Study of the Monoclonal Antibody IMT-009 in Patients With Advanced Solid Tumors or Lymphomas

Study Overview
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Brief Summary
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This is a Phase 1/2a open-label, multicenter, dose escalation and dose expansion trial in which IMT-009 will be administered by the intravenous (IV) route to participants with solid tumors or lymphomas. The main goals of this study are to: Find the recommended dose of IMT-009 that can be safely given to participants Learn more about the side effects of IMT-009 Learn more about pharmacokinetics of IMT-009 Learn more about the effectiveness of IMT-009 Learn more about different pharmacokinetic biomarkers and how they might change in the presence of IMT-009

Detailed Description
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IMT-009 is an Fc-attenuated monoclonal antibody that binds with high affinity and selectivity to CD161, a receptor that is broadly expressed on NK and a subset of memory T cells, blocking interactions between the receptor and its cognate ligand, CLEC2D, which is expressed on the surface of both cancer cells and immune cells. Preclinical data confirm that CD161 blockade with IMT-009 results in enhanced anti-tumor activity. This is a Phase 1/2a, open label dose escalation study of IMT-009, a fully human monoclonal antibody targeting CD161, given as a single agent in Phase 1 and potentially in combination with other antineoplastic agents in Phase 2.

Official Title
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A Phase 1/2a, First-in-Human (FIH), Open-Label, Dose-Escalation and Dose Expansion Study of the Monoclonal Antibody IMT-009 in Patients With Advanced Solid Tumors or Lymphomas

Conditions
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Non Small Cell Lung Cancer, Head and Neck Squamous Cell Carcinoma, Triple Negative Breast Cancer, Cutaneous Squamous Cell Carcinoma, Hormone Receptor Positive Breast Carcinoma, Small Bowel Cancer, Esophageal Cancer, Colorectal Cancer, Diffuse Large B Cell Lymphoma, Hodgkin Lymphoma, Burkitt Lymphoma, T-cell Lymphoma

Intervention / Treatment
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* Drug: IMT-009


