A First-in-human Trial of GEN3017 in Hodgkin Lymphoma and Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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The purpose of this trial is to evaluate the safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of GEN3017 as a monotherapy in participants with relapsed or refractory (R/R) CD30-expressing lymphomas. GEN3017 will be administered via subcutaneous injections. All participants will receive active drug; no one will be given placebo.

Detailed Description
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This multicenter trial will be conducted in 2 parts: Dose Escalation (phase 1) and Expansion (phase 2a). The Dose Escalation Part (phase 1) of the trial will evaluate dose-limiting toxicities (DLTs) to determine the recommended phase 2 dose (RP2D), and if reached, the maximum tolerated dose (MTD) for R/R CD30+ classical Hodgkin lymphoma (cHL) and R/R CD30+ T-cell lymphoma (TCL), respectively. The Expansion Part (phase 2a) will evaluate the anti-tumor activity of GEN3017 at the RP2D and selected dosage(s) will be assessed together with safety, immunogenicity, pharmacokinetics, and pharmacodynamics in R/R CD30+ cHL participants (including adults; and adolescent and young adults) and in participants with selected R/R CD30+ TCL subtypes (adults only).

Official Title
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A Phase 1/2a, Open-Label, Dose Escalation Trial of GEN3017 With Expansion Cohorts in Relapsed or Refractory CD30+ Classical Hodgkin Lymphoma and CD30+ Non-Hodgkin Lymphoma

Conditions
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Classical Hodgkin Lymphoma, Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: GEN3017


