Loncastuximab + Rituximab for Central Nervous System Lymphoma

Overseen By Rachel Kingsford

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Utah

Must not be taking: Antineoplastics, Chemotherapy

Disqualifiers: Stroke, Diabetes, Infections, HIV, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the combination of loncastuximab tesirine (an antibody-drug conjugate) and rituximab is safe and effective for treating central nervous system lymphomas, a cancer affecting the brain and spinal cord. Researchers aim to evaluate the effectiveness of these drugs after patients undergo a targeted radiation procedure called stereotactic radiosurgery. Individuals with central nervous system lymphoma who have tried at least one prior treatment or cannot use certain high-dose therapies might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you cannot use other cancer treatments (except corticosteroids) while participating. It's best to discuss your current medications with the study team to get specific guidance.

Is there any evidence suggesting that loncastuximab tesirine and rituximab are likely to be safe for humans?

Research has shown that combining the drugs loncastuximab tesirine and rituximab may help treat certain types of lymphoma. In studies with patients who had follicular lymphoma, this treatment was generally well-tolerated, though some side effects occurred. Most patients experienced manageable reactions, such as low blood counts and fatigue, while serious side effects were less common.

Currently, this combination is being tested in a new trial for lymphomas affecting the brain and spinal cord. Researchers are determining the best dose and monitoring its safety. As this trial is in its early stages, the primary goal is to ensure the treatment's safety for participants. Those considering joining should discuss the potential risks and benefits with a doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for central nervous system lymphoma such as chemotherapy and radiation, loncastuximab tesirine offers a unique approach by using an antibody-drug conjugate. This means it combines an antibody specifically designed to target lymphoma cells with a potent drug that kills these cells upon delivery. Researchers are excited because this targeted mechanism could potentially reduce harm to healthy cells and improve outcomes by delivering treatment directly to the cancerous cells. Additionally, combining loncastuximab tesirine with rituximab, another targeted treatment, might enhance the overall effectiveness against this challenging form of lymphoma.

What evidence suggests that loncastuximab tesirine and rituximab might be an effective treatment for central nervous system lymphoma?

Studies have shown that combining loncastuximab tesirine with rituximab can help treat certain types of lymphoma. Specifically, in patients with relapsed or hard-to-treat follicular lymphoma, this combination resulted in a 94.6% rate of disease stability over 12 months. Most patients' conditions remained stable during that period. The current trial tests this combination for lymphomas in the brain and spinal cord, building on its success with other lymphoma types. Although specific results for these brain and spinal cord lymphomas are not yet available, positive outcomes in other studies suggest potential benefits. ^{1 2 4 5 6}

Are You a Good Fit for This Trial?

This trial is for individuals with primary or secondary central nervous system lymphomas. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and may be excluded based on factors like other medical conditions, previous treatments, or medications that could interfere with the study.

Inclusion Criteria

I agree to use effective birth control during and after my treatment.

My blood, liver, and kidney functions are within normal ranges.

I have CNS lymphoma or DLBCL with CNS involvement and it's either not responding to treatment or I can't have high-dose methotrexate.

Exclusion Criteria

I am not using any cancer drugs except for corticosteroids.

Known history of hypersensitivity to CD19 antibody, components of study medication

Pregnant or lactating or intending to become pregnant during the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stereotactic Radiosurgery (SRS)

Participants undergo stereotactic radiosurgery as part of the treatment protocol

1 week

Treatment

Participants receive loncastuximab tesirine and rituximab (lonca-R) to determine safety, tolerability, and maximum tolerated dose

6 months

Multiple cycles, frequency not specified

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Loncastuximab Tesirine
• Rituximab

Trial Overview The trial is testing the safety and effectiveness of a combination of drugs called loncastuximab tesirine and rituximab (Lonca-R) when given after stereotactic radiosurgery—a precise radiation therapy—in patients with CNS lymphomas.

How Is the Trial Designed?

Group I: Treatment: All Patients Experimental Treatment 1 Intervention

This study has two main goals: Goal 1: The study will investigate the safety and tolerability of loncastuximab tesirine and rituximab (lonca-R). Goal 2: The study will determine the maximum tolerated dose of lonca-R.

