Loncastuximab Tesirine + Dexamethasone for Waldenstrom Macroglobulinemia

Recruiting at 4 trial locations

Overseen By Kirsten Meid

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Shayna Sarosiek, MD

Must be taking: Anti-CD20, BTK inhibitors

Must not be taking: Investigational agents, Immunosuppressants

Disqualifiers: CNS lymphoma, HIV, Hepatitis, others

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

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

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

Compensation: Varies

Number of Visits: 6

Duration: 24 weeks

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety and effectiveness of a new treatment, loncastuximab tesirine (a type of targeted therapy), for individuals with Waldenström Macroglobulinemia, a blood cancer that causes symptoms like fatigue and bleeding. Participants will receive this treatment along with dexamethasone (a corticosteroid) to assess its potential to improve their condition. Suitable candidates have Waldenström Macroglobulinemia requiring treatment and have previously tried at least two treatments, including specific cancer drugs. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you cannot be on any investigational agents or systemic immunosuppressant therapy while participating in the study.

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

Research has shown that loncastuximab tesirine is generally safe and tolerable. Specifically, data from five clinical studies involving 401 patients indicated that it is usually well-tolerated, with some patients experiencing long-term benefits. While some side effects occurred, they were manageable.

Dexamethasone, the other drug in this trial, is commonly used and has a well-known safety record. It has been part of various treatment plans for conditions like Waldenström Macroglobulinemia, and its safety is well-documented.

In summary, both loncastuximab tesirine and dexamethasone have been studied for safety. Loncastuximab tesirine has manageable side effects, and dexamethasone is already known to be safe for many patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Waldenström Macroglobulinemia?

Loncastuximab Tesirine is unique because it offers a novel approach for treating Waldenstrom Macroglobulinemia. Unlike traditional treatments that primarily focus on chemotherapy, this drug is an antibody-drug conjugate, which means it combines an antibody that specifically targets cancer cells with a potent anti-cancer agent. This targeted method aims to deliver the drug directly to the cancer cells, potentially minimizing damage to healthy cells and reducing side effects. Researchers are excited about this treatment because it could not only be more effective but also more tolerable for patients compared to existing options.

What evidence suggests that loncastuximab tesirine might be an effective treatment for Waldenström Macroglobulinemia?

Research has shown that loncastuximab tesirine yields promising results for treating certain types of lymphoma, a blood cancer. In studies with patients whose diffuse large B-cell lymphoma returned or did not respond to other treatments, this therapy proved notably effective. Approximately 48% of these patients experienced a significant decrease in cancer size. The treatment employs an antibody-drug conjugate, which combines an antibody with a drug to specifically target and kill cancer cells. While loncastuximab tesirine is approved for other lymphomas, its effectiveness in Waldenström Macroglobulinemia remains under investigation. Participants in this trial will receive a combination of loncastuximab tesirine and dexamethasone. Early signs suggest this combination could be a valuable option for this condition. ^{6 7 8 9 10}

Who Is on the Research Team?

Shayna Sarosiek, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with Waldenström Macroglobulinemia (WM) who have had at least two prior treatments, including an anti-CD20 monoclonal antibody and a BTK inhibitor. They must not be pregnant or breastfeeding, have good organ function, no recent major surgery or infections, and agree to use contraception.

Inclusion Criteria

Able to adhere to the study visit schedule and other protocol requirements

My blood test shows high levels of IgM, more than twice the normal limit.

My condition requires treatment according to specific expert guidelines.

Exclusion Criteria

I have fluid build-up that isn't cancerous, related to Waldenström's macroglobulinemia.

I am currently on medication that suppresses my immune system.

You are currently misusing alcohol or drugs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive loncastuximab tesirine on Day 1 of every 28-day cycle for up to 6 cycles

24 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Dexamethasone
• Loncastuximab Tesirine

Trial Overview The trial is testing the safety and effectiveness of loncastuximab tesirine for WM treatment. Participants will receive this drug alongside dexamethasone to see if it helps manage their condition better than current treatments.

