There are 9 clinical trials

Clinical Trials

1 Phase 1/2 Open-Label, Multiple-dose, Dose-escalation Study to Evaluate the Safety and Tolerability of IMO-8400 in Patients With Relapsed or Refractory Waldenstrom's Macroglobulinemia

Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 90% of the patients with Waldenström's macroglobulinemia. MYD88 is a key linker protein in the signaling pathway of Toll Like Receptors (TLRs) 7, 8, and 9, and IMO-8400 is an oligonucleotide specifically designed to inhibit TLRs 7,8, and 9. The scientific hypothesis for use of IMO-8400 to treat patients with Waldenström's macroglobulinemia depends on the inhibition of mutant MYD88 signaling in the TLR pathway, thereby interrupting the proliferation of cell populations responsible for the propagation of the disease.

NCT02092909 Waldenstrom's Macroglobulinemia Drug: IMO-8400

MeSH:Waldenstrom Macroglobulinemia

HPO:Monoclonal immunoglobulin M proteinemia

Phase 1/2 Dose Escalation Study in Patients With Relapsed or Refractory Waldenstrom's Macroglobulinemia Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 90% of the patients with Waldenström's macroglobulinemia. --- L265P ---

2 Phase I/II Open-label, Multiple-dose, Dose-escalation Study to Evaluate the Safety and Tolerability of IMO-8400 in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Presence of the MyD88 L265P Mutation

Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 30% of the patients with the activated B-cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL). MYD88 is an initial adapter linker protein in the signaling pathway of the Toll Like Receptors (TLRs), including the endosomal TLRs 7, 8, and 9, for which the ligands are nucleic acids. IMO-8400 is an oligonucleotide specifically designed to inhibit ligand activation of TLRs 7,8, and 9. Recent studies indicate that in the presence of L265P mutation ligand activation of those TLRs results in markedly increased signaling with subsequent increased cell activation, cell survival, and cell proliferation. The scientific rationale for assessing the use of IMO-8400 to treat patients with DLBCL and the L265P mutation is based on laboratory observations that IMO-8400 inhibits ligand-based activation of cells with the mutation and decreases the survival and proliferation of the cell populations responsible for the propagation of the disease.

NCT02252146 Diffuse Large B Cell Lymphoma Drug: IMO-8400

MeSH:Lymphoma Lymphoma, B-Cell Lymphoma, Large B-Cell, Diffuse

HPO:B-cell lymphoma Lymphoma

Phase I/II Open-label, Multiple-dose, Dose-escalation Study to Evaluate the Safety and Tolerability of IMO-8400 in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Presence of the MyD88 L265P Mutation. --- L265P ---

Dose Escalation Study in Patients With Relapsed or Refractory DLBCL and MyD88 L265P Mutation Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 30% of the patients with the activated B-cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL). --- L265P ---

Dose Escalation Study in Patients With Relapsed or Refractory DLBCL and MyD88 L265P Mutation Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 30% of the patients with the activated B-cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL). --- L265P --- --- L265P ---

IMO-8400 is an oligonucleotide specifically designed to inhibit ligand activation of TLRs 7,8, and 9. Recent studies indicate that in the presence of L265P mutation ligand activation of those TLRs results in markedly increased signaling with subsequent increased cell activation, cell survival, and cell proliferation. --- L265P ---

The scientific rationale for assessing the use of IMO-8400 to treat patients with DLBCL and the L265P mutation is based on laboratory observations that IMO-8400 inhibits ligand-based activation of cells with the mutation and decreases the survival and proliferation of the cell populations responsible for the propagation of the disease. --- L265P ---

Inclusion Criteria: - Patients must have a diagnosis of Diffuse Large B Cell Lymphoma (DLBCL) of non-GCB subtype, established according to the World Health Organization (WHO) criteria that has been tested for the MyD88 L265P mutation. --- L265P ---

