Loncastuximab Tesirine + Rituximab for Lymphoma

(LOTIS 5 Trial)

Not currently recruiting at 168 trial locations

Overseen By ADC Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: ADC Therapeutics S.A.

Must not be taking: Antiretrovirals, Antivirals, Immunosuppressants, others

Disqualifiers: Burkitt lymphoma, Active malignancy, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of a new drug combination, loncastuximab tesirine (an antibody-drug conjugate) and rituximab (a monoclonal antibody), compared to the usual treatment for certain types of lymphoma, a blood cancer. Participants will receive either the new drug combo or standard immunochemotherapy to determine which works better. It suits individuals whose lymphoma has returned or did not respond to previous treatments and who are not candidates for stem cell transplants. This trial may benefit those with lymphoma that affects daily life and has not been successfully treated with previous therapies. As a Phase 3 trial, it represents the final step before potential FDA approval, offering participants a chance to contribute to a treatment that could soon become widely available.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had radiotherapy, chemotherapy, or other antineoplastic therapy within 14 days before starting the study drug, and you must not use any other experimental medication within 14 days or 5 half-lives before starting the study drug. It's best to discuss your current medications with the trial team.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that you should not have had radiotherapy, chemotherapy, or other antineoplastic therapy within 14 days before starting the study drug, unless approved by the Sponsor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier research has shown that the combination of loncastuximab tesirine and rituximab is generally well-tolerated by patients with hard-to-treat lymphoma. Most participants did not experience serious side effects. Common side effects included low blood cell counts, tiredness, and nausea, which can be managed with proper medical care. This treatment is in an advanced study phase, indicating substantial evidence supports its safety. It has been tested in many people and has consistently demonstrated safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Loncastuximab Tesirine combined with Rituximab for treating lymphoma because it introduces a novel approach compared to standard therapies like R-CHOP or R-GemOx. Loncastuximab Tesirine is an antibody-drug conjugate that specifically targets cancer cells, delivering a potent cytotoxic agent directly to these cells. This targeted delivery method aims to minimize damage to healthy cells, potentially reducing side effects. Additionally, the combination with Rituximab, a widely used monoclonal antibody, could enhance the overall effectiveness against lymphoma by attacking the cancer from multiple angles.

What evidence suggests that this trial's treatments could be effective for lymphoma?

Research has shown that using the drugs loncastuximab tesirine and rituximab together holds promise for treating certain types of lymphoma. In this trial, participants in the experimental arms will receive this combination. Many patients in previous studies experienced a complete response, meaning their cancer became undetectable. Specifically, one study found that 94.6% of patients did not experience cancer progression over a year. Early research also suggests that adding rituximab can help maintain tumor control for longer periods. These findings support the potential effectiveness of this treatment in managing lymphoma. Meanwhile, participants in the comparator arm will receive the standard immunochemotherapy regimen R-GemOx. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

Adults with Diffuse Large B-Cell Lymphoma who have relapsed or didn't respond to previous treatments can join. They must be in good enough health for the trial, not planning a stem cell transplant, and agree to use effective contraception. People can't join if they're pregnant/breastfeeding, recently used experimental drugs/vaccines, had certain recent treatments including loncastuximab tesirine or R-GemOx, have uncontrolled diseases like HIV/HBV/HCV or severe heart conditions.

Inclusion Criteria

Measurable disease as defined by the 2014 Lugano Classification

My diagnosis is DLBCL or high-grade B-cell lymphoma with specific gene rearrangements.

My condition did not improve after receiving a combination of treatments.

Exclusion Criteria

I have been diagnosed with Burkitt lymphoma.

Any other significant medical illness, abnormality, or condition

History of Stevens-Johnson syndrome or toxic epidermal necrolysis

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Loncastuximab Tesirine combined with Rituximab or standard immunochemotherapy for up to 8 cycles

24 weeks

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Loncastuximab Tesirine
• Rituximab

Trial Overview The study is testing whether combining Loncastuximab Tesirine with Rituximab is more effective than standard immunochemotherapy for treating Diffuse Large B-Cell Lymphoma. Participants will either receive this new combination therapy or the usual treatment involving Gemcitabine and Oxaliplatin.

How Is the Trial Designed?

Group I: Part 2: Loncastuximab Tesirine + Rituximab (Lonca-R) Experimental Treatment 2 Interventions

Randomized participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m\^2 every Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m\^2 Q3W for up to 6 additional cycles.

Group II: Part 1: Loncastuximab Tesirine + Rituximab (Lonca-R) Experimental Treatment 2 Interventions

Part 1 consists of a non-randomized safety run-in period evaluating the study drug for the first 20 participants. Participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m\^2 Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m\^2 Q3W for up to 6 additional cycles.

Group III: Part 2: Standard Immunochemotherapy (R-GemOx) Active Control 3 Interventions

Randomized participants will receive R-GemOx consisting of rituximab, gemcitabine and oxaliplatin as a standard immunochemotherapy treatment on Day 1 or Day 2 of each cycle for up to 8 cycles, where 1 Cycle is 2 weeks. R-GemOx will be administered via an intravenous infusion of rituximab 375 mg/m\^2 + gemcitabine 1000 mg/m\^2 + oxaliplatin 100 mg/m\^2 every 2 weeks (Q2W) for up to 8 cycles.

Loncastuximab Tesirine is already approved in United States, European Union for the following indications:

Approved in United States as Zynlonta for:

• Diffuse large B-cell lymphoma (DLBCL)
• DLBCL arising from low-grade lymphoma
• High-grade B-cell lymphoma

Approved in European Union as Zynlonta for:

• Diffuse large B-cell lymphoma (DLBCL)
• DLBCL arising from low-grade lymphoma
• High-grade B-cell lymphoma

Who Is Running the Clinical Trial?

ADC Therapeutics S.A.

Lead Sponsor

Trials

32

Recruited

2,700+

Published Research Related to This Trial

In a study of 20 newly diagnosed patients with Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL), Zytux™ showed an overall response rate of 85%, with 35% achieving a complete response and 50% a partial response, indicating its efficacy in treating these conditions.

Zytux™ demonstrated a safety profile comparable to the reference drug MabThera®, suggesting it may be a viable alternative with similar or improved safety and efficacy for patients with NHL and CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of biosimilar rituximab (ZytuxTM) in newly diagnosed patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia. Alwan, AF., Abdulsahib, MA., Abbas, DD., et al.[2020]

Rituximab significantly improves progression-free survival in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma when combined with chemotherapy, based on results from multiple randomized trials involving various treatment regimens.

The drug is generally well tolerated, with infusion reactions being the most common side effect, and it is considered cost-effective for treating certain types of lymphoma, reinforcing its status as a standard care option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on rituximab in chronic lymphocytic leukemia, low-grade or follicular lymphoma, and diffuse large B-cell lymphoma. Keating, GM.[2017]

Rituximab was the first monoclonal antibody approved for cancer therapy and has significantly improved survival rates in patients with diffuse large cell lymphoma when combined with CHOP chemotherapy.

Initially approved in 1997 for relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma, rituximab is also being researched for other B-cell malignancies and nonmalignant diseases like autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: review and clinical applications focusing on non-Hodgkin's lymphoma. King, KM., Younes, A.[2015]

In a study of 183 non-Hodgkin lymphoma patients treated with rituximab, the incidence of late-onset neutropenia (LON) was found to be 6%, with a median onset time of 75 days after treatment.

While most cases of LON were asymptomatic and resolved within 100 days, there were instances of serious complications, including infections, highlighting the need for careful monitoring of patients undergoing rituximab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late-Onset Neutropenia After Rituximab-Containing Therapy for Non-Hodgkin Lymphoma. Aguiar-Bujanda, D., Blanco-Sánchez, MJ., Hernández-Sosa, M., et al.[2015]

Rituximab is a highly effective monoclonal antibody for treating various B-cell lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma, demonstrating a strong activity with low toxicity.

The combination of rituximab with chemotherapy (R-CHOP) has shown the highest efficacy reported for any chemotherapy regimen in treating diffuse large B-cell lymphoma and follicular lymphoma, although some patients may still be resistant to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab therapy in malignant lymphoma. Coiffier, B.[2022]

Rituximab significantly improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) and follicular lymphoma when combined with chemotherapy, based on results from multiple randomized trials.

The treatment is generally well tolerated, with infusion reactions being the most common side effect, and it is considered cost-effective for various lymphoma types, reinforcing its status as a standard care option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma. Keating, GM.[2021]

In a study of 83 patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia, switching between the reference rituximab and its biosimilars (TRUXIMA and RIXATHON) did not lead to any new safety concerns, with adverse events being similar to those reported in existing literature.

