GEN3014 Safety Trial in Relapsed or Refractory Hematologic Malignancies

Study Overview
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Brief Summary
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The drug that will be investigated in the study is an antibody, GEN3014. Since this is the first study of GEN3014 in humans, the main purpose is to evaluate safety. Besides safety, the study will determine the recommended GEN3014 dose to be tested in a larger group of participants and assess preliminary clinical activity of GEN3014. GEN3014 will be studied in relapsed or refractory multiple myeloma (also known as RRMM) and other blood cancers. The study consists of 3 parts: The Dose Escalation will test increasing doses of GEN3014 to find a safe dose level to be tested in the other two parts. Expansion Part A will further test the GEN3014 dose determined from the Dose Escalation Part. Expansion Part B will compare intravenous (IV) GEN3014 with the approved multiple myeloma drug, subcutaneous (SC) daratumumab. Participants in the US will not participate Expansion Part B. Participants will receive either investigational GEN3014 or daratumumab; none will be given placebo. The study duration will be different for the individual participants. Overall, the study may be ongoing up to 5 years after the last participant's first treatment.

Detailed Description
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This trial will be conducted in 3 parts: Dose Escalation (phase 1), Expansion Parts, A and B (phase 2). All participants in the Dose Escalation, GEN3014 will be evaluated in RRMM and R/R AML, will receive GEN3014, administered at various dose levels in 28-day cycles. Dose Limiting Toxicities (DLTs) will be assessed during the first treatment cycle and the Maximum Tolerated Dose (MTD) and/or Recommended phase 2 dose (RP2D) will be determined. Expansion Part A, GEN3014 will be further evaluated in 4 cohorts: anti-CD38 mAb-naive RRMM, anti-CD38 mAb-refractory RRMM, R/R DLBCL, and R/R AML at the RP2D identified from the Dose Escalation per protocol. Expansion Part B, GEN3014 IV will be compared to daratumumab SC, head-to-head (H2H) to evaluate whether GEN3014 may be more potent in anti-CD38 mAb-naïve RRMM participants.

Official Title
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An Open-Label, Multicenter, Phase 1/2 Trial of GEN3014 (HexaBody®-CD38) in Relapsed or Refractory Multiple Myeloma and Other Hematologic Malignancies

Conditions
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Multiple Myeloma (MM), Diffuse Large B Cell Lymphoma (DLBCL), Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Biological: GEN3014
* Drug: Daratumumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Must have fresh bone marrow samples collected at Screening. Dose Escalation phase, Expansion part A (for MM and AML) and Expansion part B- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0, 1, or 2. Expansion part A (for DLBCL): ECOG PS 0 or 1. Expansion part A - Has acceptable laboratory test results during the Screening period. A woman of reproductive potential must agree to use adequate contraception during the trial and for 12 months after the last GEN3014 or daratumumab SC administration. A woman of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) at Screening and additionally, for Expansion Part B, within 72 hours of the first dose of study treatment prior to dosing. A woman must agree not to donate eggs (ova, oocytes) for assisted reproduction during the trial and for 12 months after receiving the last dose of GEN3014 or daratumumab SC. 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 and all men must not donate sperm during the trial and for 12 months after receiving the last dose of GEN3014 or daratumumab SC. Specific for RRMM: Must have documented multiple myeloma as defined by the criteria below and have evidence of disease progression on the most recent prior treatment regimen based on IMWG criteria: Prior documentation of monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy-proven plasmacytoma and, Measurable disease at baseline as defined by any of the following: Immunoglobulin (Ig) G, IgA, IgD, or IgM myeloma: Serum M-protein level ≥0.5 g/dL (≥5 g/L) or urine M protein level ≥200 mg/24 hours or, Light chain myeloma: Serum Ig free light chain (FLC) ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio. Note: Participants with RRMM must have exhausted standard therapies, at the investigator's discretion. For anti-CD38 mAb-naive RRMM Cohort: Participant received at least 3 prior lines of therapy including a PI and an IMiD in any order, or is double refractory to a PI and an IMiD; or participant received ≥ 2 prior lines of therapy if 1 of those lines included a combination of PI and IMiD. Note: Participants should not have received any anti-CD38 antibody. Anti-CD38 mAb-naive RRMM subjects will be enrolled from ex-US countries Dose Escalation phase - For anti-CD38 mAb-treated RRMM Cohort: Participant has received at least 2 prior lines of therapy and must have discontinued daratumumab or isatuximab for at least 4 weeks prior to the first dose of GEN3014. Note: Participants should not have received any other anti-CD38 antibody except daratumumab or isatuximab. Specific for R/R AML: Relapsed or refractory AML, both de novo or secondary; must have failed all conventional therapy. Acute promyelocytic leukemia (APL) is excluded from this trial. Participant with relapsed AML who received at least 2 prior therapies for AML with the exception of hydroxyurea. Participant with refractory AML who received at least 1 prior line of therapy for AML with the exception of hydroxyurea. Participant's life expectancy at Screening is judged to be at least 3 months. Specific for DLBCL: Expansion phase: Relapsed or refractory DLBCL, both de novo or histologically transformed. Participants with R/R DLBCL must have exhausted standard therapies, at the investigator's discretion. Expansion phase: Received at least 2 prior lines of systemic therapy, with 1 being a CD20-containing chemoimmunotherapy. Expansion phase: Have at least 1 measurable site of disease as per Lugano criteria. Expansion phase: Must have available archival or fresh tumor tissue or both to submit to a central laboratory for CD38 assay. Key Exclusion Criteria Prior treatment with any CD38-directed therapies (eg, daratumumab, isatuximab, CD38 CAR-T, bispecific Ab) in anti-CD38 mAb-naive RRMM Cohort. Note: Prior daratumumab or isatuximab exposure is allowed for anti-CD38 mAb-treated RRMM participants in the Dose Escalation and anti-CD38 mAb-refractory RRMM Cohort in the Expansion Part A. Treatment with an anti-cancer agent, chemotherapy, radiation therapy, or major surgery within 2 weeks prior to the first dose of study treatment (Dose Escalation and Expansion Part A) or randomization (Expansion Part B). Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of study treatment (Dose Escalation and Expansion Part A) or randomization (Expansion Part B). Cumulative dose of corticosteroids more than the equivalent of ≥140 mg of prednisone within 2-week period before the first dose of study treatment (Dose Escalation and Expansion Part A) or maximum cumulative dose of dexamethasone 160 mg within 28 days of randomization (Expansion Part B). Has clinically significant cardiac disease. 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) tumor or known CNS involvement at Screening. Has known history/positive serology for hepatitis B. Known medical history or ongoing hepatitis C infection that has not been cured. Known history of seropositivity of human immunodeficiency virus (HIV) (Dose Escalation and Expansion Part A) or to be positive for HIV with details in the protocol (Expansion Part B). Currently receiving any other investigational agents. 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 study treatment. A man who plans to father a child while enrolled in this trial or within 12 months after the last dose of study treatment. Specific Exclusion Criteria for RRMM: Prior allogeneic hematopoietic stem cell transplant (HSCT). Autologous HSCT within 3 months of the first dose of GEN3014. Specific Exclusion Criteria for R/R AML: <5% blasts in blood or bone marrow at Screening. Prior autologous HSCT. Allogenic HSCT within 3 months of the first dose of GEN3014. Active graft-versus-host-disease requiring immunosuppressive treatment. Any immunosuppressive medication (eg, calcineurin inhibitors) must be stopped ≥4 weeks prior to the first dose of GEN3014. 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: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation part is sequential while the expansion Part A cohorts are parallel. Expansion Part B is sequential to Expansion Part A RRMM cohort. In Expansion Part B, participants with RRMM are randomized (1:1) to treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GEN3014<br>Experimental: GEN3014 Participants in Dose Escalation phase with Relapsed or refractory myeloid myeloma (RRMM) R/R acute myeloid leukemia (AML) Participants in Expansion Part A with RRMM (anti-CD38 mAb-naïve) RRMM (anti-CD38 mAb-refractory) R/R diffuse large B-cell lymphoma (DLBCL) R/R AML Participants in Expansion Part B with • RRMM (anti-CD38 mAb-naïve) | Biological: GEN3014<br>* GEN3014 is administered by intravenous (IV) infusion.<br>* Other names: HexaBody®-CD38;|
| Active Comparator: Daratumumab<br>Participants in Expansion Part B with - RRMM (anti-CD38 mAb-naïve) | Drug: Daratumumab<br>* Daratumumab is administered by subcutaneous (SC) injections.<br>* Other names: DARZALEX FASPRO®;|

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) | To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) to be studied in the Expansion part. DLT will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria version 5.0. | Up to 28 days during the first cycle | 