Being treated with other anti-cancer therapies (approved or investigational) 7. Has an active infection requiring systemic antibiotics 8. Has had surgery requiring general anesthesia within 4 weeks of starting the study 9. Has heart failure of Class III or IV Inclusion Criteria: - Patients must have a diagnosis of Diffuse Large B Cell Lymphoma (DLBCL) of non-GCB subtype, established according to the World Health Organization (WHO) criteria that has been tested for the MyD88 L265P mutation. --- L265P ---

3 Phase II Trial of Ixazomib, Dexamethasone and Rituximab in Patients With Untreated Waldenstrom's Macroglobulinemia

This research study is evaluating a drug called ixazomib (also known as MLN9708) in combination with dexamethasone and rituximab (the regimen is called IDR) as a possible treatment for Waldenstrom's Macroglobulinemia (WM).

NCT02400437 Waldenstrom's Macroglobulinemia Drug: Ixazomib Drug: Dexamethasone Drug: Rituximab

MeSH:Waldenstrom Macroglobulinemia

HPO:Monoclonal immunoglobulin M proteinemia

Response rate by MYD88 L265P and CXCR4-WHIM status. --- L265P ---

To evaluate the attainment of response, and depth of response and expression of MYD88 L265P and CXCR4-WHIM mutations in WM. --- L265P ---

4 Molecular Disease Profile of Haematological Malignancies. A Prospective Registry Study by the Rete Ematologica Lombarda (REL) Clinical Network

In this prospective multicentric study, the University of Pavia together with the Fondazione IRCCS Policlinico San Matteo, Pavia and the IRCCS Fondazione Maugeri, Pavia, Italy will provide a systematic analysis of gene mutations in hematological malignancies by using NGS techniques. Patients with a conclusive diagnosis of haematological malignancies according to WHO criteria referred to the Rete Ematologica Lombarda clinical network (REL, www.rel-lombardia.net) will be enrolled. The investigators will analyse genomic DNA extracted from hematopoietic cells at different time points of patient disease. The study contemplates the use of molecular platforms (Next Generation Sequencing, NGS) aimed at the identification of recurrent mutations in myeloid and lymphoid neoplasms, respectively. Screening of gene mutations by NGS will be prospectively implemented in the context of REL clinical network. Patient samples will be analyzed at diagnosis and sequentially during the course of the disease at specific timepoints. The researchers will analyze the correlations between somatic mutations, specific clinical phenotypes (according to the WHO classification) and disease evolution. This will allow to: 1) identify new recurrent genetic mutations involved in the molecular pathogenesis of hematological malignancies; 2) define the role of mutated genes, distinguishing between genes which induce a clonal proliferation of hematopoietic stem cells, and genes which determine the clinical phenotype of the disease; 3) identify mutations which are responsible for disease evolution; 4) define the diagnostic/prognostic role of the identified mutations, and update the current disease classifications and prognostic scores by including molecular parameters. A systematic biobanking of biological material will be provided.

NCT02459743 Hematological Malignancies

MeSH:Hematologic Neoplasms Neoplasms

HPO:Hematological neoplasm Leukemia Neoplasm

Moreover in last years, researchers from the University of Pavia gave a significant contribution in the definition of the molecular basis of lymphoid neoplasms (i.e., BRAF V600E mutation in Hairy cell Leukemia, MYD88 L265P mutation in Waldenstrom disease, and SF3B1 mutations in Chronic Lymphocytic Leukemia). --- V600E --- --- L265P ---

5 Study of Phosphatidylinositol-3-kinase (PI3K) Inhibitor, Idelalisib (GS-1101), in IgM-Associated AL Amyloid

The investigators expect to enroll 15 participants with relapsed or refractory IgM-associated AL amyloidosis onto this Phase II clinical trial. Idelalisib will be self-administered orally at a dose of 100 mg twice daily (may be increased to 150 mg (one tablet) twice daily after 3 months at investigator discretion). Participants will be treated until disease progression, unacceptable toxicity, or decision to withdraw from the trial. Disease evaluations will be performed every three months until disease progression.

