First-in-Human (FIH) Trial of GEN3009 in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas

Study Overview
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Brief Summary
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The drug that will be investigated in the study is an antibody, GEN3009. Since this is the first study of GEN3009 in humans, the main purpose is to evaluate safety. Besides safety, the study will determine the recommended GEN3009 dose to be tested in a larger group of patients and assess preliminary clinical activity of GEN3009. GEN3009 will be studied in a broad group of cancer patients, having different kinds of lymphomas. All patients will get GEN3009 either as a single treatment (monotherapy) or in combination with another antibody-candidate for treatment of cancer in the blood. The study consists of two parts: Part 1 tests increasing doses of GEN3009 (escalation), followed by Part 2 which tests the recommended GEN3009 dose from Part 1 (expansion).

Detailed Description
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This trial will be conducted in 2 parts: Part 1 (Dose Escalation) and Part 2 (Dose Expansion). All subjects in Part 1 will receive GEN3009, administered at various dose levels in 28-day cycles. Dose Limiting Toxicity (DLT) will be assessed during the first treatment cycle of Part 1 and the Maximum Tolerated Dose (MTD) and/or Recommended phase 2 dose (RP2D) will be identified. Subjects in Part 2 will be treated with the Part 1-defined RP2D of GEN3009. Some subjects will receive GEN3009 in combination of a fixed dose of another antibody-candidate. Subjects in Part 2 are assigned either to one of 3 groups: Part 2 Monotherapy (hereafter referred to as 'Part 2A'), Part 2 Combination Safety Run-in ('Part2B') or Part 2 Combination ('Part2C'). Various types of B-cell NHLs are studied, including diffuse large B cell lymphoma (DLBCL), high-grade B cell lymphoma (HGBCL), mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Official Title
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Safety and Efficacy of GEN3009 (DuoHexaBody®-CD37) in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma - A First-in-Human, Open-label, Phase 1/2a Dose Escalation Trial With Dose Expansion Cohorts

Conditions
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Diffuse Large B-cell Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma, Small Lymphocytic Lymphoma, Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, High-grade B-cell Lymphoma, Primary Mediastinal Large B-cell Lymphoma

Intervention / Treatment
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* Biological: GEN3009
* Biological: Epcoritamab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Be at least 18 years of age. Must sign an informed consent form prior to any screening procedures. Dose Escalation: Has histologically or cytologically confirmed relapsed and/or refractory B-cell NHL with no available standard therapy or is not a candidate for available standard therapy, and for whom, in the opinion of the investigator, the experimental therapy may be beneficial. All subjects must have received at least two prior lines of systemic therapy. Dose Expansion: Has histologically or cytologically confirmed relapsed or refractory B-cell NHL. All subjects must have received at least 2 prior lines of systemic therapy, and, For FL and DLBCL, at least 1 of the 2 prior lines of treatment must have been a CD20 containing systemic regimen; For CLL, subjects must have received at least one prior line of BTK inhibitor or BCL 2 inhibitor. Has one of the eligible subtypes of B-cell NHL : Dose Escalation: (DLBCL, HGBCL, PMBCL, FL, MCL, MZL, SLL, or CLL). Dose Expansion: (DLBCL, FL, CLL) Has measurable disease for B-cell NHL or has active disease for Chronic Lymphocytic Leukemia (CLL). Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Has adequate hepatic, renal, and bone marrow functions. Before the first dose of GEN3009, during the trial, and for 12 months after the last dose of GEN3009 and/or the combination, a woman must be either not of childbearing potential or of childbearing potential and practicing a highly effective method of birth control, and must have a negative serum beta-human chorionic gonadotropin (beta-hCG) and urine pregnancy test at screening. