Tazemetostat + Rituximab + Bendamustine for Follicular Lymphoma

Recruiting at 4 trial locations

Overseen By Allison Lipps

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vaishalee Kenkre

Must not be taking: CYP3A4/5 inhibitors

Disqualifiers: Active infection, Concurrent malignancy, CNS metastases, others

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

Compensation: Varies

Number of Visits: 6

42 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is planned as a single arm clinical trial of tazemetostat in combination with bendamustine and rituximab with both a phase I and phase II component. All patients will receive tazemetostat twice daily on days 1-28 in combination with bendamustine 90 mg/m2 IV on days 1 and 2 and rituximab 375 mg/m2 IV on day 1 of a 28-day cycle for up to three cycles. Following this, patients will receive tazemetostat twice daily on days 1-28 and rituximab 375 mg/m2 IV on day 1 of a 28-day cycle for up to three cycles.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require chronic use of certain drugs that affect liver enzymes (CYP3A4/5 inhibitors or inducers) within 28 days before starting the trial.

What data supports the effectiveness of the drug combination Tazemetostat, Rituximab, and Bendamustine for treating follicular lymphoma?

Research shows that the combination of Bendamustine and Rituximab is effective in treating various types of indolent lymphomas, including follicular lymphoma, with high response rates and manageable side effects. Although Tazemetostat is not specifically mentioned in these studies, its inclusion in the treatment may enhance effectiveness based on its known properties. ^{1 2 3 4 5}

What safety data exists for Bendamustine in combination with Rituximab for treating lymphoma?

Bendamustine has been studied for its safety and effectiveness in patients with certain types of lymphoma, showing it can be effective, but the study also evaluated its toxicity (side effects). ^{6 7 8 9 10}

What makes the drug combination of Tazemetostat, Rituximab, and Bendamustine unique for treating follicular lymphoma?

This drug combination is unique because it includes Tazemetostat, which is an EZH2 inhibitor that targets specific genetic mutations in cancer cells, potentially enhancing the effectiveness of Rituximab and Bendamustine, which are already known to be effective in treating various lymphomas. This combination may offer a novel approach by targeting cancer cells more precisely, potentially improving outcomes for patients with follicular lymphoma. ^{3 4 11 12 13}

Research Team

Vaishalee P. Kenkre

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

Adults with high tumor burden follicular lymphoma, grades 1-2 or 3A, who haven't had certain prior treatments can join. They must have good organ function and no history of severe heart disease, active infections, other cancers in the last 3 years (with some exceptions), CNS metastases, uncontrolled HIV/AIDS or hepatitis C.

Inclusion Criteria

I have been active and mostly self-sufficient in the last 10 days.

My cancer is at stage II, III, or IV according to the Ann Arbor system.

Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

Exclusion Criteria

I do not have active brain metastases or leptomeningeal disease.

I do not have an active infection needing treatment within 4 weeks of starting the study drug.

Treatment with any investigational drug within 4 weeks prior to registration.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Participants receive tazemetostat with bendamustine and rituximab for up to 3 cycles. Dose escalation of tazemetostat is conducted to determine the recommended Phase 2 dose.

12 weeks

3 visits (in-person) per cycle

Phase II Treatment

Participants receive tazemetostat and rituximab for up to 3 additional cycles at the recommended Phase 2 dose.

12 weeks

3 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Bendamustine
• Rituximab
• Tazemetostat

Trial Overview The trial tests Tazemetostat combined with Bendamustine and Rituximab for untreated high-burden follicular lymphoma. It's a two-phase study where all patients get these drugs in cycles: first three cycles include all three drugs; next three just Tazemetostat and Rituximab.

Participant Groups

Group I: Investigational Group Experimental Treatment 3 Interventions

Phase 1: 90 mg/m\^2 of bendamustine by IV on Day 1 and 2 of a 28 day cycle (up to 3 Cycles) 375 mg/m\^2 of rituximab by IV on Day 1 of a 28 day cycle (up to 3 Cycles) Participants enrolled in this phase will be given one of 3 different dose levels of tazemetostat along with the drugs above (for up to 3 Cycles). 3 patients will be assigned to the lowest dose level and if the dose is tolerated, 3 more patients will be enrolled one dose level higher. Up to 18 participants being enrolled. Dose Level 1: 400 mg of tazemetostat orally twice daily Dose Level 2: 600 mg of tazemetostat orally twice daily Dose Level 3: 800 mg of tazemetostat orally twice daily Phase 2: 6 patients from Phase 1 who were treated at the recommended Phase 2 dose will be added to 21 additional patients. 375 mg/m\^2 of rituximab through IV on Day 1 of a 28 day cycle (Cycles 1-6) Tazemetostat orally twice daily of a 28 day cycle (Cycles 1-6)

Bendamustine is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Treanda for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in European Union as Ribomustin for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma

Approved in Canada as Levact for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in Japan as Bendamustine hydrochloride for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Who Is Running the Clinical Trial?

