Phase 1/2 Dose Escalation Study in Patients With Relapsed or Refractory Waldenstrom's Macroglobulinemia

Study Overview
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Brief Summary
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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.

Detailed Description
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Eligible subjects will be enrolled and assigned to escalating dose cohorts. Treatment will be administered by subcutaneous injection.

Official Title
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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

Conditions
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Waldenstrom's Macroglobulinemia

Intervention / Treatment
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* Drug: IMO-8400


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a diagnosis of relapsed Waldenstrom's Macroglobulinemia. In addition to the above, key inclusion and exclusion criteria are listed below. Inclusion Criteria: At least 18 years of age. Agree to use contraception Hemoglobin ≥ 7.5 g/dL, - Absolute neutrophil count ≥ 1.0 x 109/L (1000/mm3), - Platelets ≥ 50,000/μL Exclusion Criteria: Is nursing or pregnant 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, at the initiation of study drug, received cytotoxic chemotherapy or a Bruton's tyrosine kinase (BTK)-inhibitor (e.g. ibrutinib) within the past 3 weeks or rituximab within the past 2 months Has an active infection requiring systemic antibiotics. Has had surgery requiring general anesthesia within 4 weeks of starting the study. Has autoimmune cytopenia (anemia, thrombocytopenia, leukopenia). Has heart failure of Class III or IV. Has sensory or motor neuropathy limiting daily activities.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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 at escalating dose levels<br>IMO-8400 at escalating dose levels by subcutaneous injection | Drug: IMO-8400<br>* IMO-8400 at escalating dose levels by subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of IMO-8400 in Patients With Waldenstrom's Macroglobulinemia | Safety and tolerability of IMO-8400 in patients with Waldenstrom's Macroglobulinemia: Assessment of adverse events | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | Best Overall Response using criteria from the VIth International Workshop in Waldenstrom's Macroglobulinemia | Up to 24 weeks | 
| Identify the Number of Patients Experiencing DLTs at Each Dose Level | To identify an appropriate dose of IMO-8400 for further clinical evaluation via evaluation of DLT at each dose level | 28 days | 
| Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - Cmax. | Pharmacokinetics of escalating dose levels of IMO 8400 administered by SC injection - Cmax. | Cycle 1 Week 1 Day 1: Samples were obtained pre-dose (within 1 hr prior to injection) and post-dose at 1 hr (+/-5 min), 2 hrs (+/-10 min) and 4 hrs (+/-15 min) | 
| Pharmacokinetics of Escalating Dose Levels of IMO 8400 Administered by SC Injection - AUC0-t (hr*ng/mL) | Pharmacokinetics of escalating dose levels of IMO 8400 administered by SC injection - AUC0-t (hr*ng/mL) . | Cycle 1 Week 1 Day 1: Samples were obtained pre-dose (within 1 hr prior to injection) and post-dose at 1 hr (+/-5 min), 2 hrs (+/-10 min) and 4 hrs (+/-15 min) |