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control. Subjects must have a life expectancy of at least 3 months. Key Exclusion Criteria: Prior treatment with a CD37-targeting agent. Prior allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Prior treatment with a CD3xCD20 bispecific antibody (Combination Expansion cohort only). Autologous HSCT within 3 months before the first dose of GEN3009. Lymphomas leukemic phase: high absolute lymphocyte count or the presence of abnormal cells in the peripheral blood indicating circulating lymphoma cells. Treatment with an anti-cancer biologic including anti-CD20 therapy, radio-conjugated or toxin-conjugated antibody or chimeric antigen receptor (CAR) T-cell therapy within 4 weeks or 5 half-lives, whichever is shorter, before the first dose of GEN3009. Treatment with small molecules such as BTK inhibitors, BCL2 inhibitors, or PI3K inhibitors within 5 half-lives prior to the first dose of GEN3009. Chemotherapy or radiation therapy within 2 weeks of the first dose of GEN3009. Treatment with an investigational drug or an invasive investigational medical device within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of GEN3009, and at any time during the study treatment period. Autoimmune disease or other diseases that require permanent or high-dose immunosuppressive therapy. Received a cumulative dose of corticosteroids more than the equivalent of 250 mg of prednisone within the 2-week period before the first dose of GEN3009. Has uncontrolled intercurrent illness. Seizure disorder requiring therapy (such as steroids or anti-epileptics) (Combination Expansion cohort only). Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy. Primary central nervous system (CNS) lymphoma or known CNS involvement at screening. Known past or current malignancy other than inclusion diagnosis. Had allergic reactions to anti-CD20 or anti-CD37 monoclonal antibody treatment or intolerant to GEN3009 or to the combination therapy excipients. Has had major surgery within 4 weeks before screening or will not have fully recovered from surgery, or has major surgery planned during the time the subject is expected to participate in the trial (or within 4 weeks after the last dose of GEN3009 and/or the combination therapy). Known history/positive serology for hepatitis B. Known medical history or ongoing hepatitis C infection that has not been cured. Known history of seropositivity for HIV infection. Is a woman who is pregnant or breast-feeding, or who is planning to become pregnant while enrolled in this trial or within 12 months after the last dose of GEN3009 and/or the combination therapy. Is a man who plans to father a child while enrolled in this trial or within 12 months after the last dose of GEN3009 and/or the combination therapy. Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Additionally, vulnerable subjects or subjects under guardianship, curatorship, judicial protection or deprived of liberty), are excluded from participation in this trial. Exposed to live/live attenuated vaccine within 4 weeks prior to initiation of GEN3009 treatment. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Monotherapy Arm<br> | Biological: GEN3009<br>* GEN3009 will be administered by intravenous (IV) infusion in cycles of 28 days<br>* Other names: DuoHexaBody®-CD37;|
| Experimental: Combination Arm<br> | Biological: GEN3009<br>* GEN3009 will be administered by intravenous (IV) infusion in cycles of 28 days<br>* Other names: DuoHexaBody®-CD37;Biological: Epcoritamab<br>* Epcoritamab will be administered by subcutaneous (SC) injections in cycles of 28 days<br>* Other names: EPKINLY™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2B: Dose liming toxicity (DLT) | To identify the recommended phase 2 dose (RP2D) and if reached, the MTD | During the first treatment cycle (28 days) in each cohort | 
| Part 1 and Part 2B: Incidence of Adverse Events | To assess the safety and tolerability of GEN3009 as monotherapy and of GEN3009 in combination | From screening until 30 days after last dose for Part 1 and 60 days after last dose for Part 2B | 
| Part 1 and Part 2B: Number of participants with clinically significant shifts from baseline in clinical laboratory parameters | Clinical laboratory parameters assessed: hematology, chemistry, coagulation, immunoglobulins and urinalyses | From screening until 30 days after last dose for Part 1 and 60 days after last dose for Part 2B | 
| Part 1 and Part 2B: Number of participants with clinically significant shifts from baseline in vital signs | Vital signs assessed: systolic and diastolic blood pressure, heart rate, temperature and pulse oximetry | From screening until 30 days after last dose for Part 1 and 60 days after last dose for Part 2B | 
| Part 1 and Part 2B: Number of participants with dose interruptions and dose delays, including dose intensity | Assessment of frequency of dose interruptions, dose delays and dose intensity | From enrollment until treatment discontinuation (assessed up to 5 years) | 