NCT02590588 Amyloidosis Drug: Idelalisib

MeSH:Amyloidosis

HPO:Amyloidosis

IgM paraprotein identified on serum immunofixation electrophoresis OR light chain-restricted CD20+ lymphoplasmacytic population on biopsy of bone marrow or lymph node (identified by H&E/immunohistochemistry or flow cytometry) OR positive myeloid differentiation primary response gene 88 (MYD88-L265P) OR CXCR4WHIM mutation (CXCR4 mutation - warts, hypogammaglobulinemia, infections, myelokathexis) on submitted samples 3.1.2 --- L265P ---

6 Expression of Ku70/XRCC6 and Others NHEJ Components in Waldenström's Macroglobulinemia in Comparison With Others B-cell Lymphoproliferative Disorders and Normal B Cells.

Waldenström's macroglobulinemia is a rare disease whose pathophysiology remains at present poorly understood, although a recurrent mutation (L265P MYD88) has recently been described. Unlike other lymphoproliferative disorders, there is a defect in isotype switching, mechanism involving AID and NHEJ complex. Using a two-dimensional electrophoresis technology, our group showed that MW had a specific proteomic profile, and one of the differentially expressed proteins is Ku70 (encoded by XRCC6 belonging to NHEJ complex) . The investigators purpose to explore the mechanisms of underexpression of Ku70/XRCC6 (genetic or epigenetic modification) in comparison with other lymphoid malignancies and normal B cells.

NCT02640287 Waldenström Macroglobulinemia Biological: Blood or bone marrow samples

MeSH:Waldenstrom Macroglobulinemia

HPO:Monoclonal immunoglobulin M proteinemia

Expression of Ku70/XRCC6 and Others NHEJ Components in Waldenström's Macroglobulinemia in Comparison With Others B-cell Lymphoproliferative Disorders and Normal B Cells.. Expression of Ku70/XRCC6 in Waldenström's Macroglobulinemia Waldenström's macroglobulinemia is a rare disease whose pathophysiology remains at present poorly understood, although a recurrent mutation (L265P MYD88) has recently been described. --- L265P ---

Inclusion Criteria: - Patient over 18 years, affiliated to the social regimen - Written consent collected MW group : - Patient with a diagnosis of MW according to WHO criteria (based on the results of serum protein electrophoresis, bone marrow analysis with immunophenotyping, cytogenetic analysis and mutation L265P MyD88) Other SLP : - Patient with diagnosis of Chronic Lymphocytic Leukemia, Splenic Marginal Zone Lymphoma or Multiple Myeloma Healthy volunteers : - volunteers without blood disorders Exclusion Criteria: - Women of childbearing age who do not have an effective means of contraception - Pregnant or nursing - Demonstration of a kappa or lambda monotype on B lymphocytes - healthy volunteer with B-cell malignancy Inclusion Criteria: - Patient over 18 years, affiliated to the social regimen - Written consent collected MW group : - Patient with a diagnosis of MW according to WHO criteria (based on the results of serum protein electrophoresis, bone marrow analysis with immunophenotyping, cytogenetic analysis and mutation L265P MyD88) Other SLP : - Patient with diagnosis of Chronic Lymphocytic Leukemia, Splenic Marginal Zone Lymphoma or Multiple Myeloma Healthy volunteers : - volunteers without blood disorders Exclusion Criteria: - Women of childbearing age who do not have an effective means of contraception - Pregnant or nursing - Demonstration of a kappa or lambda monotype on B lymphocytes - healthy volunteer with B-cell malignancy Waldenström Macroglobulinemia Waldenstrom Macroglobulinemia null --- L265P ---

