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Dose Escalation Study in Patients With Relapsed or Refractory DLBCL and MyD88 L265P Mutation

NCT02252146

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Dose Escalation Study in Patients With Relapsed or Refractory DLBCL and MyD88L265P <span class="go-doc-concept go-doc-keyword">Mutation</span>

Title

  • Brief Title: Dose Escalation Study in Patients With Relapsed or Refractory DLBCL and MyD88L265P Mutation
  • Official Title: Phase I/II Open-label, Multiple-dose, Dose Escalation Study to Evaluate the Safety and Effectiveness of IMO-8400 in Patients With Relapsed or Refractory DLBCL and Presence of the MyD88L265P Mutation
  • Clinical Trial IDs

    NCT ID: NCT02252146

    ORG ID: 8400-402

    Trial Conditions

    Diffuse Large B Cell Lymphoma

    Trial Interventions

    Drug Synonyms Arms
    IMO-8400 at one of three dose levels/cohorts Drug: IMO-8400 0.6 mg/kg/week x 24 weeks administered as equal divided doses twice weekly by subcutaneous injection (Cohort A1), Drug: IMO-8400 1.2 mg/kg/week x 24 weeks administered as equal divided doses twice weekly by subcutaneous injection (Cohort A2), Drug: IMO-8400 2.4 mg/kg/week x 24 weeks administered as equal divided doses twice weekly by subcutaneous injection (Cohort A3) IMO-8400

    Trial Purpose

    Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in
    approximately 10% of the patients with 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.

    Detailed Description

    Eligible subjects will be enrolled and assigned to one of three dose cohorts. Treatment will
    be administered twice weekly by subcutaneous injection. Subjects will receive treatment for
    24 weeks and then be followed for an additional 5 weeks.

    Trial Arms

    Name Type Description Interventions
    IMO-8400 Experimental Experimental cohorts A1, A2, and A3 IMO-8400 at one of three dose levels/cohorts

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have a diagnosis of Diffuse Large B Cell Lymphoma (DLBCL) that has
    relapsed after a previous treatment or has shown partial or no response to previous
    treatment and that has the L265P mutation as determined by a designated central
    laboratory.

    - In addition to the above, key inclusion and exclusion criteria are listed below.

    1. Be at least 18 years of age

    2. Agree to use contraception

    Exclusion Criteria:

    1. Is nursing or pregnant

    2. Has body weight < 50 kg

    3. Has BMI > 34.9 kg/m2

    4. Has a positive test for human immunodeficiency virus (HIV-1 or -2) hepatitis C virus
    (HCV) or hepatitis B surface antigen (HBsAg)

    5. Receiving chronic systemic corticosteroid therapy > 20 mg of prednisone daily

    6. 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Safety and tolerability of IMO-8400 in patients with Diffuse Large B-Cell Lymphoma (DLBCL)

    Secondary Outcome Measures

    Assess the treatment effect (clinical activity)

    Identify a dosage of IMO-8400 for further evaluation

    Characterize the pharmacokinetics of escalating dosages of IMO-8400

    Trial Keywords

    DLBCL

    MYD88 L265P

    Lymphoma

    Diffuse Large B Cell Lymphoma

    Idera

    IMO 8400