Imatinib in KIT-negative Systemic Mastocytosis

NCT ID: NCT01297777

Last Updated: 2016-08-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-01-31
• Study Completion Date: 2015-08-31

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.

Conditions

Systemic Mastocytosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Imatinib mesylate

Imatinib mesylate 300 or 400 mg daily for 12 months.

Group Type: EXPERIMENTAL

Imatinib Mesylate

Intervention Type: DRUG

• 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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Gleevec; STI571

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospital Virgen de la Salud

OTHER

Sponsor Role: lead

Responsible Party

LUIS ESCRIBANO

Director Instituto de Estudios de Mastocitosis de Castilla La Mancha

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Luis Escribano, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Instituto de Estudios de Mastocitosis de Castilla La Mancha

Locations

Instituto de Estudios de Mastocitosis de Castilla La Mancha; Hospital Virgen del Valle

Toledo, Toledo, Spain

Countries

Spain

References

Zermati Y, De Sepulveda P, Feger F, Letard S, Kersual J, Casteran 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. doi: 10.1038/sj.onc.1206120.

Reference Type: BACKGROUND

PMID: 12569358 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12901973 (View on PubMed)

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. doi: 10.1016/j.leukres.2005.08.015. Epub 2005 Sep 22.

Reference Type: BACKGROUND

PMID: 16183119 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11861291 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16741248 (View on PubMed)

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.

Reference Type: RESULT

PMID: 15070706 (View on PubMed)

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.

Reference Type: RESULT

PMID: 18567837 (View on PubMed)

Other Identifiers

EudraCT 2010-019189-94

Identifier Type: -

Identifier Source: org_study_id