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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
Eligible subjects will be enrolled and assigned to one of five dose cohorts. Treatment will be administered by subcutaneous injection until progression or intolerable toxicity.

Official Title
-----------------
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

Conditions
-----------------
Diffuse Large B Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: IMO-8400


Participation Criteria
=================
Eligibility Criteria
-----------------
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. In addition to the above, key inclusion and exclusion criteria are listed below. Be at least 18 years of age Agree to use contraception Exclusion Criteria: Is nursing or pregnant DLBCL of GCB subtype Has BMI > 34.9 kg/m2 Has a positive test for human immunodeficiency virus (HIV-1 or -2) hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) Receiving chronic systemic corticosteroid therapy > 20 mg of prednisone daily Being treated with other anti-cancer therapies (approved or investigational) Has an active infection requiring systemic antibiotics Has had surgery requiring general anesthesia within 4 weeks of starting the study Has heart failure of Class III or IV

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMO-8400<br>IMO-8400 0.3 mg/kg twice weekly, 0.6 mg/kg twice weekly, or 1.2 mg/kg twice weekly | Drug: IMO-8400<br>* MO-8400 given subcutaneously twice weekly<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events, Injection Site Reactions, and Concomitant Medications | Frequency of adverse events, injection site reactions, and concomitant medications observed | Up to 2 years from first patient visit | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
DLBCL, MYD88 L265P, Lymphoma, Diffuse Large B Cell Lymphoma, Idera, IMO 8400