Clinical Trials

Inclusion Criteria:

• Patient must be 18 years of age or older.
• Patient must meet the following entry criteria for the applicable expansion cohort:
• For expansion part R/R aNHL cohort:
  • Documented CD20+ mature B-cell neoplasm according to WHO classification Swerdlow et al., 2016 (Swerdlow et al., 2016) or WHO classification 2008 based on representative pathology report
  • Diffuse large B-cell lymphoma (de novo or transformed from all indolent subtypes including Richter’s transformation), including: 
  • Patients with “double-hit” or “triple-hit” DLBCL (technically classified inWHO 2016 as HGBCL, with MYC and BCL2 and/or BCL6 translocations)
    Note: Other double-/triple-hit lymphomas are not eligible
  • Other aggressive B-NHL (beginning in Stage 2):
  • Primary mediastinal (thymic) large B-cell lymphoma (PMBCL)
  • High-grade B-cell lymphoma
  • Follicular lymphoma grade 3B (FL 3B)
  • Relapsed or refractory disease and previously treated with at least 2 lines of systemic antineoplastic therapy including at least 1 anti-CD20 monoclonal antibodycontaining therapy
    Note: Relapsed disease is defined as disease that has recurred ≥ 6 months after completion of therapy. Refractory disease is defined as disease that either progressed during therapy or progressed within 6 months (< 6 months) of completion of therapy.
  • Either failed prior autologous hematopoietic stem cell transplantation (HSCT), or ineligible for autologous HSCT due to age, ECOG performance status, comorbidities, and/or insufficient response to prior treatment
• For expansion part R/R iNHL cohort:
  • Documented CD20+ mature B-cell neoplasm according to WHO classification Swerdlow et al., 2016 (Swerdlow et al., 2016) or WHO classification 2008 based on representative pathology report
  • Histologic confirmed FL grade 1, 2, or 3A at initial diagnosis without clinical or pathological evidence of transformation
  • Marginal zone lymphomas (nodal, extranodal, and splenic)
  • Small lymphocytic lymphoma
  • Relapsed or refractory disease and previously treated with at least 2 lines of systemic antineoplastic therapy including at least 1 anti-CD20 monoclonal antibody-containing therapy
    Note: Relapsed disease is defined as disease that has recurred ≥6 months after completion of therapy. Refractory disease is defined as disease that either progressed during therapy or progressed within 6 months (< 6 months) of completion of therapy.
  • Previously treated with an alkylating agent or lenalidomide
  • Relapsed or refractory to the last prior line therapy. Previous lymphoma therapy is defined as 1 of the following: At least 2 months of single-agent therapy, at least 2 consecutive cycles of combination therapy, autologous HSCT, immunomodulatory therapy, or radioimmuno-therapy
• For expansion part R/R MCL cohort:
  • Documented CD20+ MCL according to WHO classification Swerdlow et al., 2016 or WHO classification 2008 based on representative pathology report with either cyclin D1 overexpression or presence of the translocation t(11;14).
  • Stage II-IV with a need for treatment.
  • Previously treated with at least 2 prior lines of systemic antineoplastic therapy including at least 1 prior anti-CD20 mAb-containing regimen.
  • Previously treated with a BTKi and either progressing (relapsed or refractory) or intolerant to BTKi
  • Relapsed or refractory to the most recent line of therapy.
    Note: Relapsed disease is defined as disease that has recurred ≥6 months after completion of therapy. Refractory disease is defined as disease that either progressed during therapy or progressed within 6 months (< 6 months) of completion of therapy.
  • If bridging therapy with BTKi is administered during the screening period, the patient must be able to undergo a repeat baseline PET-CT (and bone marrow aspirate/biopsy, if applicable) to assess baseline disease status prior to first administration of GEN3013 (if bridging therapy to the start of GEN3013 administration is more than 2 weeks).
• Measurable disease:
  • Fluorodeoxyglucose (FDG)-avid lymphomas: Measurable disease with computerized tomography (CT) (or magnetic resonance imaging [MRI]) scan with involvement of 2 or more clearly demarcated lesions/nodes with a 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 short axis ≥ 1.0 cm) AND FDG positron emission tomography (PET) scan that demonstrates positive lesion(s) compatible with CT (or MRI) defined anatomical tumor sites.
• ECOG performance status 0, 1, or 2
• Lymphocyte counts <5×10^9/L. For MCL: < 50×10^9/L.
• Platelet counts ≥ 75×10^9/L or, in the presence of bone marrow involvement or splenomegaly, ≥ 50×10^9/L.
• Absolute neutrophil counts ≥ 1.0×10^9/L; growth factor support allowed in case of bone marrow involvement.
• Patient must meet the following criteria regarding time since previous anti-neoplastic agent(s):
  • At least 4 weeks from last dose of non-investigational systemic chemotherapy;
  • At least 4 weeks or 5 half-lives from last dose of other non-investigational antineoplastic agents, whichever is shorter (except any anti-CD20 mAb or BTKi);
  • At least 5 half-lives from last dose of investigational agents except for prior chimeric antigen receptor T-cell (CAR-T) therapy from which 30 days must pass prior to first GEN3013 administration.
• Resolution of toxicities from prior therapy to a grade that does not contraindicate trial participation in the opinion of the investigator.
• If receiving glucocorticoid treatment at screening, must be a maximum daily dose of prednisone 10 mg (or equivalent) and a total of no more than 140 mg over the last 14 days prior to the first dose of GEN3013.
• Before the first dose of GEN3013, during the trial and for 12 months after last administration of GEN3013, a woman must be either
  • Not of childbearing potential* : premenarchal; postmenopausal (> 45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone [FSH] level > 40 IU/L or mIU/mL); permanently sterilized (e.g., bilateral tubal occlusion [which includes tubal ligation procedures as consistent with local regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy;
  • Of childbearing potential and practicing a highly effective method of birth control (as defined by the EU Clinical Trial Facilitation Group) consistent with local regulations regarding the use of birth control methods for patients participating in clinical trials; e.g., established use of oral, injected or implanted combined (estradiol and progesterone containing) hormonal contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); male partner sterilization (the vasectomized partner should be the sole partner for that patient); true abstinence (when this is in line with the preferred and usual lifestyle of the patient).

