Loncastuximab Tesirine + Venetoclax for Non-Hodgkin's Lymphoma

Overseen By Paolo Caimi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Paolo Caimi, MD

Must not be taking: Strong CYP3A inhibitors/inducers

Disqualifiers: Pregnancy, Autoimmune disease, HIV, others

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 18 weeks (6 cycles of 21 days each)

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and correct dosing of two new cancer drugs, loncastuximab tesirine (an antibody-drug conjugate) and venetoclax (a BCL-2 inhibitor), for treating a type of non-Hodgkin's lymphoma that hasn't responded to other treatments. Researchers aim to determine how these drugs work together to help patients whose B cell lymphoma has returned or persisted despite previous treatments. Individuals who have undergone at least two different lymphoma treatments and still have measurable disease might be suitable for this study. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive these new drugs.

Do I need to stop taking my current medications for the trial?

The trial requires you to stop taking strong CYP3A inhibitors or inducers at least 14 days or 5 half-lives before starting the study drugs. If you're on these medications, you'll need to discontinue them before participating.

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

Research shows that combining loncastuximab tesirine and venetoclax is generally safe for people with relapsed or hard-to-treat non-Hodgkin's lymphoma. In earlier studies, patients tolerated the combination well, and no treatment-related deaths occurred. Some side effects appeared but were manageable. Loncastuximab tesirine alone has demonstrated lasting positive effects in other studies, suggesting its long-term efficacy. Venetoclax, already approved for other conditions, supports its safety profile. Overall, the combination appears promising, with evidence indicating it is fairly well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Loncastuximab Tesirine combined with Venetoclax for treating Non-Hodgkin's Lymphoma because this combination offers a novel approach. Loncastuximab Tesirine is an antibody-drug conjugate, which specifically targets cancer cells and delivers a potent cytotoxic agent directly to them, minimizing damage to healthy cells. Venetoclax, on the other hand, inhibits BCL-2, a protein that helps cancer cells survive. This dual-action strategy is different from many current treatments that don't specifically target these pathways, potentially leading to more effective and less toxic outcomes.

What evidence suggests that this combination treatment could be effective for B cell lymphoma?

Research shows that using loncastuximab tesirine and venetoclax together, as studied in this trial, may help treat non-Hodgkin's lymphoma that has returned or is resistant to other treatments. Some studies have found these drugs safe and effective for this condition. Loncastuximab tesirine targets and destroys cancer cells, while venetoclax aids in killing them by blocking a protein that prevents cell death. Venetoclax has already succeeded in treating other blood cancers, like chronic lymphocytic leukemia, and has improved survival rates. Early results suggest that this combination could be similarly effective for certain types of non-Hodgkin's lymphoma. ^{1 4 6 7 8}

Who Is on the Research Team?

Paolo Caimi, MD

Principal Investigator

Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with Non-Hodgkin Lymphoma who've had at least two prior treatments and still have measurable disease. They must be in a stable condition, not pregnant or breastfeeding, willing to use effective contraception, and without serious unresolved treatment side effects from previous therapies.

Inclusion Criteria

Participants must meet clinical indications for treatment

I agree to use birth control and not donate sperm.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

I will have a stem cell transplant using my own cells within 30 days before starting the study drug.

I had a stem cell transplant from a donor within the last 60 days.

I cannot take drugs by mouth due to a digestive condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive loncastuximab tesirine intravenously on day 1 and venetoclax orally on days 1-5 of each 21-day cycle, with premedication and hydration

Up to 18 weeks (6 cycles of 21 days each)

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Loncastuximab Tesirine
• Venetoclax

Trial Overview

The study tests combining loncastuximab tesirine with venetoclax to treat B cell lymphoma that has come back or hasn't responded to other treatments. The main focus is finding the right dose and checking if this drug combo is safe.

How Is the Trial Designed?

Group I: Loncastuximab tesirine & venetoclax Experimental Treatment 2 Interventions

Participants will receive a baseline disease assessment via PET/CT in FDG avid lymphomas; CT scan (chest, abdomen, pelvis; inclusion of neck in selected cases). Bome marrow biopsy in selected cases. Premedication includes: * Allopurinol (to reduce uric acid) 300mg orally daily starting day -1 and continuing at least until day 7 of each cycle. * Dexamethasone (steroid pre-medication) 4mg orally twice daily on day -1, day 1 and day 2 of each cycle. * Adequate oral hydration starting on day -1 or -2, defined as 1 - 2 liters of oral intake of liquids in 24 hours Study treatment to be given every 21 days. * Loncastuximab tesirine (50 - 150 μg/kg) intravenously (IV) on day 1 of each 21-day cycle * Venetoclax (400 - 800 mg) orally, every day on days 1 - 5 of each 21-day cycle. Dose ramp-up on cycle 1 (over days 1 - 5 for target dose 400mg, 1 - 6 for target dose 600mg and 1 - 7 for target dose 800mg

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?

Paolo Caimi, MD

Lead Sponsor

Trials

5

Recruited

170+

Brian Hill, MD, PhD

Lead Sponsor

Trials

3

Recruited

90+

Brian Hill

Lead Sponsor

Trials

2

Recruited

60+

Published Research Related to This Trial

A study involving 321 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) found that venetoclax (VEN) used alone (VENmono) and in combination with rituximab (VENcombo) showed similar overall response rates (81% for VENmono vs 84% for VENcombo) and no significant differences in progression-free survival (PFS) or overall survival (OS) after a median follow-up of 13.4 months.

The addition of the anti-CD20 antibody rituximab to venetoclax did not improve survival outcomes, indicating that VENmono may be as effective as VENcombo in this patient population, which had a high treatment burden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective comparison of venetoclax alone or in combination with an anti-CD20 monoclonal antibody in R/R CLL. Mato, AR., Roeker, LE., Eyre, TA., et al.[2020]

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]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

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]

In a study involving 272 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), higher concentrations of venetoclax led to a quicker reduction in lymphocyte counts and tumor size, resulting in a high objective response rate (ORR) of 84.8% at a daily dose of 400 mg.

Importantly, increasing the dose of venetoclax did not correlate with a higher risk of serious adverse events like neutropenia or infections, suggesting that the 400 mg daily regimen is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Freise, KJ., Jones, AK., Eckert, D., et al.[2018]

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 the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

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