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

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

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").

Study Overview

• Status: Terminated
• Conditions: Follicular Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Chronic Lymphocytic Leukemia; Diffuse Large B-cell Lymphoma; Small Lymphocytic Lymphoma; High-grade B-cell Lymphoma; Primary Mediastinal Large B-cell Lymphoma
• Intervention / Treatment: Biological: GEN3009; Biological: Epcoritamab

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • UZ Leuven
• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet
  • Odense, Denmark
    • Odense Universitetshospital
  • Vejle, Denmark
    • Vejle Sygehus
• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam UMC, locatie VUmc
• Spain
  • Barcelona, Spain
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain
    • Hospital Universitario Fundacion Jimenez Diaz
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • ICO Badalona - Hospital Universitari Germans Trias i Pujol
  • L'Hospitalet De Llobregat
    • Barcelona, L'Hospitalet De Llobregat, Spain, 08908
      • ICO L'Hospitalet - Hospital Duran i Reynals
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina (MUSC)
  • Texas
    • Dallas, Texas, United States, 75390
      • The University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98133
      • University of Washington - Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Be at least 18 years of age.
2. Must sign an informed consent form prior to any screening procedures.

3. 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,

   1. For FL and DLBCL, at least 1 of the 2 prior lines of treatment must have been a CD20 containing systemic regimen;
   2. For CLL, subjects must have received at least one prior line of BTK inhibitor or BCL 2 inhibitor.

4. 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)

5. Has measurable disease for B-cell NHL or has active disease for Chronic Lymphocytic Leukemia (CLL).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7. Has adequate hepatic, renal, and bone marrow functions.
8. 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.
9. 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.
10. Subjects must have a life expectancy of at least 3 months.

Key Exclusion Criteria:

1. Prior treatment with a CD37-targeting agent.
2. Prior allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
3. Prior treatment with a CD3xCD20 bispecific antibody (Combination Expansion cohort only).
4. Autologous HSCT within 3 months before the first dose of GEN3009.
5. Lymphomas leukemic phase: high absolute lymphocyte count or the presence of abnormal cells in the peripheral blood indicating circulating lymphoma cells.
6. 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.
7. Chemotherapy or radiation therapy within 2 weeks of the first dose of GEN3009.
8. 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.
9. Autoimmune disease or other diseases that require permanent or high-dose immunosuppressive therapy.
10. 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.
11. Has uncontrolled intercurrent illness.
12. Seizure disorder requiring therapy (such as steroids or anti-epileptics) (Combination Expansion cohort only).
13. Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy.
14. Primary central nervous system (CNS) lymphoma or known CNS involvement at screening.
15. Known past or current malignancy other than inclusion diagnosis.
16. Had allergic reactions to anti-CD20 or anti-CD37 monoclonal antibody treatment or intolerant to GEN3009 or to the combination therapy excipients.
17. 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).
18. Known history/positive serology for hepatitis B.
19. Known medical history or ongoing hepatitis C infection that has not been cured.
20. Known history of seropositivity for HIV infection.
21. 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.
22. 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.
23. 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.
24. Exposed to live/live attenuated vaccine within 4 weeks prior to initiation of GEN3009 treatment.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Monotherapy Arm	Biological: GEN3009; GEN3009 will be administered by intravenous (IV) infusion in cycles of 28 days; Other Names: DuoHexaBody®-CD37
Experimental: Combination Arm	Biological: GEN3009; GEN3009 will be administered by intravenous (IV) infusion in cycles of 28 days; Other Names: DuoHexaBody®-CD37; Biological: Epcoritamab; Epcoritamab will be administered by subcutaneous (SC) injections in cycles of 28 days; Other Names: GEN3013; DuoBody®-CD3xCD20; EPKINLY™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs)	DLTs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, except for TLS (Cairo-Bishop grading) and CRS/ICANS (Lee et al., 2019). These criteria include: all Grade 5 toxicities; hematologic events including thrombocytopenia Grade 4, neutropenia Grade 4, Febrile neutropenia Grade 3 or 4, Grade 3 or 4 hemorrhage associated with thrombocytopenia of ≥Grade 3, anemia of Grade 4 and tumor lysis syndrome (TLS) Grade 4; and non-hematologic AEs of Grade 3 or higher excluding certain fevers, hypotension, laboratory values, Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), nausea, vomiting, diarrhea, fatigue/asthenia, or alopecia (no grading), which meet certain additional criteria.	During the first treatment cycle (Cycle length=28 days)
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs	An AE is any untoward medical occurrence in a clinical trial participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as an AE that meets one of the following criteria: is fatal or life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant (an event that jeopardizes the participant or may require medical or surgical intervention to prevent one of the outcomes listed above [medical and scientific judgment must be exercised in deciding whether an AE is "medically significant"]); required inpatient hospitalization or prolongation of existing hospitalization. TEAEs are defined as AEs which begin, or worsen, during the on-treatment period ending 4 weeks after the last dose of study medication.	From first dose until 30 days after the last dose (up to 15.5 months)
Number of Participants With AEs of Special Interest (AESI)	AESIs are defined as events (serious or non-serious) that are of scientific and medical concern specific to the sponsor's product or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor may be appropriate.	From first dose until 30 days after the last dose (up to 15.5 months)
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as TEAEs	Laboratory parameters included hematology, serum chemistries and urinalysis. Clinically significant laboratory abnormalities were based upon the Investigator's discretion. Laboratory parameters captured as AEs are reported in this outcome measure.	From first dose until 30 days after the last dose (up to 15.5 months)
Number of Participants With Clinically Notable Vital Signs	Criteria for clinically notable (elevated and below normal values respectively) vital signs are as follows: Systolic Blood Pressure (SBP): ≥180 millimeters of mercury (mmHg) and an increase ≥20 mmHg from baseline, ≤90 mmHg and a decrease ≥20 mmHg from baseline; Diastolic Blood Pressure (DBP): ≥105 mmHg and an increase ≥15 mmHg from baseline, ≤50 mmHg and a decrease ≥15 mmHg from baseline; Heart rate: ≥120 beats per minute (bpm) with an increase of ≥15 bpm from baseline, ≤50 bpm and a decrease ≥15 bpm from baseline; Temperature: > 38 degree Celsius (°C) and < 35°C. Number of participants with clinically notable elevated and below normal vital signs values up to end of treatment are reported.	From first dose up to end of treatment (up to 14.5 months)
Number of Participants With Dose Delays and Dose Interruptions	Number of participants with dose delays and dose Interruptions due to AE, Coronavirus disease 2019 (COVID-19), drug administration issues and other unspecified reasons are reported.	From first dose until 30 days after the last dose (up to 15.5 months)
Actual Dose Intensity	Actual dose intensity (milligrams per cycle [mg/cycle]) is calculated as cumulative dose/number of cycles initiated.	From first dose until 30 days after the last dose (up to 15.5 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apparent Total Plasma Clearance (CL) of GEN3009		Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2 hours (h) and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
Volume of Distribution of GEN3009		Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Day 7 of GEN3009		Pre-dose and 5 minutes post-dose on days 1, 2 and 4 (S2 only); 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
AUC From Time 0 to Infinity (AUCinf) of GEN3009		Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
AUC From Time 0 to Time of Last Dose (AUClast) of GEN3009		Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
Maximum Observed Plasma Concentration (Cmax) of GEN3009		Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
Time to Reach Cmax (Tmax) of GEN3009		Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
Trough Concentrations (Ctrough) of GEN3009		Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
Terminal Elimination Half-Life (t 1/2) of GEN3009		Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
Number of Participants With Positive Anti-drug Antibodies (ADAs)	Venous blood samples will be collected for measurement of serum concentrations of ADAs. Number of participants with positive ADAs are reported in this outcome measure. The detection of ADAs was performed using validated, specific and sensitive Electrochemiluminescence Immunoassay (ECLIA) method.	From first dose until 30 days after the last dose (up to 15.5 months)
Duration of Response (DoR)	DoR is defined as the time from the first documentation of objective tumor response [Complete response (CR) or Partial response (PR)] to the date of first disease progression (PD) or death as assessed by the investigator based on Lugano criteria for B-cell non-Hodgkin lymphoma (B-cell NHL) and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) for chronic lymphocytic leukemia (CLL). Detailed definition of CR, PR and PD as per Lugano and iwCLL criteria in the protocol appendices.	From date of first documented CR or PR up to disease progression or death (up to approximately 3 years 4 months)
Time to Response (TTR)	TTR: time from first dose of administration until date of first response as assessed by investigator based on Lugano criteria for B-cell NHL and iwCLL for CLL. It is derived for all participants who achieved PR or CR. Detailed definitions of CR, PR and PD as per Lugano and iwCLL criteria in the protocol appendices.	From date of first documented CR or PR up to disease progression or death (up to approximately 3 years 4 months)
Progression-free Survival (PFS)	PFS is defined as the time in days from Day 1 of Cycle 1 to the day of first documented PD, or the day of death due to any cause, whichever comes first as assessed by investigator based on Lugano Criteria for B-cell NHL and iwCLL for CLL. PFS was estimated using the Kaplan-Meier method. Detailed definitions of PD as per Lugano and iwCLL criteria in the protocol appendices.	From day of first dose until disease progression or death due to any cause (up to approximately 3 years 4 months)
Overall Survival (OS)	The OS is defined as the time from the start of study treatment until death due to any cause. The OS was estimated using Kaplan-Meier method.	From day of first dose until disease progression or death due to any cause (up to approximately 3 years 4 months)
Objective Response Rate (ORR)	ORR: the percentage of participants who achieved a best overall response (BOR) of CR or PR as assessed by investigator based on Lugano Criteria for B-cell NHL and iwCLL for CLL. Detailed definitions of CR and PR as per Lugano and iwCLL criteria in the protocol appendices.	From day of first dose until disease progression or death due to any cause (up to approximately 3 years 4 months)
CR Rate	CR rate was estimated using Clopper-Pearson method. Detailed definitions of CR as per Lugano and iwCLL criteria in the protocol appendices.	From day of first dose until disease progression or death due to any cause (up to approximately 3 years 4 months)

Collaborators and Investigators

• Sponsor: Genmab
• Collaborators: AbbVie

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2020
• Primary Completion (Actual): November 21, 2022
• Study Completion (Actual): July 28, 2023

Study Registration Dates

• First Submitted: April 1, 2020
• First Submitted That Met QC Criteria: April 20, 2020
• First Posted (Actual): April 24, 2020

Study Record Updates

• Last Update Posted (Actual): October 24, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Anti-CD37, monoclonal antibodies, DuoHexabody®
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell
• Other Study ID Numbers: GCT3009-01; 2019-002752-16 (EudraCT Number); NL72025.056.20 (Registry Identifier: The Netherlands CCMO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No