Inclusion Criteria: - Patient over 18 years, affiliated to the social regimen - Written consent collected MW group : - Patient with a diagnosis of MW according to WHO criteria (based on the results of serum protein electrophoresis, bone marrow analysis with immunophenotyping, cytogenetic analysis and mutation L265P MyD88) Other SLP : - Patient with diagnosis of Chronic Lymphocytic Leukemia, Splenic Marginal Zone Lymphoma or Multiple Myeloma Healthy volunteers : - volunteers without blood disorders Exclusion Criteria: - Women of childbearing age who do not have an effective means of contraception - Pregnant or nursing - Demonstration of a kappa or lambda monotype on B lymphocytes - healthy volunteer with B-cell malignancy Inclusion Criteria: - Patient over 18 years, affiliated to the social regimen - Written consent collected MW group : - Patient with a diagnosis of MW according to WHO criteria (based on the results of serum protein electrophoresis, bone marrow analysis with immunophenotyping, cytogenetic analysis and mutation L265P MyD88) Other SLP : - Patient with diagnosis of Chronic Lymphocytic Leukemia, Splenic Marginal Zone Lymphoma or Multiple Myeloma Healthy volunteers : - volunteers without blood disorders Exclusion Criteria: - Women of childbearing age who do not have an effective means of contraception - Pregnant or nursing - Demonstration of a kappa or lambda monotype on B lymphocytes - healthy volunteer with B-cell malignancy Waldenström Macroglobulinemia Waldenstrom Macroglobulinemia null --- L265P --- --- L265P ---

7 Observational Study of the Prevalence of Some Genetic Mutations in Patients With Neuropathy Associated With Anti-Myelin-associated Glycoprotein (MAG) Antibodies.

Anti-MAG (Myelin Associated Glycoprotein) neuropathy is related to clonal B lymphocyte proliferation producing an monoclonal immunoglobulin (IgM) with anti-MAG activity. IgM may be a reflection of malignant lymphoproliferative syndrome (Waldenström disease) or, more often, monoclonal gammopathy of unknown significance. The anti-MAG antibody has a direct toxicity on the myelin sheath of the peripheral nervous system responsible for a length-dependent demyelinating polyneuropathy. Clinically, this results in a sensitive, ataxic predominant polyneuropathy in the lower limbs, sometimes associated with a tremor of attitude and action tremor of the upper limbs. Clonal B cells at the origin of IgM production may have acquired mutations affecting MYD88 (MYD88 L265P mutation) and CXCR4 (Whim-like CXCR4 mutation). The prevalence of the MYD88 L265P mutation is estimated to be 50% in monoclonal gammopathies of undetermined significance and more than 80% in Waldenström disease. CXCR4 Whim-like mutations are found in 40% of patients with Waldenström's disease. No studies have reported the prevalence of these mutations in patients with anti-MAG neuropathies.

NCT03268161 Neuropathy Demyelinating Diagnostic Test: Mutational analysis of clonal B cells

MeSH:Peripheral Nervous System Diseases

HPO:Abnormal peripheral nervous system morphology Peripheral neuropathy Polyneuropathy

Clonal B cells at the origin of IgM production may have acquired mutations affecting MYD88 (MYD88 L265P mutation) and CXCR4 (Whim-like CXCR4 mutation). --- L265P ---

The prevalence of the MYD88 L265P mutation is estimated to be 50% in monoclonal gammopathies of undetermined significance and more than 80% in Waldenström disease. --- L265P ---

Prevalence of MYD88 L265P mutations in anti-MAG neuropathies. --- L265P ---

Mutational status of MYD88 L265P is assessed using high-throughput sequencing (HTS) and allele specific polymerase chain reaction (AS-PCR). --- L265P ---

8 Non-invasive Diagnostics and Monitoring of Minimal Residual Disease and Clonal Evolution in Waldenström's Macroglobulinemia and in IgM Monoclonal Gammopathy of Undetermined Significance

Multicenter retrospective and prospective observational study including patients with WM or IgM-MGUS evaluated at the time of diagnosis and during the disease course using highly sensitive techniques.

