Efficacy and Safety Trial of Epcoritamab With or Without Lenalidomide as First Line Therapy for Subjects With Diffuse Large B-cell Lymphoma

JRCT ID: jRCT2021230015

Registered date:07/07/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: People must be newly diagnosed with DLBCL and anthracycline-ineligible.
• Date of first enrollment: 13/10/2023
• Target sample size: 12
• Countries of recruitment: Belgium,Japan,United Kingdom,Japan,France,Japan,Spain,Japan,United States,Japan,Sounth Korea,Japan,Italy,Japan
• Study type: Interventional

Intervention(s)

Diffuse large B-cell lymphoma (DLBCL) is one of the most common subtypes of B-cell Non-Hodgkin lymphoma (NHL), accounting for 30% to 40% of cases and incidence is rising steadily. In the United States, 81,560 new cases of NHL are estimated for 2021, and about 20,720 patients will die from their disease. DLBCL is considered a disease of the elderly, with a median age of about 70 years at diagnosis.
For newly diagnosed DLBCL, first-line (1L) combination immunochemotherapy, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the treatment of choice. The efficacy of this regimen was first demonstrated in older patient populations (>60) with initial publications dating back almost 2 decades ago.
Since then, a variety of different strategies and approaches have aimed to improve upon outcomes further, which in conjunction with the dramatic increase in understanding of disease etiopathogenesis, has contributed to the introduction of novel agents, advanced staging/risk assessment and disease monitoring.
And while anthracycline-containing regimens plus an anti-CD20 monoclonal antibody (mAb) -specifically, R CHOP- remain a cornerstone in the treatment armamentarium, doxorubicin is known to be associated with an increased risk of cardiac toxicity, particularly congestive heart failure, with increasing cumulative dose, thus restricting the use of such regimens in many elderly patients and in patients with comorbid conditions known to impact tolerability of cardiotoxic therapies.
Furthermore, despite advancements in the understanding of disease biology, comprehensive data regarding the impact of comorbidities on treatment choices and/or generalized applicability is limited and alternative frontline treatment approaches have not been well-described in large series.
Accordingly, outcomes in elderly and anthracycline-ineligible patients remain poor, with lower responses to treatment and shorter survival in this population.
Thus, treatment of newly diagnosed DLBCL in the anthracycline-ineligible population continues to be challenging, as these patients are not eligible to receive standard curative therapy. Therefore, novel efficacious therapies are needed for these patients.
Epcoritamab is a humanized, IgG1-bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, inducing activation and cytotoxic activity of T cells enabling killing of target lymphoma cells. It has a regular immunoglobulin G1 (IgG1) structure and biochemical characteristics typical of a human IgG1 antibody.
Preclinical findings include:
- In vitro, epcoritamab induced potent activation and cytotoxic activity of CD4+ and CD8+ T cells in the presence of CD20-expressing cells, independent of the T-cell receptor (TCR)-encoded specificity of the T cell.
- Ex vivo, epcoritamab induced potent cytotoxicity in tumor cells derived from patients with DLBCL and follicular lymphoma (FL), irrespective of prior treatment with anti-CD20 mAbs.
- Epcoritamab induced profound B-cell depletions in the peripheral blood and lymphoid organs of cynomolgus monkeys.
- Preclinical data suggest that lenalidomide may enhance epcoritamab-induced T-cell-mediated killing.
Preliminary data have shown that epcoritamab has a manageable safety profile and yielded clinically meaningful responses, including durable complete responses (CRs) in heavily pretreated subjects with DLBCL or indolent NHL.
Lenalidomide is a second-generation immunomodulatory drug, which has direct antineoplastic activity mediated by inhibition of tumor cell proliferation and angiogenesis, with the antiangiogenic activity being in part through inhibition of bFGF, VEGF, and TNF-a-induced endothelial cell migration. In addition, lenalidomide is known to stimulate T-cell proliferation, and modulate cytokine production, and in human lymphomas, lenalidomide has been shown to modulate T-cell function by repairing T-cell immunologic synapse dysfunctions that are associated with disease biology. Moreover, a recent phase 2 trial in relapsed/refractory (R/R) DLCBL has highlighted the ability of lenalidomide to enhance the activity of accessory immune cells including natural killer cells and macrophages.
Lenalidomide has also been used in combination with R-CHOP in attempts to further improve the outcome of DLBCL in the front-line setting. Lenalidomide has been demonstrated to safely improve responses in combination with multiple treatment modalities, such as mAbs, proteasome inhibitors, and stem cell transplant with an acceptable safety profile. Furthermore, preliminary data from the ongoing phase 1b/2 trial GCT3013-02, Arm 2 (epcoritamab + rituximab + lenalidomide) support a manageable safety profile and no additive or overlapping toxicities for the combination of epcoritamab + lenalidomide.
The purpose of this trial is to evaluate the efficacy and safety of epcoritamab monotherapy or epcoritamab plus lenalidomide as 1L therapy in elderly anthracycline-ineligible subjects with DLBCL.