How Is the Trial Designed?

Group I: Loncastuximab Tesirine + Dexamethasone Experimental Treatment 2 Interventions

Participants will be given * Loncastuximab Tesirine on Day 1 of every 28 day study cycle and continue for up to 6 cycles. Participants will also receive pre-medications to reduce the chance of having a sensitivity reaction to the study treatment. Participants who tolerate the study treatment without a reaction may have pre-medications changed per determination of their doctor. * Dexamethasone will be given prior to study treatment on Day -1 or up to 2 hours prior to loncastuximab tesirine and the day after treatment

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?

Shayna Sarosiek, MD

Lead Sponsor

Trials

2

Recruited

70+

ADC Therapeutics S.A.

Industry Sponsor

Trials

32

Recruited

2,700+

Published Research Related to This Trial

Rituximab regimens are commonly used for treating Waldenström's macroglobulinemia (WM) due to their proven efficacy in hematologic malignancies, but there is no established standard of care for this rare disease.

A variety of investigational treatments, including newer monoclonal antibodies and other targeted therapies, are being evaluated in clinical trials, highlighting the importance of tailoring therapy based on individual patient factors to optimize treatment response and minimize side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Waldenström's macroglobulinemia: a clinical perspective in the era of novel therapeutics. Dimopoulos, MA., Kastritis, E., Ghobrial, IM.[2023]

In a study of 160 patients with Waldenstrom macroglobulinemia, the bendamustine-rituximab (BR) regimen showed a trend towards longer progression-free survival (PFS) compared to dexamethasone, rituximab plus cyclophosphamide (DRC), with 2-year PFS rates of 88% for BR versus 61% for DRC, although the difference was not statistically significant (p=0.07).

Both treatment regimens had comparable overall response rates and grade ≥3 adverse events, indicating similar safety profiles, and the effectiveness of both regimens was not influenced by the presence of the MYD88L265P mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia. Paludo, J., Abeykoon, JP., Shreders, A., et al.[2018]

Recent insights into the biology and genomics of Waldenström macroglobulinemia (WM) are guiding the development of new treatment strategies, emphasizing the importance of genetic markers like MYD88, CXCR4, and TP53 in therapy selection.

The Consensus Panel 7 recommends prioritizing clinical trials that explore limited duration therapies and novel combinations, while considering bendamustine-rituximab and dexamethasone-rituximab-cyclophosphamide as standard treatments for frontline studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Report of consensus panel 7 from the 11th international workshop on Waldenström macroglobulinemia on priorities for novel clinical trials. Tam, CS., Kapoor, P., Castillo, JJ., et al.[2023]

The updated treatment recommendations for Waldenström macroglobulinemia (WM) emphasize personalized therapy based on individual patient characteristics, with mature data supporting the use of rituximab in combination with other agents like cyclophosphamide or bendamustine for durable responses.

New treatment options, including monoclonal antibodies and second-generation proteasome inhibitors, are emerging, and autologous stem cell transplantation may be considered for young patients with specific high-risk features, highlighting the importance of clinical trials for advancing WM treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Dimopoulos, MA., Kastritis, E., Owen, RG., et al.[2022]

In a study of 204 treatment-naïve patients with Waldenström's macroglobulinemia, the combination of bortezomib, dexamethasone, and rituximab (B-DRC) showed an 80.6% progression-free survival rate at 24 months, compared to 72.8% for the standard DRC treatment, indicating B-DRC may offer better long-term outcomes.