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?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

ADC Therapeutics S.A.

Industry Sponsor

Trials

32

Recruited

2,700+

Published Research Related to This Trial

In a study of 81 patients with newly diagnosed primary CNS lymphomas, the addition of rituximab to high-dose methotrexate (HD-MTX) significantly increased the complete response (CR) rate from 36% to 73%.

Patients receiving the combination treatment of HD-MTX and rituximab also experienced a median progression-free survival of 26.7 months, compared to just 4.5 months for those on HD-MTX alone, indicating a substantial improvement in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Holdhoff, M., Ambady, P., Abdelaziz, A., et al.[2022]

In a case study of a 66-year-old man with relapsed CD20-positive primary central nervous system lymphoma, treatment with intraventricular rituximab led to a complete clearance of lymphoma cells in the cerebrospinal fluid, indicating its potential effectiveness against leptomeningeal relapse.

The treatment was generally safe, with only mild and reversible side effects observed, suggesting that intraventricular administration of rituximab could be a feasible option for managing PCNSL, warranting further investigation in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraventricular and intravenous treatment of a patient with refractory primary CNS lymphoma using rituximab. Pels, H., Schulz, H., Manzke, O., et al.[2019]

Loncastuximab tesirine-lpyl, an anti-CD19 antibody-drug conjugate, has shown a 48.6% overall response rate in patients with relapsed, refractory diffuse large B-cell lymphoma, indicating its efficacy as a treatment option.

The drug has a tolerable safety profile, with common side effects including neutropenia and thrombocytopenia, leading to its recent FDA approval for treating this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma: a review of clinical data. Furqan, F., Hamadani, M.[2022]

In a phase 1 study involving 183 patients with relapsed or refractory B-cell non-Hodgkin lymphoma, loncastuximab tesirine demonstrated a promising overall response rate of 45.6%, with 26.7% achieving complete responses, indicating its potential as an effective treatment option.

The study established a recommended dose of 150 µg/kg for phase 2 trials, with an acceptable safety profile characterized by manageable hematologic toxicities, suggesting that loncastuximab tesirine could be a viable alternative to current therapies for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Hamadani, M., Radford, J., Carlo-Stella, C., et al.[2022]

Loncastuximab tesirine is an antibody-drug conjugate that targets B cell lymphomas, specifically approved for relapsed/refractory diffuse large B cell lymphoma (DLBCL) after two or more lines of treatment.

The drug works by using an anti-CD19 antibody to deliver a DNA-alkylating agent directly to B cells, enhancing its efficacy in targeting cancer cells while minimizing damage to healthy cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loncastuximab Tesirine: First Approval. Lee, A.[2021]

Loncastuximab tesirine-lpyl, an anti-CD19 antibody-drug conjugate, has shown a 48.3% overall response rate in patients with relapsed, refractory diffuse large B-cell lymphoma during the phase II LOTIS-2 trial, indicating its efficacy as a treatment option.

The drug demonstrated a tolerable safety profile with common side effects including neutropenia and thrombocytopenia, and no new safety concerns were identified in the phase II trial, suggesting it is safe for further testing in various non-Hodgkin lymphoma subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loncastuximab tesirine for diffuse large B-cell lymphoma. Zurko, J., Hamadani, M.[2021]

A patient with refractory lymphomatous meningitis was successfully treated for over 6 years using intraventricular rituximab, suggesting it may be an effective option for difficult cases of primary central nervous system lymphoma.

The long-term use of intraventricular rituximab showed minimal severe side effects, with only two infections related to the Ommaya reservoir, indicating a favorable safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful long-term control of lymphomatous meningitis with intraventricular rituximab. Birnbaum, T., Baumgarten, Lv., Dudel, C., et al.[2015]

The combination treatment of high dose methotrexate (HD-MTX), temozolomide (TMZ), and rituximab (R) significantly improved progression-free survival (PFS) and overall survival (OS) in patients with primary central nervous system lymphoma (PCNSL), with median PFS of 56.7 months compared to 7.3 months for those receiving only HD-MTX and TMZ.