Vaishalee Kenkre

Lead Sponsor

Trials

1

Recruited

40+

Epizyme, Inc.

Industry Sponsor

Trials

34

Recruited

2,800+

University of Wisconsin, Madison

Collaborator

Trials

1,249

Recruited

3,255,000+

Findings from Research

Bendamustine demonstrated a high objective response rate of 74.3% in 99 patients with relapsed/refractory Hodgkin and non-Hodgkin lymphoma, indicating its efficacy as a salvage treatment after multiple lines of chemotherapy.

The most common side effects included lymphopenia, anemia, and neutropenia, with serious side effects occurring in a minority of patients, suggesting that while bendamustine is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of bendamustine in relapsed or refractory lymphoma cases: a Turkish Oncology Group study. Karadurmus, N., Paydas, S., Esin, E., et al.[2022]

In a study of 65 patients with marginal zone lymphomas (MZL) treated with the rituximab plus bendamustine (BR) regimen, the overall response rate was 89.2%, with 58.5% achieving a complete response, indicating that BR is an effective first-line treatment option.

The treatment was associated with manageable side effects, primarily neutropenia, fatigue, and nausea, with no treatment-related deaths reported, suggesting that BR is a safe option for MZL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine-rituximab regimen in untreated indolent marginal zone lymphoma: experience on 65 patients. Morigi, A., Argnani, L., Lolli, G., et al.[2020]

Bendamustine, when combined with rituximab, shows strong effectiveness in treating relapsed and refractory indolent lymphoma, with positive results observed in various patient groups, including those who have not previously received rituximab.

Interim results from a phase III trial indicate that the bendamustine and rituximab combination may be a promising alternative to the standard CHOP regimen for treating indolent lymphomas, suggesting a favorable safety and efficacy profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine in chronic lymphocytic leukemia and refractory lymphoma. Rummel, MJ.[2015]

In a phase II clinical trial involving 37 Japanese patients with relapsed or refractory follicular lymphoma, the combination of bendamustine and rituximab (RB-120) demonstrated a high overall response rate of 91.9% and a complete response rate of 86.5%.

The treatment showed promising long-term outcomes with a 3-year progression-free survival of 70.9% and overall survival of 88.9%, while the most common severe side effects were hematologic, including lymphopenia and neutropenia, but no treatment-related deaths occurred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine-120 plus rituximab therapy for relapsed or refractory follicular lymphoma: a multicenter phase II study. Sakai, R., Ohmachi, K., Sano, F., et al.[2019]

Bendamustine is effective in treating relapsed indolent lymphomas that are resistant to other treatments, thanks to its unique mechanism of action as both an alkylating agent and a purine analog.

It has a favorable safety profile, causing no hair loss and only moderate side effects, making it suitable for elderly patients and allowing for outpatient treatment when combined with other therapies like rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine HCL for the treatment of relapsed indolent non-Hodgkin's lymphoma. Weide, R.[2021]

In a study of 100 patients with rituximab-refractory indolent B-cell lymphoma, single-agent bendamustine demonstrated a high overall response rate of 75%, with a median duration of response of 9.2 months.

While bendamustine was effective, it also caused significant side effects, including hematologic toxicities like neutropenia (61%) and non-hematologic issues such as nausea (77%) and infections (69%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study. Kahl, BS., Bartlett, NL., Leonard, JP., et al.[2021]

In a study of 30 patients with advanced non-small cell lung cancer undergoing high-dose cisplatin chemotherapy, tropisetron effectively controlled acute nausea and vomiting with a complete plus major control rate of up to 86% across treatment cycles.

Tropisetron also demonstrated efficacy in preventing delayed nausea and vomiting, with control rates reaching 87%, and was generally well-tolerated, with mild side effects like headache and diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of tropisetron in the prevention of cisplatin-induced nausea and vomiting in advanced non-small cell lung cancer. Thongprasert, S.[2019]

In a study of 24 children undergoing chemotherapy, tropisetron effectively controlled severe emesis in 70% of cases, demonstrating significant efficacy compared to conventional antiemetics.

Tropisetron was found to be safe, with no severe adverse effects reported, although mild side effects like headache and constipation occurred in a few instances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of emesis by tropisetron (Navoban) in children receiving cytotoxic therapy for solid malignancies. Otten, J., Hachimi-Idrissi, S., Balduck, N., et al.[2018]

In a study of 115 chemotherapy-naive patients, tropisetron was significantly more effective than a combination of dexamethasone and metoclopramide in preventing nausea and vomiting during chemotherapy, with 76% of patients on tropisetron remaining free of vomiting within the first 24 hours compared to only 39% in the control group.