B-DRC resulted in higher major response rates (57.0% vs. 32.5%) and a quicker time to first response (3.0 months vs. 5.5 months) compared to DRC, while both treatments had similar safety profiles, suggesting B-DRC is both effective and well tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib-Dexamethasone, Rituximab, and Cyclophosphamide as First-Line Treatment for Waldenström's Macroglobulinemia: A Prospectively Randomized Trial of the European Consortium for Waldenström's Macroglobulinemia. Buske, C., Dimopoulos, MA., Grunenberg, A., et al.[2023]

The combination therapy of bortezomib, dexamethasone, and rituximab (BDR) resulted in a high overall response rate of 96% and significant reductions in disease markers in 23 patients with untreated Waldenström macroglobulinemia, with responses observed as early as 1.4 months after starting treatment.

While BDR therapy was effective, it was associated with peripheral neuropathy as the most common side effect, necessitating adjustments in treatment schedules and the use of prophylactic antiviral therapy due to herpes zoster infections in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. Treon, SP., Ioakimidis, L., Soumerai, JD., et al.[2023]

In a study of 10 elderly Chinese patients with Waldenström macroglobulinemia, low-dose bortezomib and dexamethasone (lBD) demonstrated an 80% overall response rate, with significant reductions in serum immunoglobulin M levels in some patients.

After a median follow-up of 36 months, all patients were alive, and six had no disease progression, indicating that lBD is both effective and tolerable for treating this condition in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose bortezomib and dexamethasone as primary therapy in elderly patients with Waldenstrӧm macroglobulinemia. Zhang, YP., Yang, X., Lin, ZH., et al.[2018]

In a 5-year study involving 150 participants with Waldenström's macroglobulinemia, the combination of ibrutinib and rituximab significantly improved disease outcomes and prolonged the time without disease progression compared to rituximab alone.

Participants receiving the combination treatment also reported a greater improvement in quality of life, and the side effects were manageable and decreased over time, confirming the long-term safety and efficacy of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenström's macroglobulinemia. Buske, C., Tedeschi, A., Trotman, J., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05190705

NCT05190705 | Loncastuximab Tesirine in WM This study is being done to examine the safety and effectiveness of loncastuximab tesirine as a possible treatment for participants with Waldenström ...

2. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2021/761196Orig1s000MultidisciplineR.pdf

761196Orig1s000 - accessdata.fda.gov Efficacy: Efficacy of loncastuximab tesirine is based on the results from ... See the final approved USPI for ZYNLONTA (loncastuximab tesirine‐lpyl) accompanying.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37646659/

long-term efficacy and safety from the phase II LOTIS-2 study Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study.

4. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper211573.html

4404 A Phase II Trial of Loncastuximab Tesirine in Patients ... Secondary outcomes are evaluating the depth of hematologic response, the median progression free survival, the effect of bone marrow disease burden on disease ...

5. youtube.com youtube.com/watch?v=hxllG_AEsK8

A Phase II trial of loncastuximab tesirine in previously treated ... This is the first experience that we have on an immunotherapy of this nature in patients with wilderom so it's an Innovative study.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10485051/

Efficacy and safety of front-line treatment regimens for ... The outcomes of interest were: response rates based on International Waldenstrom Macroglobulinaemia Working Group (IWWM) criteria [16] ( ...

7. frontiersin.org frontiersin.org/journals/hematology/articles/10.3389/frhem.2024.1425677/pdf

Effectiveness, safety, and Patients and methods: We retrospectively describe the results of 36 consecutive treatment-naïve patients with WM who were treated from June ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7448596/

Ixazomib, dexamethasone, and rituximab in treatment-naive ... Ixazomib, dexamethasone, and rituximab (IDR) was associated with overall, major, and very good partial response rates of 96%, 77%, and 19%.

9. frontiersin.org frontiersin.org/journals/hematology/articles/10.3389/frhem.2024.1425677/full

data from the Sicilian Myeloma Network Effectiveness, safety, and tolerability of delayed dexamethasone, rituximab, and cyclophosphamide as first-line treatment in patients with Waldenström ...

10. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.00105

Final Analysis of the Phase I/II HOVON124/ECWM-R2 Study We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM.