This study has been transitioned to CTIS with ID 2023-504802-12-00 check the CTIS register for the current data. Dose Escalation Objectives:Primary:* Determine maximum tolerated dose (MTD) and RP2DSecondary:* Establish tolerability of epcoritamab*…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Dose escalation:
Primary:
* Dose limiting toxicity
* Adverse events
Dose expansion:
* Overall response rate (ORR) determined by Lugano criteria as assessed by
independent review committee (IRC)
Optimization
Rate of >= Grade 2 CRS events and all grade CRS events from first dose of
epcoritamab through 7 days following administration of the second full dose of
epcoritamab
Secondary outcome
Dose escalation:
Secondary:
* Cytokine measures
* Laboratory parameters (biochemistry, hematology including immunophenotyping
for absolute T-cell and B-cell counts as well as T-cell activation and
exhaustion markers)
* PK parameters (clearance, volume of distribution and
area-under-the-concentration-time curve (AUC0-Clast and AUC0-*), maximum
concentration (Cmax), time of Cmax (Tmax), pre dose values, and half-life)
* Immunogenicity of epcoritamab
* Anti-lymphoma activity, i.e. resolution of constitutional symptoms, reduction
in tumor size, objective and best response (ORR, CR and PR)
* Duration of response
* Progression free survival
* Time to next anti-lymphoma therapy (TTNT)
* Overall survival (OS)
Expansion Efficacy End Points per IRC and Optimization Efficacy End Points per
investigator:
- Duration of response (DOR) determined by Lugano criteria
- Complete response (CR) rate determined by Lugano criteria
- Duration of CR (DoCR) by Lugano criteria
- Progression-free survival (PFS) determined by Lugano criteria
- Time to response (TTR) determined by Lugano criteria
- Objective and best response rate determined by Lymphoma Response to
Immunomodulatory Therapy Criteria (LYRIC)
- PFS determined by LYRIC
- DOR determined by LYRIC
- DoCR determined by LYRIC
- TTR determined by LYRIC
- Overall survival (OS)
- Time to next (anti-lymphoma) therapy (TTNT)
- Rate of MRD negativity
- Safety (i.e., adverse events, laboratory parameters [biochemistry, hematology
including immunophenotyping for absolute T-cell and B-cell
counts as well as T-cell activation and exhaustion markers], hospitalizations,
and cytokine measures)
- PK parameters (clearance, volume of distribution, Cmax, Tmax, trough
concentrations, and half-life) and incidence of ADAs to GEN3013
- Changes in lymphoma symptoms as measured by the Functional Assessment of
Cancer Therapy - Lymphoma (FACT-Lym)
- Rate of >= Grade 2 CRS events and all grade CRS events following first full
dose
- Rate of >= Grade 2 CRS events and all grade CRS events overall
Background summary
There is an unmet medical need for new efficacious therapies for the population
of patients with B-cell malignancies whose disease is no longer
responsive to standard therapies.
The purpose of the dose escalation part of this trial is to establish the
maximum tolerated dose of epcoritamab and the recommended phase 2 dose
(RP2D) of epcoritamab in patients with relapsed, progressive or refractory
B-cell lymphoma.
The purpose of the expansion part of this trial is to evaluate the efficacy and
safety of epcoritamab at the RP2D in patients with the following B-cell
non-Hodgkin lymphomas (B-NHL) with limited therapeutic options:
* Aggressive relapsed or refractory B-NHL (aNHL cohort) including:
o Diffuse large B-cell lymphoma (DLBCL)
o High grade B-cell lymphoma (HGBCL)
o Primary mediastinal B-cell lymphoma (PMBCL)
o Follicular lymphoma (FL) grade 3B
* Indolent relapsed or refractory B-NHL (iNHL cohort) including:
o FL grade 1-3A
o Marginal zone lymphoma (MZL)
o Small lymphocytic lymphoma (SLL)
* Mantle cell lymphoma (MCL)
Epcoritamab is a bispecific antibody recognizing the T-cell antigen CD3 and the
B-cell antigen CD20; the mechanism of action is engagement of T-cells as
effector cells to induce killing of CD20-expressing B-cells and tumor cells.
CD20 is a clinically validated target for treatment of B-cell
malignancies. Since the resistance of B-cell malignancies to CD20-targeting
monocloncal antibodies is not due to the loss of CD20 expression or CD20
mutation, epcoritamab aims to target CD20 with a different mechanism of action.
Epcoritamab efficiently induced killing of various B-cell lymphoma cell lines
in vitro. Moreover, epcoritamab induced potent anti-tumor activity in vivo, in
lymphoma xenograft models in mice with a human immune system or with human
effector cells. In cynomolgus monkeys, epcoritamab induced dose-dependent
B-cell depletion in both peripheral blood and lymphoid organs, with time to
recovery related to the treatment dose.
Study objective
This study has been transitioned to CTIS with ID 2023-504802-12-00 check the CTIS register for the current data.
Dose Escalation Objectives:
Primary:
* Determine maximum tolerated dose (MTD) and RP2D
Secondary:
* Establish tolerability of epcoritamab
* Establish pharmacokinetic (PK) profile after single and multiple doses
* Evaluate immunogenicity
* Evaluate anti-lymphoma activity
Exploratory:
* To evaluate biomarkers predictive of clinical response to epcoritamab
* To evaluate pharmacodynamic markers linked to the mechanism of action of
epcoritamab
Dose expansion objectives:
Primary:
* To evaluate clinical efficacy as determined by Lugano criteria
Secondary:
* To further evaluate clinical efficacy as determined by Lugano criteria
*To evaluate the clinical efficacy as determined by LYRIC
* To further evaluate clinical efficacy
* To evaluate MRD status as a clinical efficacy endpoint
* To evaluate safety and tolerability of epcoritamab
* To evaluate the PK and immunogenicity of epcoritamab
* To evaluate patient-reported outcomes (PROs) related to lymphoma symptoms
Exploratory:
* To evaluate biomarkers predictive of clinical response to epcoritamab
* To evaluate pharmacodynamic markers linked to the mechanism of action of
epcoritamab
* To evaluate PROs related to well-being and general health status
Optimization part
Primary
*Determine whether an alternative priming/intermediate dose regimen may reduce
CRS risk
Secondary
*To evaluate safety and tolerability of alternative priming/intermediate dosing
regimens
*Establish PK and pharmacodynamic profile after single and multiple doses
*Evaluate immunogenicity
*Evaluate clinical efficacy as determined by Lugano criteria
*To evaluate MRD status as a clinical efficacy endpoint
Exploratory
To evaluate pharmacodynamic markers linked to the mechanism of action of
epcoritamab
Study design
This is an open label, phase 1/2 trial in patients with relapsed, progressive
and/or refractory mature B-cell lymphoma. The dose escalation part will
determine the MTD and RP2D. The expansion part will be conducted in 2 stages.
In Stage 1, patients with DLBCL, FL grades 1-3A and R/R MCL will be enrolled
and response data will be collected. Following an interim futility analysis,
additional patients with DLBCL, FL grades 1-3A and R/R MCL may be enrolled for
Stage 2 in order to reach the sample size required for statistical analysis. In
addition, patients with other aNHL or iNHL subtypes as described above may be
enrolled in Stage 2.
A separate optimization part will explore alternative priming/intermediate dose
levels to reduce the incidence and severity of CRS in patients with DLBCL, FL
grades 1-3A, and MCL.
Intervention
Epcoritamab will be administered as a subcutaneous (SC) injection in cycles of
4 weeks, i.e. 28 days.
The dose-levels will be determined by the starting dose and the escalation
steps taken in the trial.
A minimum anticipated biologic effect level (MABEL)-derived SC starting
(priming) dose of 4.0 µg (microgram) flat. The priming dose for the first
patient will be followed with a subsequent dose that will be as a maximum 12.8
µg (microgram) flat dose.
In the optimization part, dose levels will be determined by the starting dose
and escalation steps.
Study burden and risks
* For full details, see the study schedules on pages 50-65 of the study
protocol.
* Participation in this study will last approximately 12 months and include
approximately 28 (part 1)/ 31 ( part 2) visits to the study site. The study
visits will take approximately 2 - 6 hours on average each, with the exception
of C1, 2, 3 and 4 in the dose escalation phase and C3 in the dose expansion
phase ( see additional remark section).
* During the screening, the patient is presented with an informed consent form.
This is reviewed and if the patient wishes to take part it is signed by the
patient and examiner. Medical history of the patient is reviewed with the
patient.
