricular ejection fraction < 50%).
  • Pregnancy or breastfeeding.
  • Female patients who do not use contraceptive methods.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01297777

Locations
Spain
Instituto de Estudios de Mastocitosis de Castilla La Mancha; Hospital Virgen del Valle
Toledo, Spain, 45071
Sponsors and Collaborators
Hospital Virgen de la Salud
Investigators
Principal Investigator: Luis Escribano, MD, PhD Instituto de Estudios de Mastocitosis de Castilla La Mancha
  More Information

Additional Information:
Publications:

Responsible Party: LUIS ESCRIBANO, Director Instituto de Estudios de Mastocitosis de Castilla La Mancha, Hospital Virgen de la Salud
ClinicalTrials.gov Identifier: NCT01297777     History of Changes
Other Study ID Numbers: EudraCT 2010-019189-94 
Study First Received: February 16, 2011
Last Updated: April 21, 2015
Health Authority: Spain: Ministry of Health

Keywords provided by Hospital Virgen de la Salud:
Mast cell
Mastocytosis
Mast cell disease

Additional relevant MeSH terms:
Mastocytosis
Mastocytosis, Systemic
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Skin Diseases
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 21, 2016