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Phase 1 Males and females ≥18 years of age at the time of consent Patients who have histologically or cytologically-documented, unresectable locally advanced, or metastatic solid malignancy or designated lymphoma that is progressing or has failed the therapies listed below or who are intolerant of or are ineligible for or refuse standard of care therapy as detailed below. Patients previously pre-treated with a checkpoint inhibitor must be anti-PD-L1 relapsed/refractory defined as having clear evidence of radiologic or clinical progression while on or within 4 months of their last anti-PD-L1 dose. There is no limit to the number of prior treatment regimens a patient may have had prior to enrollment. Has one of the following solid tumor or lymphoma indications: Non-small cell lung cancer (NSCLC) - squamous or non-squamous: Must have received prior chemotherapy and a checkpoint inhibitor (either sequentially or in combination) per PD-L1 status Must not have a documented EGFR, ALK, ROS, RET, BRAFV600E, Met exon 14 skipping, KRAS mutation Head and neck squamous cell carcinoma (HNSCC) HPV+ or -: Must have received prior treatment with a platinum-based chemotherapy and a checkpoint inhibitor (either sequentially or in combination) per PD-L1 status Triple negative breast cancer (TNBC): Must have received prior treatment with chemotherapy (anthracycline, and/or taxanes, and/or platinum, and/or gemcitabine); in combination with a checkpoint inhibitor if PD-L1+; a PARPi for patients with gBRCA mutations, and sacituzumab govitecan Cutaneous squamous cell carcinoma: Must have received prior treatment with a checkpoint inhibitor Hormone receptor positive (HR+) breast cancer: - Must have received endocrine therapy, a CDK 4/6 inhibitor (preferably in combination with endocrine therapy in the 1st line or 2nd line setting or as monotherapy), a PI3K inhibitor and endocrine therapy for tumors with PIK3CA activating mutation; and a PARPi for patients with gBRCA mutations Small bowel carcinoma: Must have received prior treatment with at least one 5FU or capecitabine based regimen (such as but not limited to FOLFOX, FOLFIRI or CAPOX) with or without bevacizumab, and a PD1/PD-L1 inhibitor alone or in combination with CTLA4 inhibitor (for MSI-H or dMMR tumors) Esophageal cancer: Must have received prior treatment with a platinum-based chemotherapy and a checkpoint inhibitor (either sequentially or in combination per PD-L1 status), and an anti-HER2 agent for patients with known HER2 overexpressing tumors Colorectal cancer (MSS & MSI-H/dMMR): Must have received at least one 5FU chemotherapy-based regimen, with bevacizumab or cetuximab/panitumumab, and / or a PD1/PD-L1 (single agent or combination with CTLA4) for dMMR/MSI-H tumors For patients with known BRAF V600E mutation: must have received prior treatment with a combination of encorafenib and cetuximab or panitumumab Histologically confirmed diffuse large B cell lymphoma (DLBCL) Must have received at least 2 prior lines of therapy including prior treatment with chemotherapy and an anti-CD20 antibody (ie, CHOP) Must be ineligible or refuse therapies with demonstrated clinical benefit such as for example CAR-T or autologous stem cell transplant Hodgkin lymphoma: - Must have received at least 3 prior systemic therapies, including combination chemotherapy (ie, ABVD). Burkitt lymphoma: Must have received at least 2 prior lines of therapy Must be ineligible or refuse therapies with demonstrated clinical benefit T cell lymphoma: Must have received at least 2 prior systemic therapies, including combination chemotherapy (eg, CHOP). Patients with solid tumors have measurable disease based on RECIST 1.1. In hematological malignancies LYRIC/Lugano will be used. Phase 2A Inclusion criteria for these patients will remain similar to those used during Phase 1. Key Exclusion Criteria: Phase 1 Any prior Grade 4 immune-mediated adverse event (imAE) or Grade 3 imAE requiring steroid treatment (>10 mg/day prednisone or equivalent dose for more than 12 weeks) while receiving immunotherapy that has been documented within the 12 months prior to enrollment. Unresolved toxicity higher than Grade 1 CTCAE v 5 (or higher) attributed to any prior therapy/procedure at screening, except for alopecia. Prior history of serious hypersensitivity reaction to treatment with a monoclonal antibody Patients who are currently pregnant or breastfeeding Use of other investigational drugs (drugs not marketed for any indication) within 14 days or at least 5 half-lives (whichever is shorter) before investigational enrollment (Day 1, Cycle 1 dosing) Patient with history of malignancy (other than the one for which he/she participates in the study or than basal cell carcinoma definitively resected, or other in situ cancers) - unless the patient has undergone curative therapy with no evidence of that disease for 3 years Patients currently receiving cancer therapy (ie, chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery, and/or tumor embolization) or expected to require any other form of antineoplastic therapy while on study. Patients with active, known or suspected autoimmune disease requiring systemic treatment (corticosteroids or other active immunosuppressive medications) within the past 6 months - with the exclusion of vitiligo, resolved asthma/atopia or alopecia areata; hypothyroidism stable on hormone replacement. Known CNS metastases (unless clinically stable for at least 4weeks prior to enrollment and off steroids for at least 7 days- exceptions above for physiologic replacement doses of hydrocortisone) Myocardial infarction, symptomatic congestive heart failure (NYHA> Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of screening Patient has history of or current HIV, Hepatitis B or C infection, even if not active and/or controlled Phase 2A Exclusion criteria are expected to remain the same as Phase 1 unless there is a need to further refine expansion cohort populations for Phase 2a. Patients must have a CD161 and CLEC2D positive tumor demonstrated by the IHC CLIA assay for each analyte.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMT-009 Dose Escalation<br>Participants will receive an assigned dose level of IMT-009 monotherapy in dose escalation. Up to 44 Participants will be enrolled in the Phase 1 portion of the study. | Drug: IMT-009<br>* Participants will receive an IV infusion of IMT-009 on Day 1 during each 21-day cycle.<br>|