| Dose Escalation: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | From first dose until the end of the safety follow-up period (30 days after last dose) | 
| Expansion Part A: Objective Response Rate (ORR) of GEN3014 | ORR is defined as the percentage of participants with a partial response (PR), or better based on International Myeloma Working Group (IMWG) criteria for MM participants, based on Lugano criteria for DLBCL participants, and based on International Working Group (IWG) response criteria for AML participants. | Up to 8 years | 
| Expansion Part B: Objective Response Rate (ORR) of GEN3014 IV vs Daratumumab SC in Anti-CD38 mAb-naive RRMM Participants | ORR is defined as the percentage of participants with a PR, or better based on IMWG criteria. | Up to 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Maximum (peak) Plasma Concentration (Cmax) of GEN3014 |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Dose Escalation: Time to Reach Cmax (Tmax) of GEN3014 |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Dose Escalation: Pre-dose (trough) Concentrations (Cthrough) of GEN3014 |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Dose Escalation: Area Under the Concentration Time Curve From Zero to Last Quantifiable Sample (AUC0-last) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Dose Escalation: Area Under the Concentration Time Curve From Zero to 168 hours (AUC0-168 h) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Dose Escalation: Accumulation Ratio in Cmax (RA, Cmax) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Dose Escalation: Accumulation Ratio in AUC (RA, AUC) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Dose Escalation: Number of NK-cells and Other Leukocytes Subsets | NK-cells and other leukocytes absolute counts in blood and tumor samples will be assessed. | Predose and postdose at multiple timepoints of each Cycle up to Cycle 6 and thereafter only in even Cycles (Cycle length=28 days) | 
| Dose Escalation: Percentage of NK-cells and Other Leukocytes Subsets | NK-cells and other leukocytes percentage in blood and tumor samples will be assessed. | Predose and postdose at multiple timepoints of each Cycle up to Cycle 6 and thereafter only in even Cycles (Cycle length=28 days) | 
| Dose Escalation: Change From Baseline in Cytokine levels up to Cycle 1 | Change in cytokine levels in blood samples will be assessed. | Cycle 1 (cycle length = 28 days) | 
| Dose Escalation: Change From Baseline in CH50 and C2 level up to Cycle 1 | Change in CH50 and C2 levels in blood samples will be assessed. | Cycle 1 (cycle length = 28 days) | 
| Dose Escalation: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014 |  | From first dose until treatment discontinuation (Up to 8 years) | 
| Dose Escalation: Objective Response Rate (ORR) of GEN3014 | ORR is defined as the percentage of participants with a PR or better based on IMWG criteria for MM participants, and based on IWG response criteria for AML participants. | Up to 8 years | 
| Dose Escalation: Clinical Benefit Rate (CBR) of GEN3014 | CBR was determined by the investigator according to the IMWG response criteria for MM participants. | Up to 8 years | 
| Dose Escalation: Duration of Response (DOR) of GEN3014 | DOR is defined as time from first response (PR or better) to timing of disease progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants and based on IWG response criteria for AML participants. | Up to 8 years | 
| Dose Escalation: Time-to-response (TTR) of GEN3014 | TTR is defined as the time from date of first dose to time of response (PR or better) based on IMWG criteria for MM participants and based on IWG response criteria for AML participants. | Up to 8 years | 
| Dose Escalation: Progression-free survival (PFS) of GEN3014 | PFS is defined as the time from the date of the first dose, or date of randomization to the date of progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants and based on IWG response criteria for AML participants. | Up to 8 years | 
| Dose Escalation: Overall Survival (OS) of GEN3014 | OS is defined as the time from the date of first dose to the date of death due to any cause. | Up to 8 years | 
| Expansion Part A: Clinical Benefit Rate (CBR) of GEN3014 | CBR was determined by the investigator according to the IMWG response criteria for MM participants. | Up to 8 years | 
| Expansion Part A: Duration of Response (DOR) of GEN3014 | DOR is defined as time from first response (PR or better) to timing of disease progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants, based on Lugano criteria for DLBCL participants, and based on IWG response criteria for AML participants. | Up to 8 years | 
