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

Trial Summary

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.

What data supports the effectiveness of the drug combination Zanubrutinib and Odronextamab for treating Richter's Transformation?

Research on a similar drug combination, Tislelizumab plus Zanubrutinib, showed promising results for treating Richter's Transformation, with 58.3% of patients responding to the treatment. This suggests that combining a BTK inhibitor like Zanubrutinib with other agents could be effective for this condition. ^{1 2 3 4 5}

What safety data exists for the treatment Zanubrutinib + Odronextamab in humans?

In a study involving patients with Richter transformation, a combination of the drug zanubrutinib with another drug, tislelizumab, was generally well-tolerated. The most common side effects were infections, stomach issues, and blood-related problems. ^{1 2 5 6 7}

How is the drug combination of Zanubrutinib and Odronextamab unique for treating Richter's Transformation?

The combination of Zanubrutinib and Odronextamab is unique because Zanubrutinib is a next-generation Bruton's tyrosine kinase (BTK) inhibitor that is more selective and has fewer side effects compared to older BTK inhibitors, while Odronextamab is a novel treatment that targets specific proteins on cancer cells. This combination aims to improve treatment outcomes for Richter's Transformation, a condition with limited effective therapies. ^{2 5 8 9 10}

What is the purpose of this trial?

This phase I trial tests the safety and side effects of zanubrutinib in combination with odronextamab and how well it works in treating patients with Richter's transformation. Zanubrutinib, a tyrosine kinase inhibitor, blocks a protein called Bruton tyrosine kinase (BTK), which may help keep cancer cells from growing. Odronextamab is a bispecific monoclonal antibody that can bind to two different antigens at the same time. Odronextamab binds to CD20 found on B-cells (a type of white blood cell) and on many B-cell cancers and to CD3 on T-cells (also a type of white blood cell) and may interfere with the ability of cancer cells to grow and spread. Giving zanubrutinib in combination with odronextamab may be safe, tolerable and/or effective in treating patients with Richter's transformation.

Research Team

Alexey V. Danilov

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

An update for Richter syndrome - new directions and developments. [2022]

2. England 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. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Biology and Treatment of Richter Transformation. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Richter's syndrome: biology and therapy. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Novel Richter Syndrome Xenograft Models to Study Genetic Architecture, Biology, and Therapy Responses. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Ibrutinib and rituximab induced rapid response in refractory Richter syndrome. [2020]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. [2023]

10. United States 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. [2023]