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

Each potential subject must fulfill all of the following criteria to be
enrolled in the trial.
- Be at least 18 years of age.
- Must sign an informed consent form (ICF) prior to any screening procedures.
- Has histologically or cytologically confirmed relapsed or refractory Bcell NHL
o For the dose escalation: with no available standard therapy or is not a
candidate for available standard therapy. All subjects must have
received at least 2 prior lines of systemic therapy, and,
a. For all indolent NHL (FL, MZL, and SLL) as well as aggressive NHL (DLBCL,
HGBCL, and PMBCL), at least 1 of the 2 prior lines of treatment must have been
a CD20-containing systemic regimen;
b. For MCL, subjects must have had or are otherwise ineligible for treatment
with a BTK inhibitor, and;
c. For CLL, subjects must have received at least 1 prior line of BTK inhibitor
or BCL-2 inhibitor.
o For the expansion (including Safety Run-in): All subjects must have received
at least 2 prior lines of systemic therapy, and,
a. For FL and DLBCL, at least 1 of the 2 prior lines of treatment must have
been a CD20-containing systemic regimen;
b. For CLL, subjects must have received at least one prior line of BTK
inhibitor or BCL-2 inhibitor.
- Has 1 of the following B-cell NHL subtypes for the Dose Escalation:
o DLBCL, de novo or histologically transformed
o HGBCL
o PMBCL
o FL, with advanced symptomatic disease and with a need for treatment
o MCL, without leukemic manifestation
o MZL, either nodal, extranodal, or mucosa associated, with a need for
treatment initiation based on symptoms and/or disease burden
o SLL, with a need for treatment based on symptoms and/or disease burden
o CLL with active disease that needs treatment based on the International
Workshop on Chronic Lymphocytic Leukemia [iwCLL] criteria) and the following
B-cell NHL subtypes for the Expansion (including safety run-in):
o DLBCL, de novo or histologically transformed
o FL Grade 1, 2 and 3a, with advanced symptomatic disease and with a need for
treatment initiation
o CLL, must have active disease that needs treatment with at least 1 of the
following criteria being met:
a. Evidence of progressive marrow failure as manifested by the development of,
or worsening of, anemia and/or thrombocytopenia
b. Massive (ie, >=6 cm below the left costal margin) or progressive or
symptomatic splenomegaly
c. Massive nodes (ie, >=10 cm in longest diameter) or progressive or symptomatic
lymphadenopathy
o GEN3009 + GEN3013 combination cohort only: Documented CD20+DLBCL or FL based
on representative pathology report
- Has measurable disease for B-cell NHL or for CLL.
- Has ECOG performance status of 0 or 1.
- Has acceptable laboratory parameters.
- A woman of reproductive potential must agree to use adequate contraception
during the trial and for 12 months after the last GEN3009 and/or GEN3013
administration. Adequate contraception is defined as highly effective methods
of contraception (refer to Appendix 12 for more information). In countries
where 2 highly effective methods of contraception are required, both methods
will be required for inclusion.
- A woman of childbearing potential must have a negative serum betahCG at
screening.
- 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 GEN3009 and/or GEN3013.

Any potential subject who meets any of the following criteria will be excluded
from participating in the trial.
- Prior treatment with a CD37-targeting agent.
- For the Expansion (including safety run-in): GEN3009 + GEN3013 combination
cohort only: Prior treatment with a CD3 × CD20 bispecific antibody.
- Prior allogeneic HSCT.
- Autologous HSCT within 3 months before the first dose of GEN3009.
- For the Expansion (including safety run-in): Lymphomas leukemia phase: high
absolute lymphocyte count or the presence of abnormal cells in the peripheral
blood indicating circulating lymphoma cells
- 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. Treatment with small molecules such as BTK
inhibitors, BCL2 inhibitors, or PI3K inhibitors within 5 half-lives prior to
the first dose of GEN3009.
- Chemotherapy or radiation therapy within 2 weeks of the first dose of GEN3009.
- 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, and at any time during the study treatment period.
- 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.
- Has uncontrolled intercurrent illness (refer to Protocol Section 5.2 for
details).
- For the Expansion (including safety run-in): GEN3009 + GEN3013 combination
cohort only: Seizure disorder requiring therapy (such as steroids or
anti-epileptics)
- 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) lymphoma or known CNS involvement at
screening.
- Has known past or current malignancy other than inclusion diagnosis (refer to
Section 5.2 for details).
- Had allergic reactions to anti-CD20 or anti-CD37 monoclonal antibody
treatment or intolerant to GEN3009 excipients (refer to the GEN3009 IB for more
information).
- For the Expansion (including safety run-in): Intolerant to GEN3013 excipients
(refer to the GEN3013 IB for more information).
- Has had major surgery, (eg, requiring general anesthesia) within 4 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 and/or GEN3013).
- 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 for HIV infection.
- 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 and/or GEN3013.
- Is a man who plans to father a child while enrolled in this trial or within
12 months after the last dose of GEN3009 and/or GEN3013.
- 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. Additionally, vulnerable subjects or subjects
under guardianship, curatorship, judicial protection or deprived of liberty),
are excluded from participation in this trial.
- Prior treatment with live, attenuated vaccines within 4 weeks prior to
initiation of GEN3009. Examples of live vaccines include, but are not limited
to, the following: measles, mumps, rubella, varicella/zoster (chicken pox),
yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal
influenza vaccines for injection are generally killed virus vaccines and are
allowed; however, intranasal influenza vaccines (eg, FluMist®) are live
attenuated vaccines and are not allowed. Experimental and/or nonauthorized
SARS-CoV-2 vaccinations are not allowed.
- Dose escalation only: Lymphomas leukemia phase: high absolute lymphocyte
count or the presence of abnormal cells in the peripheral blood indicating
circulating lymphoma cells.