Zanubrutinib + Odronextamab for Richter's Transformation

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inducers/inhibitors, Corticosteroids

Disqualifiers: Organ transplant, Uncontrolled infection, Cardiac disease, others

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

Compensation: Varies

Number of Visits: 5

Duration: 12 cycles (approximately 9 months)

23 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effects of combining zanubrutinib and odronextamab for individuals with Richter's transformation, where chronic lymphocytic leukemia (CLL) becomes diffuse large B-cell lymphoma. Zanubrutinib blocks a protein that aids cancer cell growth, while odronextamab (Ordspono) targets specific proteins on cancer and immune cells to help prevent cancer spread. This trial may suit those diagnosed with Richter's transformation who have not responded well to previous treatments or are treatment-naïve. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, it mentions that you cannot take certain medications like strong CYP3A4 inducers/inhibitors during the study. It's best to discuss your current medications with the study team.

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

Research has shown that both zanubrutinib and odronextamab have undergone safety testing in people. Zanubrutinib has been used in many patients with various blood cancers and is generally well-tolerated. Common side effects include a reduction in certain blood cells, such as neutrophils, which help fight infections.

Odronextamab has also been studied in patients with similar conditions. In some studies, about 53% of patients experienced side effects that led to treatment pauses or delays. These findings indicate that while side effects may occur, both treatments have been used in clinical settings and are monitored for safety.

As this is a phase 1 trial, it focuses on understanding the safety and side effects of using these drugs together, so the safety profile remains under close observation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about zanubrutinib and odronextamab for treating Richter's Transformation because they bring innovative approaches to tackling this challenging condition. Unlike traditional chemotherapy treatments, zanubrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that specifically targets cancer cell signaling, potentially leading to fewer side effects and better patient outcomes. Odronextamab, on the other hand, is a bispecific antibody designed to engage both cancer cells and immune cells, essentially directing the body's immune system to attack the cancer more effectively. Together, these two novel mechanisms offer a promising new way to manage Richter's Transformation that could outperform the current standard of care.

What evidence suggests that zanubrutinib and odronextamab might be effective for Richter's transformation?

In this trial, participants will receive a combination of odronextamab and zanubrutinib. Research has shown that odronextamab yields promising results in treating certain B-cell cancers. Specifically, one study found that 52% of patients experienced a reduction or disappearance of their cancer, with 31.5% achieving complete remission. Zanubrutinib has also proven effective, particularly when combined with other treatments for Richter's transformation, demonstrating a high survival rate over 12 months. These treatments block proteins that aid cancer growth and harness the body's immune system to combat the cancer. This combination offers hope for better outcomes for individuals facing this challenging condition. ^{1 3 4 6 7}

Who Is on the Research Team?

Alexey V. Danilov

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with Richter's transformation, a condition where chronic lymphocytic leukemia changes into an aggressive type of lymphoma. Participants must have specific markers on their cancer cells and be fit enough for biopsies and scans.

Inclusion Criteria

Alkaline phosphatase (ALP) ≤ 2.5 x ULN or ≤ 5 x ULN if attributed to lymphoma involvement of the liver

Sperm donation is prohibited during the study and for 6 months after the last dose of the assigned study treatment

I am able to get out of my bed or chair and move around.

Exclusion Criteria

I have not received a live vaccine in the last 28 days.

My heart condition is not stable.

Known hypersensitivity to both allopurinol and rasburicase

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive odronextamab intravenously and zanubrutinib orally in cycles, with cycles repeating every 21 days for cycles 1-4 and every 28 days for up to cycle 12

12 cycles (approximately 9 months)

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 3 years

Follow-up visits at 4 and 12 weeks, then every 6 months

Extension

Participants may continue zanubrutinib at investigator's discretion after 12 cycles

What Are the Treatments Tested in This Trial?

Interventions

• Odronextamab
• Zanubrutinib

Trial Overview The trial tests zanubrutinib combined with odronextamab in treating Richter's transformation. Zanubrutinib blocks proteins that help cancer grow, while odronextamab targets both B-cells and T-cells to hinder cancer spread.

How Is the Trial Designed?

Group I: Treatment (odronextamab, zanubrutinib) Experimental Treatment 10 Interventions

Patients receive odronextamab IV over 4 hours on days 1, 2, 8, 9, 15 and 16 of cycle 1 and over 1-4 hours on days 1, 8 and 15 of cycles 2-4 and then on days 1 and 15 of remaining cycles. Patients with CR at cycle 9 may receive odronextamab on day 1 of remaining cycles. Starting with cycle 2, patients also receive zanubrutinib PO QD or BID of each cycle. Cycles repeat every 21 days for cycles 1-4 in the absence of disease progression or unacceptable toxicity then repeat every 28 days for up to cycle 12. After 12 cycles, patients may continue zanubrutinib at investigator's discretion. Patients also undergo ECHO or MUGA and optional bone marrow biopsy at screening and ultrasound guided biopsy of lymph node at screening and during days 2-12 of cycle 2. Additionally, patients undergo blood sample collection and PET, or CT throughout the study.

Odronextamab is already approved in European Union for the following indications:

Approved in European Union as Ordspono for:

• Relapsed/Refractory Follicular Lymphoma
• Relapsed/Refractory Diffuse Large B-cell Lymphoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Richter syndrome (RS), a high-grade transformation of chronic lymphocytic leukaemia, is a chemotherapy-resistant condition with a poor prognosis, showing a median overall survival of only about 8 months, particularly affecting elderly and immunosuppressed patients.

Emerging treatments, including second-generation Bruton tyrosine kinase inhibitors like acalabrutinib and novel monoclonal antibodies, may offer new hope for improving outcomes in RS, highlighting the need for ongoing clinical trials and precision medicine approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update for Richter syndrome - new directions and developments. Eyre, TA., Schuh, A.[2022]

Zanubrutinib is a next-generation BTK inhibitor that shows improved selectivity and reduced off-target toxicities compared to ibrutinib, making it a safer option for treating B-cell malignancies.

In recent clinical trials, zanubrutinib demonstrated significant efficacy in improving progression-free survival in patients with chronic lymphocytic leukemia (CLL) and showed better safety profiles, including a lower risk of serious side effects like atrial fibrillation and major bleeding compared to ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. Wolska-Washer, A., Robak, T.[2023]

A 53-year-old man with Richter syndrome, who was heavily pretreated and resistant to previous therapies, showed a significant response to a combination of rituximab and ibrutinib after just one month of treatment.

This case highlights the potential effectiveness of rituximab and ibrutinib as a therapeutic option for patients with Richter syndrome, suggesting further investigation into their use in this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib and rituximab induced rapid response in refractory Richter syndrome. Lamar, Z., Kennedy, L., Kennedy, B., et al.[2020]

Richter's syndrome, which occurs in up to 10% of chronic lymphocytic leukemia patients, leads to a rapid decline in health and has a median survival of less than 6 months with conventional chemotherapy.

Current therapies like hyperCVXD and yttrium-90 ibritumomab tiuxetan have not significantly improved survival rates, highlighting the need for targeted treatments based on the specific genetic and epigenetic abnormalities associated with the transformation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Richter's syndrome: biology and therapy. Yee, KW., O'Brien, SM., Giles, FJ.[2019]

In a study of 25 patients with Richter transformation, acalabrutinib showed an overall response rate of 40%, with 8% achieving a complete response and 32% a partial response, indicating some efficacy in this challenging patient population.

While acalabrutinib was generally well tolerated, with manageable side effects, the median progression-free survival was only 3.2 months, suggesting that its effectiveness as a monotherapy is limited and highlighting the need for further research into combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study. Eyre, TA., Schuh, A., Wierda, WG., et al.[2022]

In the phase 3 SEQUOIA trial involving adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), zanubrutinib significantly improved progression-free survival compared to the standard treatment of bendamustine plus rituximab (BR).

Patients treated with zanubrutinib reported better health-related quality-of-life outcomes at 12 and 24 weeks, including improvements in global health status, physical functioning, and reduced symptoms of diarrhea, fatigue, and nausea/vomiting compared to those receiving BR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. Ghia, P., Barnes, G., Yang, K., et al.[2023]

In a phase 2 study involving 59 patients with Richter transformation of chronic lymphocytic leukemia, the combination of the PD-1 inhibitor tislelizumab and the BTK inhibitor zanubrutinib resulted in a significant overall response rate of 58.3%, surpassing the predefined threshold of 40%.

The treatment was well-tolerated, with a 12-month overall survival rate of 74.7%, indicating that this combination therapy is both effective and safe for patients with this aggressive form of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. Al-Sawaf, O., Ligtvoet, R., Robrecht, S., et al.[2023]

In a phase II study involving 217 patients with relapsed/refractory follicular lymphoma, the combination of zanubrutinib and obinutuzumab (ZO) showed a significantly higher overall response rate (ORR) of 69% compared to 46% for obinutuzumab alone, indicating greater efficacy.

The safety profile of ZO was manageable, with common side effects including thrombocytopenia and neutropenia, and serious adverse events like atrial fibrillation occurring in only 3% of patients, suggesting that ZO could be a promising treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma. Zinzani, PL., Mayer, J., Flowers, CR., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12003196/

Odronextamab monotherapy in patients with relapsed ... Here, we report the long-term efficacy and safety results of odronextamab in patients with R/R DLBCL from the phase 2 ELM-2 study (NCT03888105).

2. nature.com nature.com/articles/s43018-025-00921-6

primary efficacy and safety analysis in phase 2 ELM-2 trial At the 29.9-month efficacy follow-up, the ORR was 52.0% and CR rate was 31.5%. Median durations of response and CR were 10.2 and 17.9 months, ...

3. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/436/499483/Final-Analysis-of-the-Phase-2-ELM-2-Study

Final Analysis of the Phase 2 ELM-2 Study: Odronextamab in ... 17% of pts had transformed disease from indolent lymphoma and 5% had Richter's transformation; 12% were double-hit and 6% triple-hit. In total, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06735664

Study Details | NCT06735664 | Zanubrutinib in ... Giving zanubrutinib in combination with odronextamab may be safe, tolerable and/or effective in treating patients with Richter's transformation. Detailed ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123050401

Final Analysis of the Phase 2 ELM-2 Study: Odronextamab ... Patient-reported outcomes were maintained or improved; of special note, patient-reported pain and emotional functioning scores improved from ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06735664

Study Details | NCT06735664 | Zanubrutinib in ... Giving zanubrutinib in combination with odronextamab may be safe, tolerable and/or effective in treating patients with Richter's transformation. Detailed ...

7. ema.europa.eu ema.europa.eu/en/documents/product-information/ordspono-epar-product-information_en.pdf

Ordspono, INN-odronextamab - European Medicines Agency The diagnosis was de novo DLBCL in 76%, DLBCL transformed from indolent lymphoma in 19%, and Richter's transformation in 6%. ... 5.3 Preclinical safety data.