* In the study patients will get physical examinations including temperature,
blood pressure, heart rate, respiratory rate and oxygen level in blood and
measurement of height and body weight.
* Blood and urine tests will be performed as well as neurological exams.
Drawing blood may be painful or cause some bruising.
* Subjects will be tested for hepatitis B, C and cytomegalovirus and also for
HIV if this was not done before.
* ECGs will be done and CT, PET or MRI scans. Where needed a lumbar puncture
will be done.
* Women of childbearing potential will have a pregnancy test done.
* A sample of a previously taken tumor biopsy will be obtained if possible at
screening or an optional fresh biopsy may be taken. 2 fresh core tumor biopsies
at start of Cycle 2 (±1 week) are mandatory for all patients with accessible
tumors, where it is considered feasible without a high risk of
complications for the patient based on the discretion of the investigator.
Additionally, where feasible, a biopsy should be collected at the end of
treatment visit. Risks of tumor biopsy include pain, small chance of bruising.
The biopsy procedure is usually performed while under local anesthesia.
* patients in the dose expansion part might have bone marrow biopsy and/or
aspirate if clinically indicated. This will be performed while under local
anesthesia. In addition, patients in the dose expansion phase will get
questionnaires to complete and lymph node examinations
* The patient will be questioned during visits regarding (adverse events) side
effects and the medication use.
* Patients will receive an unregistered drug, epcoritamab
(DuoBody-CD3xCD20).The injections of the study drug under the skin may cause
local reactions like swelling, redness, warmth and itching.
* Possible side effects of the study drug that are already known are described
in the Patient Information and Investigator's Brochure.
*Subjects in the Optimization with DLBCL or FL do not need to stay in the
hopstital, but do need to remain in close proximity of the hospital (withint 30
minutes travel distance) for 24 hours after the first full dose of epcoritamab.
Carl Jacobsens Vej 30
Valby 2500
DK
Carl Jacobsens Vej 30
Valby 2500
DK
Listed location countries
Age
Inclusion criteria
1. Patient must be 18 years of age or older (for expansion: In countries where
the legal age is 21 years of age; only patients 21 years of age or older are
eligible)
2. Documented CD20+ mature non-Hodgkin B-cell lymphoma according to WHO
classification
3. Relapsed, progressive and/or refractory disease (Cheson et al., 2007)
following treatment with an anti-CD20 monoclonal antibody
4. Patients must have received at least 2 prior lines of therapy
5. Patients must have measurable disease by imaging
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2. For
MCL: ECOG PS less than 2 required for participation.
7. For the optimization part, patients must have R/R DLBCL, or FL grades 1-3A,
or MCL (according to cohort).
Exclusion criteria
1. Primary central nervous system (CNS) lymphoma or known CNS involvement by
lymphoma
2. AST, and/or ALT greater than 3 x upper limit of normal
3. Total bilirubin greater than 1.5 x upper limit of normal
4. Creatinine clearance lower than 45 mL/min
5. Known clinically significant cardiac disease, including:
a. Onset of unstable angina pectoris within 6 months of signing ICF
b. Acute myocardial infarction within 6 months of signing ICF
c. Congestive heart failure (grade III or IV as classified by the New York
Heart Association and/or known decrease ejection fraction of lower than 45%
6. Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other
infection requiring systemic treatment (excluding prophylactic treatment) at
the time of enrolment or within the previous 2 weeks prior to the first dose of
epcoritamab, including COVID-19 infection.
7. Eligible for curative salvage therapy with high dose therapy followed by
stem cell rescue
8. Active hepatitis B (DNA PCR-positive) or hepatitis C (RNA PCR positive
infection). Subjects with evidence of prior HBV but who are PCR negative are
permitted in the trial but should receive prophylactic antiviral therapy.
9. Known human immunodeficiency virus (HIV) infection.
10. Exposed to live or live attenuated vaccine within 4 weeks prior to signing
ICF
11. Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy
within 30 days prior to first GEN3013 administration
12. Autologous HSCT within 100 days prior to first GEN3013 administration, or
any prior allogeneic HSCT or solid organ transplantation
13. Contraindication to all uric acid lowering agents
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-504802-12-00 |
| EudraCT | EUCTR2017-001748-36-NL |
| CCMO | NL64317.078.17 |