The treatment was generally well-tolerated, with only mild side effects such as grade 1-2 nausea and vomiting reported during the induction phase, and no severe grade 3/4 toxicities observed during consolidation treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of High Dose Methotrexate, Temozolomide and Rituximab in the Treatment of Patients with Primary Central Nervous System Lymphoma]. Pang, DW., Chen, FL., Guo, HG., et al.[2021]

In a retrospective study of 120 patients with aggressive B cell central nervous system lymphoma, the addition of rituximab to high-dose methotrexate-based chemotherapy was associated with improved overall survival, suggesting it may enhance treatment efficacy.

Key factors predicting better survival included younger age (≤60 years), good performance status, normal lactate dehydrogenase levels, and receiving treatment after 2004, highlighting the importance of these variables in patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. Gregory, G., Arumugaswamy, A., Leung, T., et al.[2022]

In a study of 58 patients with primary central nervous system lymphoma, the combination of rituximab and methotrexate resulted in a significantly higher total effective rate of 82.76% compared to 58.62% for methotrexate with whole brain radiotherapy.

Patients receiving rituximab experienced fewer adverse effects and better quality of life, with 1 and 3-year survival rates of 86.21% and 62.07%, respectively, compared to 58.62% and 31.03% in the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Therapeutic Efficacy of Rituximab Combined with Methotrexate on Primary Central Nervous System Lymphoma]. Luo, W., Ji, LH., Geng, H., et al.[2018]

A phase I study involving 10 patients found that intrathecal administration of rituximab is feasible and effective for treating recurrent CNS non-Hodgkin's lymphoma, with a maximum tolerated dose of 25 mg.

Out of the patients treated, six showed cytologic responses, including four complete responses, indicating that this method may improve outcomes for patients with CNS involvement of NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. Rubenstein, JL., Fridlyand, J., Abrey, L., et al.[2015]

In a phase 1 study involving 14 patients with recurrent CNS lymphoma, intraventricular rituximab combined with methotrexate was administered safely, with over 150 doses given and no serious toxicity reported.

The treatment resulted in a 75% complete cytologic response rate and a 43% overall complete response rate in the central nervous system, demonstrating its effectiveness in patients who were resistant to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Rubenstein, JL., Li, J., Chen, L., et al.[2021]

In a phase 2 trial involving 145 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), loncastuximab tesirine demonstrated a significant overall response rate of 48.3%, indicating its effectiveness as a treatment option for this challenging patient population.

The treatment was associated with an acceptable safety profile, with serious adverse events occurring in 39% of patients, but none were directly linked to loncastuximab tesirine, suggesting it may be a safe option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Caimi, PF., Ai, W., Alderuccio, JP., et al.[2021]

Citations

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

Dr Alderuccio on Loncastuximab Tesirine With Rituximab ... “We observed that [51% of patients had progression of disease within 24 months and 92%] presented with a high disease burden [based on GELF ...

2. 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 ...

3. cancernetwork.com cancernetwork.com/view/loncastuximab-tesirine-elicits-robust-responses-in-r-r-follicular-lymphoma

Loncastuximab Tesirine Elicits Robust Responses in R/R ... The 12-month progression-free survival [PFS] rate at the data cutoff was 94.6% (95% CI, 79.9%–98.6%), which included patients with difficult-to- ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05600686

Loncastuximab Tesirine and Rituximab Followed by DA- ... This phase II trial evaluates whether loncastuximab tesirine and rituximab followed by dose-adjusted doxorubicin, etoposide, vincristine, cyclophosphamide, ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39662486/

Loncastuximab tesirine with rituximab in patients ... In this study, we evaluated loncastuximab tesirine combined with rituximab for second-line and later treatment of follicular lymphoma. Methods: ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06607549

Study Details | NCT06607549 | Loncastuximab Tesirine ... The purpose of this clinical trial is to learn if drugs loncastuximab tesirine and rituximab (lonca-R) after stereotactic radiosurgery are safe and effective ...