GEN3014 Trial in Relapsed or Refractory Hematologic Malignancies

Prior treatment

• Prior treatment with any anti-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 subjects in the Dose Escalation and anti-CD38 mAb-refractory RRMM Cohort in the Expansion Part A.
• Currently receiving any other investigational agents.
• 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: 14. Prior allogeneic HSCT.
• Specific Exclusion Criteria for R/R AML: Prior autologous HSCT.
• Specific Exclusion Criteria for R/R AML: 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. Please refer to the protocol section 5.2.2 for the full list of Exclusion criteria for the Expansion Part B (Randomized H2H).
• 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).
• Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy.

Other illness

• 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).
• Has clinically significant cardiac disease
• Has known history/positive serology for hepatitis B
• Known medical history or ongoing hepatitis C infection that has not been cured.

Other

• 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.
• Specific Exclusion Criteria for RRMM: 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.
• Specific Exclusion Criteria for R/R AML: Allogenic HSCT within 3 months of the first dose of GEN3014
• Primary central nervous system (CNS) tumor or known CNS involvement at Screening.

• Must be at least 18 years of age.
  • Specific Inclusion Criteria for RRMM: 10. 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. Participants with RRMM must have exhausted standard therapies, at the investigator’s discretion.
• For anti-CD38 mAb-naive RRMM subjects: 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.
• For anti-CD38 mAb-treated RRMM participants: 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.
• Potassium level ≥3.0 mEq/L (≥3.0 mmol/L); and corrected serum calcium ≤14.0 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L).
  • Specific Inclusion Criteria for R/R AML: 14. 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 complete remission (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.
  • Specific Inclusion Criteria for R/R AML: 15. Subject with relapsed AML who received at least 2 prior therapies for AML with the exception of hydroxyurea.
  • Specific Inclusion Criteria for R/R AML: 16. Subject with refractory AML who received at least 1 prior line of therapy for AML with the exception of hydroxyurea.
  • Specific Inclusion Criteria for R/R AML: 17. Subject's life expectancy at Screening is judged to be at least 3 months. Please refer to Protocol sections 5.1.2 and 5.1.3 for the Inclusion Criteria for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H), respectively
• Must sign an informed consent form (ICF) prior to any Screening
• 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 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 also not donate sperm during the trial and for 12 months after receiving the last dose of GEN3014 or daratumumab SC.