Imatinib in KIT-negative Systemic Mastocytosis

Systemic Mastocytosis Clinical Trial

Official title:

Imatinib Mesylate Therapy in Systemic Mastocytosis Patients Lacking KIT Mutations

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01297777
• Other study ID #: EudraCT 2010-019189-94
• Status: Completed
• Phase: Phase 4
• First received: February 16, 2011
• Last updated: August 26, 2016
• Start date: January 2011
• Est. completion date: August 2015

Study information

• Verified date: August 2016
• Source: Hospital Virgen de la Salud
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: August 2015
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Mastocytosis
• Systemic Mastocytosis

Intervention

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.

Locations

Country	Name	City	State
Spain	Instituto de Estudios de Mastocitosis de Castilla La Mancha; Hospital Virgen del Valle	Toledo

Sponsors (1)

Lead Sponsor	Collaborator
Hospital Virgen de la Salud

Country where clinical trial is conducted

Spain, 

References & Publications (7)

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. — View 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. Epub 2003 Dec 24. — View 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. Epub 2006 Jun 1. — View 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 — View 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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration.	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	6 months	No
Primary	To evaluate the effect of Imatinib Mesylate on the grade of bone marrow mast cells infiltration.	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)	12 months	No
Secondary	To evaluate the effect of Imatinib Mesylate on mastocytosis skin lesions.	Skin lesions are evaluated before and after therapy by macroscopic examination and skin biopsy.	12 months	No
Secondary	To evaluate the effect of Imatinib Mesylate on mastocytosis mast-cell related symptoms.	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.	12 months	No
Secondary	To evaluate the effect of Imatinib Mesylate on mastocytosis-related megalies.	Organomegalies and adenomegalies are assessed before and after therapy by abdominal ultrasound.	12 months	No
Secondary	To evaluate the effect of Imatinib Mesylate on mastocytosis-related bone alterations.	Bone alterations are assessed before and after therapy by X-ray survey.	12 months	No
Secondary	To investigate changes after Imatinib Mesilate therapy in mast cell clonality.	Genetic abnormalities are assessed before and after therapy by sequencyng analysis of the c-kit gene and the HUMARA assay.	12 months	No
Secondary	To determine the effect of Imatinib Mesylate therapy on serum tryptase levels.	Serum tryptase is measured before and after therapy.	12 months	No
Secondary	To determine the effect of Imatinib Mesylate therapy in the psychological impact of the disease and the quality of life.	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.	12 months	No

External Links

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