| Experimental: IMT-009 Phase 2a Cohort (s)<br>Each Cohort will evaluate IMT-009 monotherapy in up to 25 Participants | Drug: IMT-009<br>* Participants will receive an IV infusion of IMT-009 on Day 1 during each 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation - number of participants with dose limiting toxicities (DLTs) from IMT-009 monotherapy |  | 21 days (Cycle 1 Day 1- Cycle 1 Day 21) | 
| Dose Escalation- Number of participants with adverse events following administration of IMT-009 |  | From informed consent (Cycle 0 Day -28) to 30 days after the last dose of IMT-009. Each cycle is 21 days | 
| Phase 2a Cohort(s) Overall Response Rate (ORR) based on RECIST 1.1 or Lugano criteria (lymphomas only) to assess anti-tumor activity of IMT-009 in each cohort |  | Every 6 weeks from Cycle 1 Day 1, until disease progression or death or start of a new anti-cancer therapy, up to 2 years. Each cycle is 21 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation and Phase 2a Cohort(s)- Pharmacokinetic Analysis: Area under the plasma concentration-time curve (AUC) of IMT-009 when given as monotherapy. |  | Cycle 1 Day 1 to 90 days after treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Pharmacokinetic Analysis: Maximum plasma concentration (Cmax) of IMT-009 when given as monotherapy. |  | Cycle 1 Day 1 to 90 days after treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Pharmacokinetic Analysis: Minimum plasma concentration (Cmin) of IMT-009 when given as monotherapy. |  | Cycle 1 Day 1 to 90 days after treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Pharmacokinetic Analysis: Volume of distribution (Vd) of IMT-009 when given as monotherapy. |  | Cycle 1 Day 1 to 90 days after treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Pharmacokinetic Analysis: Apparent volume of distribution at steady state determined after intravenous administration (Vss) of IMT-009 when given as monotherapy. |  | Cycle 1 Day 1 to 90 days after treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Pharmacokinetic Analysis: Terminal half-life (t1/2) of IMT-009 when given as monotherapy. |  | Cycle 1 Day 1 to 90 days after treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Pharmacokinetic Analysis: Time to maximum plasma concentration (Tmax) of IMT-009 when given as monotherapy. |  | Cycle 1 Day 1 to 90 days after treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Pharmacokinetic Analysis: Clearance of IMT-009 when given as monotherapy. | Clearance is the volume of plasma cleared of IMT-009 by the body per unit time. | Cycle 1 Day 1 to 90 days after treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Number of participants who develop detectable anti-drug antibodies. |  | Cycle 1 Day 1 to 90 days after treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation- Receptor Occupancy (RO) to determine the target engagement of IMT-009. |  | Cycle 1 Day 1 to treatment discontinuation, up to 2 years. Cycles are 21 days. | 
| Dose Escalation- Overall Response Rate (ORR) based on RECIST 1.1 or Lugano criteria (lymphomas only) to assess anti-tumor activity of IMT-009 |  | Every 6 weeks from Cycle 1 Day 1, until disease progression or death or start of a new anti-cancer therapy, up to 2 years. Each cycle is 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Clinical benefit rate (CBR) based on RECIST 1.1 or Lugano criteria (lymphomas only) to assess preliminary anti-tumor activity of IMT-009 |  | Every 6 weeks from Cycle 1 Day 1, until disease progression or death or start of a new anti-cancer therapy, up to 2 years. Each cycle is 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Duration of Response (DOR) based on RECIST 1.1 or Lugano criteria (lymphomas only) to assess preliminary anti-tumor activity of IMT-009 |  | Every 6 weeks from Cycle 1 Day 1, until disease progression or death or start of a new anti-cancer therapy, up to 2 years. Each cycle is 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Progression-free survival (PFS) based on RECIST 1.1 or Lugano criteria (lymphomas only) to assess preliminary anti-tumor activity of IMT-009 |  | Every 6 weeks from Cycle 1 Day 1, until disease progression or death or start of a new anti-cancer therapy, up to 2 years. Each cycle is 21 days. | 
| Dose Escalation and Phase 2a Cohort(s)- Overall survival (OS) to assess preliminary anti-tumor activity of IMT-009 |  | Cycle 1 Day to discontinuation of study drug, then every 3 months for up to 2 years | 
| Phase 2a Cohort(s)- Number of participants with adverse events following administration of IMT-009 |  | From informed consent (Cycle 0 Day -28) to 30 days after the last dose of IMT-009. Each cycle is 21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumor, Lymphoma, CD161, Non small cell lung cancer, Head and neck squamous cell carcinoma, Triple negative breast cancer, Cutaneous squamous cell carcinoma, Hormone receptor positive breast cancer, Small bowel carcinoma, Esophageal cancer, Colorectal cancer, Diffuse large B-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, T-cell lymphoma