A Study of Imvotamab Monotherapy and in Combination in Subjects With Relapsed/Refractory Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This is a Phase 1/2 study of imvotamab in adult subjects with relapsed or refractory B-cell Non-Hodgkin Lymphoma. This study will consist of a dose-escalation stage, a combination stage, and a randomized dose-expansion stage where subjects will be enrolled into indication-specific expansion cohorts. imvotamab will be administered intravenously (IV). Additional CD20-positive NHL histologies (e.g. MZL and MCL), may be allowed with Medical Monitor approval during the Dose-Escalation Phase of the study.

Detailed Description
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Imvotamab is an engineered bispecific IgM antibody for the treatment of patients with CD20-positive cancers. It contains ten high affinity binding domains for CD20, and one binding domain for CD3. Imvotamab is able to eliminate CD20-positive lymphoma cells by engaging T-cells and lymphoma cells, leading to T-cell dependent cellular cytotoxicity. Additionally, imvotamab is also able to eliminate lymphoma cells by recruiting complement to the surface of lymphoma cells, leading to complement dependent cytotoxicity. In our preclinical studies, we observed activity against rituximab resistant cells carrying low levels of CD20. We have also observed much lower cytokine release with imvotamab relative to comparable IgG format bispecific T-cell engaging antibodies, which is expected to result in reduced risk of the serious adverse effects from cytokine release syndrome (CRS). For the combination stage, imvotamab will be combined with loncastuximab tesirine, a CD19-targeting antibody drug conjugate.

Official Title
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A Phase 1/2 Open-label, Multicenter Study Evaluating the Safety and Pharmacokinetics of Imvotamab (IGM-2323) as a Single Agent and in Combination in Subjects With Relapsed/Refractory Non-Hodgkin Lymphomas

Conditions
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Non-Hodgkin Lymphoma, Follicular Lymphoma, DLBCL, Mantle Cell Lymphoma, Marginal Zone Lymphoma

Intervention / Treatment
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* Drug: imvotamab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: > 18 years of age: ECOG PS 0 or 1 Relapsed or Refractory Follicular Lymphoma (FL), and Diffuse Large B-cell Lymphoma (DLBCL), Mantle cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL) in dose escalation Relapsed or refractory to at least two prior systemic treatment regimens (must include anti-CD20 chemo-immunotherapy regimen). FL/MZL may be enrolled with a least 2 prior systemic regimens which must include an anti-CD20, without the need for a prior chemotherapy regimen) At least one bi-dimensionally measurable lesion (>1.5cm in it's longest dimension by computerized tomography (CT scan) Good organ function Not eligible for autologous stem cell transplant (DLBCL subjects), due to chemoresistant disease, medically unfit (organ function), or unwilling. Key Exclusion Criteria: Prior allogeneic transplant ASCT within 100 days prior to the first imvotamab administration. Lack of response to prior treatment with CAR-T therapy, subjects with less than 3 months from prior CAR-T therapy to first dose of imvotamab, and prior CAR-T therapy only allowed with Medical Monitor approval. Concurrent serious co-morbidities that could limit patients full participation and compliance. Prior CD-targeting bispecific antibodies. Prior loncastuximab tesirine.

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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a (Dose Escalation)<br>Subjects will receive imvotamab via intravenous (IV) infusion weekly. No longer enrolling. | Drug: imvotamab<br>* Subjects with r/r B-cell NHL will receive IGM-2323 via IV infusion.<br>|
| Experimental: Phase 1a (Q3W)<br>Subjects will receive imvotamab via intravenous (IV) infusion every 3 weeks. No longer enrolling. | Drug: imvotamab<br>* Subjects with r/r B-cell NHL will receive IGM-2323 via IV infusion.<br>|
| Experimental: Phase 1a (Prior bi-specific)<br>Subjects treated with prior bi-specifics will receive imvotamab via IV infusion weekly. No longer enrolling. | Drug: imvotamab<br>* Subjects with r/r B-cell NHL will receive IGM-2323 via IV infusion.<br>|
| Experimental: Phase 2 (DLBCL)<br>DLBCL subjects will receive imvotamab via IV infusion at a dose and schedule to be determined after reviewing all available response and safety data. No longer enrolling. | Drug: imvotamab<br>* Subjects with r/r B-cell NHL will receive IGM-2323 via IV infusion.<br>|
| Experimental: Phase 2 (FL)<br>FL subjects will receive imvotamab via IV infusion at a dose and schedule to be determined after reviewing all available response and safety data. No longer enrolling. | Drug: imvotamab<br>* Subjects with r/r B-cell NHL will receive IGM-2323 via IV infusion.<br>|
| Experimental: Phase 1b (Combination)<br>Subjects will receive imvotamab via IV infusion weekly and loncastuximab tesirine via IV infusion every 3 weeks. | Drug: imvotamab<br>* Subjects with r/r B-cell NHL will receive IGM-2323 via IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Frequency of Adverse Events | Percentage of Adverse Events | Baseline through approximately 30 days after last study treatment | 
| Overall Response Rate (ORR) | Percentage of measurable disease in subjects who have achieved either complete response (CR) or partial response (PR) | Baseline up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Percentage of measurable disease in subjects who have achieved either complete response (CR) or partial response (PR) | Baseline up to 5 years | 
| Duration of Response (DOR) | measured from time of initial response until documented tumor progression | Baseline up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed or refractory, Lymphoma, Non-Hodgkin Lymphoma, DLBCL, Follicular Lymphoma