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Dose Escalation Part: Must be at least 18 years of age. For participants in the R/R cHL Cohort in the United States (US) and Australia, must be at least 16 years of age. Histologically confirmed R/R cHL or R/R TCL. Participants must have at least 1 measurable lesion by fluorodeoxyglucose-positron emission tomography (FDG-PET) scan demonstrating positive lesion compatible with computed tomography (CT)- or magnetic resonance imaging (MRI)-defined anatomical tumor sites and a CT scan (or MRI) with involvement of ≥1 measurable nodal lesion and/or ≥1 measurable extranodal lesion. Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1 for participants 18 years of age and above. For participants ≥16 and <18 years of age (US and Australia only), Karnofsky score of >60% per Karnofsky performance scale. Confirmed CD30-positivity in tumor biopsy prior to the first dose of GEN3017. R/R cHL Cohort: Must have relapsed or progressive cHL after receiving at least 2 or 3 prior lines of therapy; OR Refractory to the second line of therapy. Key Exclusion Criteria: Primary central nervous system (CNS) tumor or known CNS involvement. Received prior investigational CD30-targeting therapy (except brentuximab vedotin). Autologous hematopoietic stem cell transplant (HSCT) within 60 days (applies to both cHL and TCL). Allogeneic HSCT within 90 days (applies to cHL) prior to the first dose of GEN3017. Chemotherapy within 2 weeks or major surgery within 4 weeks prior to the first dose of GEN3017. Curative radiotherapy within 4 weeks or palliative radiotherapy within 2 weeks prior to the first dose of GEN3017. Treatment with an investigational drug within 4 weeks or 5 half-lives of the drug, whichever is shorter prior to the first dose of GEN3017 or currently receiving any other investigational agents. Prior treatment with live, attenuated vaccines within 30 days prior to the first dose of GEN3017. Receiving immunosuppressive drugs or systemic corticosteroids such as prednisone at doses >25 milligrams (mg) daily or its equivalent within 14 days prior to the first dose of GEN3017. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 16 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: R/R CD30+ cHL Cohort<br> | Biological: GEN3017<br>* Subcutaneous injection<br>* Other names: DuoBody® CD3xCD30;|
| Experimental: R/R CD30+ TCL Cohort<br> | Biological: GEN3017<br>* Subcutaneous injection<br>* Other names: DuoBody® CD3xCD30;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Part: Number of Participants with Dose Limiting Toxicities (DLTs) | All AEs including DLTs will be graded for severity according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), version (v) 5.0 unless otherwise specified. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the American society for transplantation and cellular therapy (ASTCT) criteria. Clinical tumor lysis syndrome (CTLS) will be evaluated according to the Cairo-Bishop classification. | During the first cycle (Cycle length = 21 days) | 
| Dose Escalation Part: Number of Participants with Adverse Events (AEs) |  | From baseline up to 60 days after last dose of study drug or until study completion or participant withdrawal (up to 5 years) | 
| Expansion Part: Objective Response Rate (ORR) | The ORR is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) per Lugano criteria assessed by an independent review committee (IRC). | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation and Expansion Part: Maximum (Peak) Plasma Concentration (Cmax) of GEN3017 |  | Predose and postdose at multiple timepoints at end of each cycle up to end of treatment (Cycle length =21 days) | 
| Dose Escalation and Expansion Part: Time to Reach Cmax (Tmax) of GEN3017 |  | Predose and postdose at multiple timepoints at end of each cycle up to end of treatment (Cycle length = 21 days) | 
| Dose Escalation and Expansion Part: Pre-dose (Trough) concentration (Ctrough) of GEN3017 |  | Predose and postdose at multiple timepoints at end of each cycle up to end of treatment (Cycle length = 21 days) | 
| Dose Escalation and Expansion Part: Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity (AUCinf) of GEN3017 |  | Predose and postdose at multiple timepoints at end of each cycle up to end of treatment (Cycle length = 21 days) | 
| Dose Escalation and Expansion Part: Area Under the Concentration-time Curve (AUC) From Time Zero to Last Quantifiable Sample (AUClast) of GEN3017 |  | Predose and postdose at multiple timepoints at end of each cycle up to end of treatment (Cycle length = 21 days) | 
| Dose Escalation and Expansion Part: Elimination Half-life (T1/2) of GEN3017 |  | Predose and postdose at multiple timepoints at end of each cycle up to end of treatment (Cycle length = 21 days) | 
| Dose Escalation and Expansion Part: Total Body Clearance (CL) of Drug From Plasma of GEN3017 |  | Predose and postdose at multiple timepoints at end of each cycle up to end of treatment (Cycle length = 21 days) | 
| Dose Escalation and Expansion Part: Volume of distribution (Vd) of GEN3017 |  | Predose and postdose at multiple timepoints at end of each cycle up to end of treatment (Cycle length = 21 days) | 
| Dose Escalation and Expansion Part: Number of Participants with Anti-drug Antibodies (ADA) to GEN3017 | Serum samples will be screened for ADAs binding to GEN3017 and the titer of confirmed positive samples will be reported. | Predose at multiple timepoints of each cycle up to end of treatment (Cycle length = 21 days) | 
| Dose Escalation and Expansion Part: Objective Response Rate (ORR) | The ORR is defined as the percentage of participants with a BOR of CR or PR per Lugano criteria based on investigator assessment. | Up to 5 years | 
| Dose Escalation and Expansion Part: Duration of Response (DOR) | DOR is defined as the time from the first documentation of response (CR or PR) to the date of progressive disease or death, whichever occurs earlier per Lugano criteria based on investigator and IRC assessment (expansion only). | Up to 5 years | 
| Dose Escalation and Expansion Part: Time to Response (TTR) | TTR is defined as the time from Cycle 1 Day 1 to first documentation of objective response in participants achieving PR or CR per Lugano criteria based on investigator and IRC assessment (expansion only). | Up to 5 years | 
| Expansion Part: Complete Response Rate (CRR) | CRR is defined as the number of participants with CR per Lugano criteria based on investigator and IRC assessment. | Up to 5 years | 
| Expansion Part: Progression Free Survival (PFS) | PFS is defined as the time from Cycle 1 Day 1 to first documented progressive disease or death due to any cause, whichever occurs earlier per Lugano criteria based on investigator and IRC assessment. | Up to 5 years | 
| Expansion Part: Overall Survival (OS) | OS is defined as the time from Cycle 1 Day 1 to the date of death due to any cause. | Up to 5 years | 
| Expansion Part: Number of Participants with AEs and Serious Adverse Events (SAEs) |  | From first dose until the end of the safety follow-up period (60 days after last dose) up to 5 years |