Tropisetron maintained its efficacy over two consecutive chemotherapy cycles, with 72% of patients remaining free of vomiting and 62% free of nausea during the first 24 hours of the second cycle, indicating it is a highly effective and well-tolerated antiemetic agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A report comparing the use of tropisetron (Navoban), a 5-HT3 antagonist, with a standard antiemetic regimen of dexamethasone and metoclopramide in cisplatin-treated patients under conditions of severe emesis. Madej, G., Krzakowski, M., Pawinski, A., et al.[2018]

In a study of 126 cancer patients undergoing moderately emetogenic non-cisplatin chemotherapy, the combination of tropisetron and dexamethasone significantly improved control of nausea and vomiting compared to tropisetron alone.

Tropisetron was found to be an effective and well-tolerated antiemetic treatment, and adding dexamethasone enhanced its efficacy without increasing adverse effects, making it a valuable option for managing chemotherapy-induced emesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tropisetron alone or in combination with dexamethasone for the prevention and treatment of emesis induced by non-cisplatin chemotherapy: a randomized trial. Adams, M., Soukop, M., Barley, V., et al.[2019]

A study analyzing the combination of bendamustine and rituximab in patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma found no significant drug-drug interactions, indicating that the efficacy of both drugs can be maintained when used together.

The pharmacokinetic analysis showed that bendamustine does not alter the clearance of rituximab, and vice versa, suggesting that these drugs can be safely coadministered without affecting their systemic exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of the potential for drug-drug interactions between bendamustine and rituximab in indolent non-Hodgkin lymphoma and mantle cell lymphoma. Darwish, M., Burke, JM., Hellriegel, E., et al.[2021]

Rituximab plus bendamustine (R-B) is less toxic and achieves similar complete remission rates compared to R-CHOP in patients with follicular lymphoma grade 3A, with 97% vs. 96% complete remissions respectively.

Patients treated with R-B experienced significantly lower relapse rates (16% vs. 41%) and longer progression-free survival (15 years vs. 11.7 years) compared to those treated with R-CHOP, making R-B a more effective first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine plus Rituximab Versus R-CHOP as First-Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study. Mondello, P., Steiner, N., Willenbacher, W., et al.[2019]

The combination of navitoclax with bendamustine, with or without rituximab, significantly enhances the treatment efficacy against various types of non-Hodgkin's lymphoma in xenograft models, indicating a promising therapeutic strategy.

Bendamustine activates p53 and caspase 3 in tumors, suggesting a mechanism of action that navitoclax further potentiates, leading to improved responses compared to traditional treatments like CHOP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Navitoclax (ABT-263) and bendamustine ± rituximab induce enhanced killing of non-Hodgkin's lymphoma tumours in vivo. Ackler, S., Mitten, MJ., Chen, J., et al.[2021]

References

1. Poland pubmed.ncbi.nlm.nih.gov

Effectiveness of bendamustine in relapsed or refractory lymphoma cases: a Turkish Oncology Group study. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Bendamustine-rituximab regimen in untreated indolent marginal zone lymphoma: experience on 65 patients. [2020]

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

Bendamustine in chronic lymphocytic leukemia and refractory lymphoma. [2015]

4. Germany pubmed.ncbi.nlm.nih.gov

Bendamustine-120 plus rituximab therapy for relapsed or refractory follicular lymphoma: a multicenter phase II study. [2019]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Bendamustine HCL for the treatment of relapsed indolent non-Hodgkin's lymphoma. [2021]

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

Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study. [2021]

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

Efficacy and tolerability of tropisetron in the prevention of cisplatin-induced nausea and vomiting in advanced non-small cell lung cancer. [2019]

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

Prevention of emesis by tropisetron (Navoban) in children receiving cytotoxic therapy for solid malignancies. [2018]

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

A report comparing the use of tropisetron (Navoban), a 5-HT3 antagonist, with a standard antiemetic regimen of dexamethasone and metoclopramide in cisplatin-treated patients under conditions of severe emesis. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Tropisetron alone or in combination with dexamethasone for the prevention and treatment of emesis induced by non-cisplatin chemotherapy: a randomized trial. [2019]

11. Germany pubmed.ncbi.nlm.nih.gov

An evaluation of the potential for drug-drug interactions between bendamustine and rituximab in indolent non-Hodgkin lymphoma and mantle cell lymphoma. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Bendamustine plus Rituximab Versus R-CHOP as First-Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Navitoclax (ABT-263) and bendamustine ± rituximab induce enhanced killing of non-Hodgkin's lymphoma tumours in vivo. [2021]