Out of 465 rituximab infusions, 84.5% of patients experienced at least one adverse event, but only 5.9% had serious grade 3-4 events, indicating that the biosimilars are as safe as the reference product when switching is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of switching between rituximab biosimilars in onco-hematology. Urru, SAM., Spila Alegiani, S., Guella, A., et al.[2021]

A phase 3 trial involving 140 adults with advanced-stage follicular lymphoma showed that the rituximab biosimilar CT-P10 has comparable efficacy to rituximab, with similar progression-free survival rates (61% for CT-P10 vs. 55% for rituximab) after 4 years.

Both CT-P10 and rituximab had similar long-term safety profiles, with 90% of CT-P10 patients and 86% of rituximab patients experiencing treatment-emergent adverse events, indicating that CT-P10 is a safe alternative for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of CT-P10 or rituximab in untreated advanced follicular lymphoma: a randomized phase 3 study. Buske, C., Jurczak, W., Sancho, JM., et al.[2021]

Rituximab significantly reduces the annualized relapse rates in patients with relapsing-remitting multiple sclerosis, with a decrease of 0.80 relapses per year based on a meta-analysis of 15 studies involving 946 patients.

The treatment is well tolerated, with only mild-to-moderate adverse events occurring in 29.6% of patients and no severe adverse events reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of rituximab for relapsing-remitting multiple sclerosis: A systematic review and meta-analysis. Hu, Y., Nie, H., Yu, HH., et al.[2019]

Rituximab, a monoclonal antibody, has significantly improved survival rates for patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) when used in combination with chemotherapy.

In patients with chronic lymphocytic leukaemia (CLL), rituximab-based chemoimmunotherapy has led to higher complete response and progression-free survival rates, demonstrating its efficacy in both untreated and relapsed cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab for the treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Hagemeister, F.[2021]

The review analyzed 56 studies on anti-CD20 monoclonal antibodies combined with chemotherapy for treating relapsed or refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL), highlighting a significant focus on rituximab due to the larger amount of available data.

Despite the promising potential of these combination regimens, the evidence remains inconclusive regarding the efficacy differences among the anti-CD20 agents, underscoring the need for more direct comparative studies to guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Evidence-based Review of Anti-CD20 Antibody-containing Regimens for the Treatment of Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Diffuse Large B-cell Lymphoma, or Follicular Lymphoma. Falchi, L., Ferrajoli, A., Jacobs, I., et al.[2019]

In a phase II study involving 54 patients with aggressive B-cell lymphomas, rituximab demonstrated significant clinical activity, achieving an overall response rate of 31%, with complete responses in 9% and partial responses in 22% of patients.

The treatment was well-tolerated, with mild adverse events primarily related to infusion syndrome, indicating that rituximab could be a safe option for patients with diffuse large B-cell lymphoma (DLCL) and mantle cell lymphoma (MCL).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Coiffier, B., Haioun, C., Ketterer, N., et al.[2022]

Citations

1. ir.adctherapeutics.com ir.adctherapeutics.com/press-releases/press-release-details/2024/ADC-Therapeutics-Announces-Completion-of-Enrollment-of-Phase-3-Confirmatory-Clinical-Trial-of-ZYNLONTA-in-Combination-with-Rituximab-in-2L-Diffuse-Large-B-Cell-Lymphoma/default.aspx

Press Release Details The Phase 3 confirmatory trial evaluating ZYNLONTA (loncastuximab tesirine-lpyl) in combination with rituximab (Lonca-R) in patients with relapsed or ...

2. zynlonta.com zynlonta.com/study-results/

Study Results | ZYNLONTA® (loncastuximab tesirine-lpyl ... ZYNLONTA® was effective for many people who had past R/R DLBCL therapies. The ZYNLONTA® clinical trial included people who had already received a variety of ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9431578/

PHASE 3 RANDOMIZED STUDY OF LONCASTUXIMAB ... Preclinical evidence suggests that the addition of rituximab to anti-CD19 ADC therapy may result in prolonged tumor control (Ryan et al. Blood 2017). Aims: ...

4. onclive.com onclive.com/view/dr-alderuccio-on-loncastuximab-tesirine-with-rituximab-in-r-r-follicular-lymphoma

Dr Alderuccio on Loncastuximab Tesirine With Rituximab ... At the current follow-up, CRs appeared durable, with a 12-month progression-free survival (PFS) rate of 94.6% (95% CI, 79.9%-98.6%). The median ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS7097

LOTIS-5: An ongoing, phase 3, randomized study of ... Phase 3 randomized study of loncastuximab tesirine plus rituximab versus immunochemotherapy in patients with relapsed/refractory (R/R) diffuse ...