MC# 21-05 - Safety and Efficacy of GEN3009 (DuoHexaBody®-CD37) in Relapsed or Refractory B-cell Non-Hodgkin Lymphoma – A First-in-Human, Open-label, Phase I/IIa Dose Escalation Trial with Dose Expansion Cohorts

  • Agent(s): GEN3009
  • Disease Type(s): Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Diffuse Large B-cell Lymphoma, Follicular Lymphoma, High Grade B-cell Lymphoma, Primary Mediastinal B-Cell Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Bispecific Antibodies
  • Molecular Target(s): CD37, E430G

Mechanism of Action

GEN3009, a bispecific CD37 antibody with the E430G hexamerization-enhancing mutation targeting two non-overlapping epitopes on CD37 (biparatopic), may enduce antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of GEN3009
  • How proteins that indicate the status of your disease are affected with use of GEN3009
  • If GEN3009 prevents or delays tumor growth or shrinks existing tumors
  • How quickly GEN3009 is removed from the bloodstream
Inclusion Criteria
  1. Be at least 18 years of age
  2. Must sign an informed consent form (ICF) prior to any screening procedures indicating that they understand the purpose of the trial, the procedures required for the trial, and are willing to participate in the trial prior to any other trial-related assessments or procedures
  3. Has histologically or cytologically confirmed relapsed 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, experimental therapy with GEN3009 may be beneficial.  All subjects must have received at least two prior lines of systemic therapy, and,
    1. For all indolent NHL (FL, MZL, and SLL) as well as aggressive NHL (DLBCL, HGBCL, and PMBCL), at least one of the two prior lines of treatment must have been a CD20-containing chemotherapy regimen;
    2. For MCL, subjects must have had or are otherwise ineligible for treatment with a BTK inhibitor, and;
    3. For CLL, subjects must have received at least one prior line of BTK inhibitor or BCL- 2 inhibitor.
    • Note: For B-cell NHL, “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.
    • For CLL, “relapsed disease” is defined as evidence of disease progression in a subject who has previously achieved a CR or PR for ≥6 months.  “Refractory disease” is defined as treatment failure (not achieving a CR or PR) or as progression within 6 months from the last dose of therapy.
  4. Has 1 of the following B-cell NHL subtypes for the Dose Escalation:
    1. DLBCL, de novo or histologically transformed
    2. HGBCL
    3. PMBCL
    4. FL, with advanced symptomatic disease and with a need for treatment
    5. MCL, without leukemic manifestation
    6. MZL, either nodal, extranodal or mucosa associated, with a need for treatment initiation based on symptoms and/or disease burden
    7. SLL, with a need for treatment based on symptoms and/or disease burden
    8. CLL, including all the following parameters:
      1. B-cell count < 100x109/L (100,000/µL) in the peripheral blood
      2. Presence of measurable lymphadenopathy and/or organomegaly
      3. Leukemic cells are small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes
      4. CLL cells on immunophenotype demonstrate a clonal B-cell population, expressing the B-cell surface markers CD19 and CD20, as well as CD5.  Subjects with bright surface immunoglobulin expression or lack of CD23 expression in > 10% of cells must lack t(11;14) translocation by interphase cytogenetics.
  5. Has 1 of the following B-cell NHL subtypes for the Expansion:
    1. DLBCL, de novo or histologically transformed
    2. FL, with advanced symptomatic disease and with a need for treatment initiation
    3. CLL, including all the following:
      1. B-cell count < 100x109/L (100,000/µL) in the peripheral blood
      2. Presence of measurable lymphadenopathy and/or organomegaly
      3. Leukemic cells are small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes
      4. CLL cells on immunophenotype demonstrate a clonal B-cell population, expressing the B-cell surface markers CD19 and CD20, as well as CD5.  Subjects with bright surface immunoglobulin expression or lack of CD23 expression in > 10% of cells must lack t(11;14) translocation by interphase cytogenetics.
  6. Has measurable disease for B-cell NHL
    1. A fluorodeoxyglucose (FDG)-positron emission tomography (PET) CT scan demonstrating positive lesion compatible with CT (or MRI)-defined anatomical tumor sites AND
    2. A CT scan (or magnetic resonance imaging [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
  7. Has active disease for CLL: Progressive or symptomatic disease with at least 1 of the following criteria being met:
    1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
    2. Massive (ie, ≥ 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
    3. Massive nodes (ie, ≥ 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
    4. Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period, or lymphocyte doubling time (LDT) < 6 months
    5. Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids
    6. Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine)
    7. Disease-related symptoms as defined by any of the following:
      1. Unintentional weight loss ≥ 10% within the previous 6 months
      2. Significant fatigue
      3. Fevers ≥ 100.5°F or 38.0°C for 2 or more weeks without evidence of infection
      4. Night sweats for ≥ 1 month without evidence of infection
  8. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  9. Has acceptable laboratory parameters as follows:

Parameter

Result

Creatinine clearance

> 50 mL/min (Cockcroft-Gault) or serum creatinine ≤ 1.5 X ULN

Serum alanine transaminase (ALT)

≤ 2.5 x upper limit of normal (ULN)

Note: If liver tumor/metastases are present, then ≤ 5 x ULN is allowed

Serum aspartate transaminase (AST)

≤ 2.5 x ULN

Note: If liver tumor/metastases are present, then ≤ 5 x ULN is allowed

Total Bilirubin

≤ 1.5 x ULN

Note: Subjects with Gilbert’s syndrome may be included if total bilirubin is ≤ 3 x ULN and direct bilirubin is ≤ 1.5 x ULN

Hemoglobin

≥ 5.6 mmol/L (9.0 g/dL)

Note: Blood transfusion may be administered during screening to meet this requirement

Absolute neutrophil count

B-cell NHL: ≥ 1.0 x 109 /L (1,000/µL)

CLL: ≥ 1.0 x 109 /L (1,000/µL) unless due to bone marrow involvement

Note: G-CSF may be administered during screening to meet this requirement

Platelet count

B-cell NHL: ≥ 75 x 109 /L (75,000/µL)

Note: In presence of bone marrow involvement or splenomegaly, platelets ≥ 50 × 109/L.

CLL: ≥ 30 x 109 /L (30,000/µL)

Note: Transfusion may be administered during screening to meet this requirement

Coagulation Status: PT/ INR/ aPTT

Prothrombin time (PT)/International normalized ratio (INR)/ Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN

  1. A woman of reproductive potential must agree to use adequate contraception during the trial and for 12 months after the last GEN3009 administration.  Adequate contraception is defined as highly effective methods of contraception. In countries where 2 highly effective methods of contraception are required, both methods will be required for inclusion.
  2. A woman of childbearing potential must have a negative serum beta-human chorionic gonadotropin (beta-hCG) at screening
  3. A woman 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 GEN3009
  4. 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, eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the trial and for 12 months after receiving the last dose of GEN3009
  5. Must be willing and able to adhere to the requirements and restrictions specified in the ICF and this protocol
Exclusion Criteria
  1. Prior treatment with a CD37-targeting agent
  2. Prior allogeneic HSCT
  3. Autologous HSCT within 3 months before the first dose of GEN3009
  4. 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
  5. Chemotherapy or radiation therapy within 2 weeks of the first dose of GEN3009
  6. 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
  7. Autoimmune disease or other diseases that require permanent or high-dose immunosuppressive therapy
  8. 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
  9. Has uncontrolled intercurrent illness, including but not limited to:
    1. Ongoing or active infection requiring intravenous antibiotics treatment at the time of enrollment or within the previous 2 weeks prior to the first dose of GEN3009
    2. Symptomatic congestive heart failure (grade III or IV as classified by the New York Heart Association ([NYHA]), unstable angina pectoris or cardiac arrhythmia
    3. Myocardial infarction, intracranial bleed, or stroke within the past 6 months
    4. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >480 msec
  10. Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy
  11. Primary central nervous system (CNS) lymphoma or known CNS involvement at screening
  12. Has known past or current malignancy other than inclusion diagnosis, except for:
    1. Cervical carcinoma of Stage 1B or less
    2. Non-invasive basal cell or squamous cell skin carcinoma
    3. Non-invasive, superficial bladder cancer
    4. Prostate cancer with a current PSA level < 0.1 ng/mL
    5. Criterion deleted as per Amendment 3
    6. Any curable cancer with a CR of >2 years duration
  13. Intolerant to GEN3009 excipients (refer to the IB for more information)
  14. Has had major surgery, (eg, requiring general anesthesia) within 3 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).  Note: Subjects with planned minor surgical procedures to be conducted under local anesthesia may participate.
  15. Has known history/positive serology for hepatitis B (unless immune due to vaccination or resolved natural infection or unless passive immunization due to immunoglobulin therapy):
    • Positive test for antibodies to the hepatitis B core antigen (anti-HBc) AND
    • Negative test for antibodies to the hepatitis B surface antigen (anti-HBs)
  16. Known medical history or ongoing hepatitis C infection that has not been cured
  17. HIV tested positive at screening
  18. 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
  19. Is a man who plans to father a child while enrolled in this trial or within 12 months after the last dose of GEN3009
  20. 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

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04358458

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Re: MC# 21-05