Outcome(s)

• Primary Outcome: Complete response (CR) rate determined by Lugano criteria

Key inclusion & exclusion criteria

• Age minimum: >= 75age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

- Must have newly diagnosed CD20+ large cell lymphoma.
- Is ineligible for anthracycline-based therapy/cytotoxic chemotherapy due to:
- Being age >= 80 years; AND/OR
- Being age >= 75 years and having important comorbid condition(s), which are likely to have a negative impact on tolerability of anthracycline-based therapy/cytotoxic chemotherapy.
- Have Immune Effector Cell-Associated Encephalopathy (ICE) score of at least 8 out of 10.
- Have Ann Arbor Stage II-IV disease.
- Have ECOG PS of 0, 1, or 2; (ECOG PS of 3 may be considered if impairment is attributed to current lymphoma/DLBCL and if pre-phase treatment during the screening phase results in an improvement of ECOG PS to <= 2 prior to enrollment).
- Have measurable disease as per Lugano criteria.
- Have acceptable organ function based on baseline bloodwork.
- Must have fresh (preferred) or archival biopsy material at screening.

Exclude criteria

Has known active, clinically significant bacterial, viral, fungal, mycobacterial, parasitic, or other infection at trial enrollment, including COVID-19 infection.
- Has severe cardiovascular disease (other than those eligibility criteria that preclude the subject from receiving anthracycline-based therapy/cytotoxic chemotherapy),
- Has been exposed to/received any of the following prior therapies, treatments, or procedures within the specified timeframes:
- Major surgery within 4 weeks prior to the first dose of epcoritamab;
- Non-investigational antineoplastic agents (except anti-CD20 monoclonal antibodies) or any investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of epcoritamab;
- Autologous hematopoietic stem cell transplantation (HSCT), CAR-T, allogeneic stem cell transplantation, or solid organ transplantation;
- Live, attenuated vaccines within 30 days prior to initiation of epcoritamab;
- Investigational vaccines within 28 days before the planned first dose of epcoritamab (ie, experimental and/or non-authorized SARS-CoV-2 vaccinations and therapies are not allowed);
- Invasive investigational medical device use within 28 days before the planned first dose of epcoritamab.
- Has primary central nervous system (CNS) tumor or known CNS involvement or intracranial involvement as confirmed by mandatory brain magnetic resonance imaging/computed tomography (MRI/CT) scan at screening and, if clinically indicated, by lumbar puncture.
- Has a seizure disorder requiring anti-epileptic therapy or experienced a seizure within 6 months of signing an informed consent form.
- Has known past or current malignancy other than inclusion diagnosis, with exceptions as stated in protocol.
- Has known or suspected allergies, hypersensitivity, or intolerance to either of the trial treatments or has known or suspected contraindication to the use of all locally available anti-cytokine therapies per local guidelines for management of cytokine release syndrome (CRS).
- Has active hepatitis B virus (HBV) (DNA polymerase chain reaction [PCR]- positive) or hepatitis C virus (HCV) (RNA PCR-positive) infection, current alcohol abuse, or cirrhosis.
- Has active cytomegalovirus (CMV) infection (DNA PCR-positive) requiring treatment.
- Has suspected active or inadequately treated latent tuberculosis.
- Has a known history of seropositivity for HIV. Note: HIV testing is required at screening only if required per local health authorities or institutional standards.

Related Information

• Primary Sponsor: Hoehn Daniela
• Secondary ID(s): NCT05660967