DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more



Imatinib in KIT-negative Systemic Mastocytosis

Information source: Hospital Virgen de la Salud
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Systemic Mastocytosis

Intervention: Imatinib Mesylate (Drug)

Phase: Phase 4

Status: Active, not recruiting

Sponsored by: Hospital Virgen de la Salud

Official(s) and/or principal investigator(s):
Luis Escribano, MD, PhD, Principal Investigator, Affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha

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.

Clinical Details

Official title: Imatinib Mesylate Therapy in Systemic Mastocytosis Patients Lacking KIT Mutations

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

Primary outcome:

To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration.

To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration.

Secondary outcome:

To evaluate the effect of Imatinib Mesylate on mastocytosis skin lesions.

To evaluate the effect of Imatinib Mesylate on mastocytosis mast-cell related symptoms.

To evaluate the effect of Imatinib Mesylate on mastocytosis-related megalies.

To evaluate the effect of Imatinib Mesylate on mastocytosis-related bone alterations.

To investigate changes after Imatinib Mesilate therapy in mast cell clonality.

To determine the effect of Imatinib Mesylate therapy on serum tryptase levels.

To determine the effect of Imatinib Mesylate therapy in the psychological impact of the disease and the quality of life.

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Instituto de Estudios de Mastocitosis de Castilla La Mancha; Hospital Virgen del Valle, Toledo 45071, Spain
Additional Information

The Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast) is the Spanish Reference Center of Mastocytosis

Related publications:

Zermati Y, De Sepulveda P, Féger F, Létard S, Kersual J, Castéran N, Gorochov G, Dy M, Ribadeau Dumas A, Dorgham K, Parizot C, Bieche Y, Vidaud M, Lortholary O, Arock M, Hermine O, Dubreuil P. Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms. Oncogene. 2003 Feb 6;22(5):660-4.

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.

Zhang LY, Smith ML, Schultheis B, Fitzgibbon J, Lister TA, Melo JV, Cross NC, Cavenagh JD. A novel K509I mutation of KIT identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy. Leuk Res. 2006 Apr;30(4):373-8. Epub 2005 Sep 22.

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.

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. Epub 2006 Jun 1.

Starting date: January 2011
Last updated: April 21, 2015

Page last updated: August 23, 2015

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017