* If the childbearing potential changes after start of the trial (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective method of birth control, as described under 31b.

A man who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control (that is the use of condom) during the trial and for 12 months after receiving the last dose of GEN3013.

• Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the trial and for 12 months after receiving the last dose of GEN3013. Men must also not donate sperm during the trial and for 12 months after receiving the last dose of GEN3013.
• The patient understands the purpose of the trial and procedures required for the trial and is capable of giving signed informed consent as which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 
• The patient must consent to provide sample(s) for evaluation of DNA.

Exclusion Criteria:

• Primary central nervous system (CNS) lymphoma or known CNS involvement by lymphoma at screening as confirmed by magnetic resonance imaging (MRI)/computed tomography (CT) scan (brain) and, if clinically indicated, by lumbar puncture.
• Known past or current malignancy other than inclusion diagnosis, except for:
  • Cervical carcinoma of Stage 1B or less;
  • Non-invasive basal cell or squamous cell skin carcinoma;
  • Non-invasive, superficial bladder cancer;
  • Prostate cancer with a current PSA level <0.1 ng/mL
  • Any curable cancer with a complete response (CR) of >2 years duration.
• AST, and/or ALT > 3 x upper limit of normal.
• Total bilirubin > 1.5 x upper limit of normal,unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin.
• Estimated GFR < 45 mL/min/1.73m^2.
• Known clinically significant cardiac disease, including:
  • Onset of unstable angina pectoris within 6 months of signing ICF;
  • Acute myocardial infarction within 6 months of signing ICF;
  • Congestive heart failure (grade III or IV as classified by the New York Heart Association and/or known decrease ejection fraction of < 45%.
• Chronic ongoing infectious diseases (except hepatitis B or hepatitis C) requiring treatment (excluding prophylactic treatment) at the time of enrolment or within the previous 2 weeks prior to the first dose of GEN3013.
• Confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy. Low-dose prednisolone for rheumatoid arthritis or similar conditions is allowed.
• Seizure disorder requiring therapy (such as steroids or anti-epileptics).
• Any prior therapy with an investigational bispecific antibody targeting CD3 and CD20.
• Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 30 days prior to first GEN3013 administration.
• Eligible for curative intensive salvage therapy followed by high dose chemotherapy with HSCT rescue.
• Autologous HSCT within 100 days prior to first GEN3013 administration, or any prior allogeneic HSCT or solid organ transplantation 
• Active hepatitis B or hepatitis C. If laboratory evidence for a chronic infection with hepatitis B close monitoring and prophylactic therapy is required.
• Known human immunodeficiency virus (HIV) infection.
• Exposed to live or live attenuated vaccine within 4 weeks prior to signing ICF.
• Pregnancy or breast feeding.
• Patient has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• Contraindication to all uric acid lowering agents.