GEN3014 Safety Trial in Relapsed or Refractory Hematologic Malignancies

Key Inclusion Criteria

Must be at least 18 years of age.
Must sign an informed consent form (ICF) prior to any Screening procedures.
Must have fresh bone marrow samples collected at Screening.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0, 1, or 2.
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 administration.
A woman of childbearing potential must have a negative serum beta- human chorionic gonadotropin (β-hCG) at Screening.
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.

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.

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:
IgG, 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: Subjects with RRMM must have exhausted standard therapies, at the investigator's discretion.
For anti-CD38 mAb-naive RRMM Cohort: Subject 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 subject received ≥ 2 prior lines of therapy if 1 of those lines included a combination of PI and IMiD. Note: Subjects should not have received any anti-CD38 antibody. Anti- CD38 mAb naive RRMM subjects will be recruited from countries where anti-CD38 therapies are not available.

For anti-CD38 mAb-treated RRMM Cohort: Subject has received at least 2 prior lines of therapy and must have discontinued daratumumab or relapsed-multiple-myeloma/" >isatuximab for at least 4 weeks prior to the first dose of GEN3014. Note: Subjects should not have received any other anti-CD38 antibody except daratumumab or isatuximab.

Specific for 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. Note: Relapse is defined by BM blasts ≥5% in patients who have been in CR previously, or reappearance of blasts in the blood, or development of extramedullary AML. Refractory is defined as not being able to achieve a CR after the initial therapy.
Subject with relapsed AML who received at least 2 prior therapies for AML with the exception of hydroxyurea.
•Subject with refractory AML who received at least 1 prior line of therapy for AML with the exception of hydroxyurea.

Subject's life expectancy at Screening is judged to be at least 3 months.

Specific for DLBCL

Relapsed or refractory DLBCL, both de novo or histologically transformed. Note: Relapsed disease is defined as the reappearance or growth of lymphoma after at least 6 months duration of response. Refractory disease is defined as failure to achieve response after at least 2 cycles of therapy or reappearance after a duration of response of <6 months. Subjects with R/R DLBCL must have exhausted standard therapies, at the investigator's discretion.
Received at least 2 prior lines of systemic therapy, with 1 being a CD20-containing chemoimmunotherapy.

Have at least 1 measurable site of disease:

A fluorodeoxyglucose (FDG)-positron emission tomography (PET) computed tomography (CT) scan demonstrating positive lesion compatible with CT (or magnetic resonance imaging [MRI])-defined anatomical tumor sites And
A CT scan (or MRI) with involvement of ≥2 clearly-demarcated lesions/nodes with long axis >1.5 cm and short axis >1.0 cm; or 1 clearly-demarcated lesion/node with a long axis >2.0 cm and a short axis ≥1.0 cm.
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 an anti-CD38 antibody except daratumumab or isatuximab.
Treatment with an anti-cancer agent, chemotherapy, radiation therapy, or major surgery within 2 weeks prior to the first dose of study treatment.
Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.
Cumulative dose of corticosteroids more than the equivalent of ≥140 mg of prednisone within 2-week period before the first dose of study treatment.
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.
HIV positive at screening
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 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.