| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (NHL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Hodgkin Lymphoma (NHL) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029547 |
| E.1.2 | Term | Non-Hodgkin's lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Dose Escalation (GEN3009 for R/R B-cell NHL Including CLL/SLL):
- Determine the MTD with and/or determine the RP2D of GEN3009
- Evaluate safety and tolerability of GEN3009
Expansion (GEN3009 for R/R, DLBCL, FL, and CLL Cohorts):
-Evaluate (preliminary) anti-tumor efficacy of GEN3009
Expansion (GEN3009 + GEN3013 Safety Run-in for R/R B-NHL):
-Identify the RP2D of GEN3009 + GEN3013 combination
-Evaluate safety and tolerability of GEN3009 + GEN3013 combination
Expansion (GEN3009 + GEN3013 for R/R DLBCL):
-Assess preliminary anti-tumor activity of GEN3009 + GEN3013 combination |
|
| E.2.2 | Secondary objectives of the trial |
Dose Escalation (GEN3009 for R/R B-cell NHL Including CLL/SLL):
- Establish PK profile of GEN3009
- Evaluate immunogenicity of GEN3009
- Evaluate preliminary anti-tumor efficacy of GEN3009
- Evaluate preliminary clinical efficacy of GEN3009
Expansion (GEN3009 for R/R, DLBCL, FL, and CLL Cohorts):
- Establish PK profile of GEN3009
- Evaluate safety and tolerability of GEN3009
- Evaluate clinical efficacy of GEN3009
- Evaluate immunogenicity of GEN3009
Expansion (GEN3009 + GEN3013 Safety Run-in for R/R B-NHL):
- Establish the PK properties of GEN3009 and GEN3013
- Evaluate immunogenicity
- Assess the preliminary anti-tumor activity of GEN3009 + GEN3013 combination
Expansion (GEN3009 + GEN3013 for R/R DLBCL):
- Further assess the preliminary anti-tumor activity of GEN3009 +
GEN3013 combination
- Evaluate the safety and tolerability of GEN3009 + GEN3013
- Establish the PK properties of GEN3009 and GEN3013
- Evaluate immunogenicity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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. |
|
| E.4 | Principal exclusion criteria |
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose Escalation (GEN3009 for R/R B-cell NHL Including CLL/SLL):
• Rate of DLTs
• Frequency and severity of adverse events (AEs)/AESIs/SAEs
• Changes in laboratory parameters
• Changes in vital signs
• Frequency of dose interruptions, dose delays, and dose intensity
Expansion(GEN3009 for R/R, DLBCL, FL, and CLL Cohorts):
• ORR
Expansion (GEN3009 + GEN3013 Safety Run-in for R/R B-NHL):
• Rate of DLTs
• Frequency and severity of AEs/AESIs/SAEs
• Changes in laboratory parameters
• Changes in vital signs
• Frequency of dose interruptions, dose delays, and dose intensity
Expansion (GEN3009 + GEN3013 for R/R DLBCL):
• CR rate |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the trial, see protocol |
|
| E.5.2 | Secondary end point(s) |
Dose Escalation (GEN3009 for R/R B-cell NHL Including CLL/SLL):
• PK parameters: clearance, volume of distribution and area under the curve (AUC) at different time points (AUC7days, AUClast and AUCinf), maximum concentration (Cmax), time to Cmax (Tmax), predose trough concentrations (Ctrough), and half-life (T1/2)
• Incidence of neutralizing anti-GEN3009 antibodies (ie, ADAs)
• Objective response rate (ORR)
• Complete response rate (CR)
• Duration of response (DoR)
• Time to response (TTR)
• Progression-free survival (PFS)
• Overall survival (OS)
Expansion (GEN3009 for R/R, DLBCL, FL, and CLL Cohorts):
• PK parameters: CL, AUC7days, AUClast, Cmax, Tmax, Ctrough, and T1/2
• Frequency and severity of AEs/AESIs/SAEs
• Changes in laboratory parameters
• Changes in vital signs
• Frequency of dose interruptions, dose delays, and dose intensity
• CR rate
• DoR
• TTR
• PFS
• OS
• Incidence of neutralizing anti-GEN3009 antibodies (ie, ADAs)
Expansion (GEN3009 + GEN3013 Safety Run-in for R/R B-NHL):
• PK parameters: CL, AUC7days, AUClast, Cmax, Tmax, Ctrough, and T1/2
• Incidence of neutralizing ADAs to GEN3009
• Incidence of neutralizing ADAs to GEN3013
• CR rate
• ORR
• DoR
• TTR
• PFS
• OS
Expansion (GEN3009 + GEN3013 for R/R DLBCL):
• ORR
• DOR
• TTR
• PFS
• OS
• Rate and duration of MRD negativity
• Frequency and severity of AEs/AESIs/SAEs
• Changes in laboratory parameters
• Changes in vital signs
• Frequency of dose interruptions, dose delays, and dose intensity
• PK parameters: CL, AUC7days, AUClast, Cmax, Tmax, Ctrough, and T1/2
• Incidence of neutralizing ADAs to GEN3009
• Incidence of neutralizing ADAs to GEN3013 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the trial, see protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Different doses of GEN3009 |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Denmark |
| France |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The trial is considered completed when the last subject dies or withdraws from the trial. However, the maximum trial duration is 5 years after the last subject’s first treatment in the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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