| Expansion Part A: Time-to-response (TTR) of GEN3014 | TTR is defined as the time from date of first dose to time of response (PR or better) for MM participants, based on Lugano criteria for DLBCL participants, and based on IWG response criteria for AML participants. | Up to 8 years | 
| Expansion Part A: Progression-free survival (PFS) of GEN3014 | PFS is defined as the time from the date of the first dose to the date of progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants, based on Lugano criteria for DLBCL participants, and based on IWG response criteria for AML participants. | Up to 8 years | 
| Expansion Part A: Overall Survival (OS) of GEN3014 | OS is defined as the time from the date of first dose to the date of death due to any cause. | Up to 8 years | 
| Expansion Part A: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) per CTCAE v5.0 |  | From first dose until the end of the safety follow-up period (30 days after last dose) | 
| Expansion Part A: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014 |  | From first dose until treatment discontinuation (Up to 8 years) | 
| Expansion Part A: Maximum (peak) Plasma Concentration (Cmax) of GEN3014 |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Expansion Part A: Time to Reach Cmax (Tmax) of GEN3014 |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Expansion Part A: Pre-dose (trough) Concentrations (Cthrough) of GEN3014 |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Expansion Part A: Area Under the Concentration Time Curve From Zero to Last Quantifiable Sample (AUC0-last) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Expansion Part A: Area Under the Concentration Time Curve From Zero to 168 hours (AUC0-168 h) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Expansion Part A: Accumulation Ratio in Cmax (RA, Cmax) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Expansion Part A: Accumulation Ratio in AUC (RA, AUC) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Expansion Part A: Accumulation Ratio in Cthrough (RA,Cthrough) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Expansion Part A: Number of NK-cells and Other Leukocytes Subsets | NK-cells and other leukocytes absolute counts in blood and tumor samples will be assessed. | Predose and postdose at multiple timepoints of each Cycle up to Cycle 6 and thereafter only in even Cycles (Cycle length=28 days) | 
| Expansion Part A: Percentage of NK-cells and Other Leukocytes Subsets | NK-cells and other leukocytes percentage in blood and tumor samples will be assessed. | Predose and postdose at multiple timepoints of each Cycle up to Cycle 6 and thereafter only in even Cycles (Cycle length=28 days) | 
| Expansion Part A: Change From Baseline in Cytokine levels up to Cycle 1 | Change in cytokine levels in blood samples will be assessed. | Cycle 1 (cycle length = 28 days) | 
| Expansion Part A: Change From Baseline in CH50 and C2 level up to Cycle 1 | Change in CH50 and C2 levels in blood samples will be assessed. | Cycle 1 (cycle length = 28 days) | 
| Expansion Part B: Ctrough levels of GEN3014 IV or Daratumumab SC on Cycle 3 Day 1 |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) | 
| Expansion Part B: Very Good Partial Response (VGPR), or better of GEN3014 IV vs Daratumumab SC |  | Up to 8 years | 
| Expansion Part B: Complete Response (CR) or better of GEN3014 IV vs Daratumumab SC |  | Up to 8 years | 
| Expansion Part B: Duration of Response (DOR) of GEN3014 IV vs Daratumumab SC | DOR is defined as time from first response (PR or better) to timing of disease progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants. | Up to 8 years | 
| Expansion Part B: Time-to-response (TTR) of GEN3014 IV vs Daratumumab SC | TTR is defined as the time from date of randomization, to time of response (PR or better) based on IMWG criteria for MM participants. | Up to 8 years | 
| Expansion Part B: Progression-free Survival (PFS) of GEN3014 IV vs Daratumumab SC | PFS is defined as the time from date of randomization to the date of progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants. | Up to 8 years | 
| Expansion Part B: Overall Survival (OS) of GEN3014 IV vs Daratumumab SC | OS is defined as the time from date of randomization to the date of death due to any cause. | Up to 8 years | 
| Expansion Part B: Time to Next Therapy (TTNT) | Time to next therapy (TTNT) for participants in the Expansion Part B is defined as the time from date of randomization to the start of subsequent anti-cancer therapy. | Up to 8 years | 
| Expansion Part B: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) per CTCAE v5.0 |  | From first dose until the end of the safety follow-up period (30 days after last dose) | 
| Expansion Part B: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014, Anti-daratumumab antibodies and Anti- rHuPH20 |  | From first dose until treatment discontinuation (Up to 8 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hexabody®, Anti-CD38, monoclonal antibody