| Part 2A: Objective Response Rate (ORR) | To evaluate preliminary anti-tumor efficacy of GEN3009 as monotherapy by change in tumor size | From 6 weeks after enrollment until treatment discontinuation, assessed up to 5 years | 
| Part 2C: Complete Response (CR) rate | To evaluate preliminary anti-tumor efficacy of GEN3009 in combination by change in tumor size | From 6 weeks after enrollment until treatment discontinuation, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total body clearance of drug from the plasma (CL) |  | At enrollment and at multiple timepoints until treatment discontinuation (assessed up to 5 years) | 
| Volume of Distribution |  | At enrollment and at multiple timepoints until treatment discontinuation (assessed up to 5 years) | 
| Area Under the Concentration-Time Curve (AUC) from Time 0 to Day 7 |  | At enrollment and at multiple timepoints until treatment discontinuation (assessed up to 5 years) | 
| The AUC from Time 0 to Infinity (AUCinf) |  | At enrollment and at multiple timepoints until treatment discontinuation (assessed up to 5 years) | 
| The AUC from Time 0 to time of last dose (AUClast) |  | At enrollment and at multiple timepoints until treatment discontinuation (assessed up to 5 years) | 
| Maximum observed concentration (Cmax) |  | At enrollment and at multiple timepoints until treatment discontinuation (assessed up to 5 years) | 
| Time to reach Cmax (Tmax) |  | At enrollment and at multiple timepoints until treatment discontinuation (assessed up to 5 years) | 
| Trough concentrations (Ctrough) |  | At enrollment and at multiple timepoints until treatment discontinuation (assessed up to 5 years) | 
| Terminal Elimination Half-Life (t 1/2) |  | At enrollment and at multiple timepoints until treatment discontinuation (assessed up to 5 years) | 
| Incidence of anti-drug antibodies [ADAs] |  | From enrollment until treatment discontinuation (assessed up to 5 years) | 
| Duration of Response (DoR) | To evaluate preliminary anti-tumor efficacy of GEN3009 as monotherapy and in combination by change in tumor size | From 6 weeks after enrollment until treatment discontinuation, assessed up to 5 years | 
| Time to Response (TTR) | To evaluate preliminary anti-tumor efficacy of GEN3009 as monotherapy and in combination by change in tumor size | From 6 weeks after enrollment until treatment discontinuation, assessed up to 5 years | 
| Progression-free survival (PFS) | To evaluate preliminary anti-tumor efficacy of GEN3009 as monotherapy and in combination by change in tumor size | From 6 weeks after enrollment until treatment discontinuation, assessed up to 5 years | 
| Overall survival (OS) | To evaluate preliminary anti-tumor efficacy of GEN3009 as monotherapy and in combination by change in tumor size | From 6 weeks after enrollment until treatment discontinuation, assessed up to 5 years | 
| Part 2C: Rate and Duration of MRD negativity | To evaluate preliminary anti-tumor efficacy of GEN3009 in combination by change in tumor size | From 6 weeks after enrollment until treatment discontinuation, assessed up to 5 years | 
| Part 1, Part 2B and part 2C: Objective Response Rate (ORR) | To evaluate preliminary anti-tumor efficacy of GEN3009 as monotherapy and in combination by change in tumor size | From 6 weeks after enrollment until treatment discontinuation, assessed up to 5 years | 
| Part 1, Part 2A and Part 2B: Complete Response (CR) rate | To evaluate preliminary anti-tumor efficacy of GEN3009 as monotherapy and in combination by change in tumor size | From 6 weeks after enrollment until treatment discontinuation, assessed up to 5 years | 
| Part 2A and 2C: Incidence of Adverse Events | To assess the safety and tolerability of GEN3009 as monotherapy and of GEN3009 in combination | From screening until 30 days after last dose for Part 2A and 60 days after last dose for Part 2C | 
| Part 2A and 2C: Number of participants with clinically significant shifts from baseline in clinical laboratory | Clinical Lab parameters assessed: hematology, chemistry, coagulation, immunoglobulins and urinalyses | From screening until 30 days after last dose for Part 2A and 60 days after last dose for Part 2C | 
| Part 2A and 2C: Number of participants with clinically significant change from baseline in vital signs | Vital signs assessed: systolic and diastolic blood pressure, heart rate, temperature and pulse oximetry | From screening until 30 days after last dose for Part 2A and 60 days after last dose for Part 2C | 
| Part 2A and 2C: Frequency of dose interruptions, dose delays, and dose intensity | Assessment of frequency of dose interruptions, dose delays and dose intensity | From enrollment until treatment discontinuation (assessed up to 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-CD37, monoclonal antibodies, DuoHexabody®