Clinical trial NCT01297777: Imatinib in KIT-negative Systemic Mastocytosis
Official title: Imatinib Mesylate Therapy in Systemic Mastocytosis Patients Lacking KIT Mutations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Systemic Mastocytosis
Keywords: Mast cell
Mastocytosis
Mast cell disease
Lead sponsor: Hospital Virgen de la Salud
Sponsor class: OTHER
First posted: 2011-02-17
Enrollment: 10
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: 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.

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 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.

Primary outcomes:
measure: To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration.
timeFrame: 6 months
measure: To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration.
timeFrame: 12 months
Secondary outcomes:
measure: To evaluate the effect of Imatinib Mesylate on mastocytosis skin lesions.
timeFrame: 12 months
measure: To evaluate the effect of Imatinib Mesylate on mastocytosis mast-cell related symptoms.
timeFrame: 12 months
measure: To evaluate the effect of Imatinib Mesylate on mastocytosis-related megalies.
timeFrame: 12 months
measure: To evaluate the effect of Imatinib Mesylate on mastocytosis-related bone alterations.
timeFrame: 12 months
measure: To investigate changes after Imatinib Mesilate therapy in mast cell clonality.
timeFrame: 12 months
measure: To determine the effect of Imatinib Mesylate therapy on serum tryptase levels.
timeFrame: 12 months
measure: To determine the effect of Imatinib Mesylate therapy in the psychological impact of the disease and the quality of life.
timeFrame: 12 months
Other outcomes:
Locations:
city: Toledo
country: Spain
facility: Instituto de Estudios de Mastocitosis de Castilla La Mancha; Hospital Virgen del Valle
Study officials:
affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha
name: Luis Escribano, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Akin C, Brockow K, D'Ambrosio C, Kirshenbaum AS, Ma Y, Longley BJ, Metcalfe DD. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol. 2003 Aug;31(8):686-92. doi: 10.1016/s0301-472x(03)00112-7.
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citation: Ma Y, Zeng S, Metcalfe DD, Akin C, Dimitrijevic S, Butterfield JH, McMahon G, Longley BJ. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood. 2002 Mar 1;99(5):1741-4. doi: 10.1182/blood.v99.5.1741.
citation: Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, Nunez R, Prados A, Aldanondo I, Sanchez L, Dominguez M, Botana LM, Sanchez-Jimenez F, Sotlar K, Almeida J, Escribano L, Orfao A. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006 Oct 1;108(7):2366-72. doi: 10.1182/blood-2006-04-015545. Epub 2006 Jun 1.
citation: Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood. 2004 Apr 15;103(8):3222-5. doi: 10.1182/blood-2003-11-3816. Epub 2003 Dec 24.
citation: Hoffmann KM, Moser A, Lohse P, Winkler A, Binder B, Sovinz P, Lackner H, Schwinger W, Benesch M, Urban C. Successful treatment of progressive cutaneous mastocytosis with imatinib in a 2-year-old boy carrying a somatic KIT mutation. Blood. 2008 Sep 1;112(5):1655-7. doi: 10.1182/blood-2008-03-147785. Epub 2008 Jun 20.