NCT03521596 Waldenstrom Macroglobulinemia Other: MRD and clonal evolution

MeSH:Waldenstrom Macroglobulinemia

HPO:Monoclonal immunoglobulin M proteinemia

To demonstrate that the rate of mutations of MYD88 (L265P) and/or CXCR4 (S338X) detected in peripheral blood and/or urine show a negligible difference with the rate of mutations detected in bone marrow samples (BM, gold standard). --- L265P ---

9 Detection by Digital PCR and Next Generation Sequencing of Recurrent Mutations in Waldenström's Disease and Study of Their Distribution in the Different Biological Compartments

Waldenström's disease (WM) is a rare, low-grade lymphoid hematopathy, accounting for 1 to 2% of malignant hematopathies and mainly affecting the elderly. This disease is characterized by lymphoplasmocyte cells infiltration into the bone marrow and by the production of a monoclonal IgM protein in the serum. This disease is accompanied by clinical manifestations of hepato-splenomegaly, signs of hyperviscosity, peripheral neuropathies and biological signs with the presence of cytopenias and cryoglobulinemia. Some forms present node or splenic involvement. While the asymptomatic form maintains overall survival close to that of the healthy subject, the symptomatic form is subject to frequent relapses and remains incurable. Current recommendations for the diagnosis and monitoring of this disease are based on protein electrophoresis from a blood sample to quantify monoclonal IgM production and a myelogram or bone marrow biopsy showing medullary infiltration by lymphoplasmocytic cells. However, protein electrophoresis is an imprecise examination since it does not quantify tumour B lymphocytes and has limitations, particularly in the case of poorly secreting forms. More than 90% of Waldenström cases have the L265P mutation of the MYD88 gene. Although this mutation is not found only in these diseases, it can help in the diagnosis. Other mutations are also present in this pathology. These mutations can define prognostic factors or possibly make it possible to identify therapeutic targets. The development of new technologies makes it possible, on the one hand, to follow the L265P mutation of MYD88 over time as a marker of response to treatment and, on the other hand, to define these prognostic markers or therapeutic targets. This study will first determine the best method for monitoring the mutation of MYD88. In a second step, the investigators will evaluate the best type of sampling and in particular whether this mutation is present in the blood in order to limit the invasive procedures such as bone marrow sampling can be limited. Finally, the investigators will evaluate the prognostic

NCT03952052 Waldenstrom's Disease Other: Determination of mutation

MeSH:Osteochondritis

More than 90% of Waldenström cases have the L265P mutation of the MYD88 gene. --- L265P ---

The development of new technologies makes it possible, on the one hand, to follow the L265P mutation of MYD88 over time as a marker of response to treatment and, on the other hand, to define these prognostic markers or therapeutic targets. --- L265P ---

Finally, the investigators will evaluate the prognostic Quantification of MYD88 L265P mutation. --- L265P ---

Comparison of level of MYD88L265P mutationin different biological compartment c.. Allelic frequency of L265P mutation of MYD 88 gene. --- L265P ---

Inclusion Criteria: - Over 18 years of age - recently diagnosed for Waldenström's disease - not yet treated for Waldenström's disease Exclusion Criteria: - Pregnancy or breast feeding - HBV or HBC positive - HIV positive Inclusion Criteria: - Over 18 years of age - recently diagnosed for Waldenström's disease - not yet treated for Waldenström's disease Exclusion Criteria: - Pregnancy or breast feeding - HBV or HBC positive - HIV positive Waldenstrom's Disease Osteochondritis The L265P mutation of MYD88 appears as an early oncogenic event in the occurrence of Waldenström disease and may already be present at the Monoclonal Gammapathy of Undetermined Signification (MGUS) to IgM stage suggesting a continuum between the two stages of the disease. --- L265P ---

Monitoring the L265P mutation of MYD88 as a marker of minimal residual disease therefore appears to be a biomarker of major interest in these diseases. --- L265P ---

Several published studies show the interest of monitoring the L265P mutation of MYD88 in MW in particular by quantification of the mutation by allele-specific PCR. --- L265P ---

The originality of this study is based on the comparison of the quantification of the MYD88 L265P mutation in all affected biological compartments (blood, plasma, bone marrow or CD19+ cells) but especially in the monitoring of the mutation at two points of minimal residual disease (mid-treatment and end of treatment). --- L265P ---

One of the parts of the project is the study of the allelic frequency of the L265P mutation of the MYD88 gene in circulating tumor DNA (ctDNA). --- L265P ---

In this study, the allele frequency of the L265P mutation of MYD88 will be compared . --- L265P ---

HPO Nodes