Polatuzumab Vedotin + Chemotherapy for Large B-Cell Lymphoma

Overseen By Ryan Lynch, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Washington

Must not be taking: Monoclonal antibodies, Investigational therapy

Disqualifiers: Burkitt lymphoma, Organ transplant, others

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

Compensation: Varies

Number of Visits: 7

Duration: 18 weeks

56 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects of polatuzumab vedotin when given with combination chemotherapy with or without glofitamab for the treatment of patients with untreated large B-cell lymphoma that grows and spreads quickly and has severe symptoms (aggressive). Polatuzumab vedotin is a monoclonal antibody, polatuzumab, linked to a toxic agent called vedotin. Polatuzumab attaches to CD79B positive cancer cells in a targeted way and delivers vedotin to kill them. Glofitamab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Drugs used in combination chemotherapy such as etoposide, cyclophosphamide, and doxorubicin work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Anti-inflammatory drugs, such as prednisone, lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Giving polatuzumab vedotin in combination chemotherapy with or without glofitamab may help treat patients with aggressive large B-cell lymphoma.

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

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that prior systemic treatment for lymphoma is not allowed, except for corticosteroids under certain conditions. It's best to discuss your current medications with the trial team to get specific guidance.

What data supports the effectiveness of the drug combination Polatuzumab Vedotin + Chemotherapy for Large B-Cell Lymphoma?

Research shows that combining rituximab with chemotherapy regimens like CHOP and EPOCH has improved outcomes in aggressive B-cell lymphomas, including better survival rates. These findings suggest that similar combinations, including Polatuzumab Vedotin, may also be effective. ^{1 2 3 4 5}

Is the combination of Polatuzumab Vedotin and chemotherapy safe for treating large B-cell lymphoma?

The combination of drugs similar to those in Polatuzumab Vedotin treatment, such as doxorubicin, cyclophosphamide, and rituximab, has been studied for safety in various lymphomas. These studies show that while these drugs can cause side effects like myelosuppression (reduced blood cell production), cardiotoxicity (heart damage), and nausea, they are generally considered safe when used under medical supervision. ^{6 7 8 9 10}

How is the drug Polatuzumab Vedotin + Chemotherapy unique for treating large B-cell lymphoma?

This treatment combines Polatuzumab Vedotin, a targeted therapy that delivers a toxic agent directly to cancer cells, with a chemotherapy regimen including drugs like cyclophosphamide and doxorubicin, which are known to be effective in treating lymphomas. The combination aims to enhance the effectiveness of standard chemotherapy by adding a targeted approach, potentially improving outcomes for patients with large B-cell lymphoma. ^{11 12 13 14 15}

Research Team

Ryan Lynch, MD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

This trial is for adults with untreated aggressive large B-cell lymphoma. Participants must have proper kidney and liver function, no severe allergies to monoclonal antibodies or chemotherapy components, and agree to use effective contraception. Those with prior systemic treatment for lymphoma (except corticosteroids), certain other health conditions, or who are pregnant cannot join.

Inclusion Criteria

Hemoglobin >= 8 g/dL

aPTT within specified limits

ANC >= 1,000/uL

Exclusion Criteria

Pregnancy, lactation, or intent to become pregnant

My CLL/SLL has transformed into a more aggressive form.

I have had cancer before, but it might not affect my eligibility.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive rituximab, polatuzumab vedotin, prednisone, etoposide, doxorubicin, and cyclophosphamide with or without glofitamab for up to 6 cycles

18 weeks

6 cycles, each 21 days apart

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Periodic visits

Treatment Details

Interventions

• Cyclophosphamide
• Doxorubicin
• Etoposide
• Polatuzumab Vedotin
• Prednisone
• Rituximab

Trial Overview The trial tests polatuzumab vedotin combined with chemotherapy drugs like cyclophosphamide, doxorubicin, etoposide, prednisone, rituximab against aggressive large B-cell lymphoma. Polatuzumab vedotin targets cancer cells specifically to deliver a toxic agent that kills them.

Participant Groups

Group I: Arm B (polatuzumab vedotin, glofitamab, chemotherapy) Experimental Treatment 14 Interventions

Patients receive rituximab IV on day 1, polatuzumab vedotin IV on day 1, prednisone PO BID on days 1-5, etoposide IV on days 1-4, doxorubicin IV on days 1-4, and cyclophosphamide IV on day 5. Starting with cycle 2, patients also receive glofitamab, over 4 hours, on day 1 and 8 of cycle 2 and day 1 of subsequent cycles. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MUGA scan or echocardiography during screening and FDG PET, CT scan, bone marrow biopsy and aspiration and blood sample collection throughout the study.

Group II: Arm A (polatuzumab vedotin, chemotherapy) [CLOSED TO ACCRUAL 05/23/2024] Experimental Treatment 13 Interventions

Patients receive rituximab IV on day 1, polatuzumab vedotin IV on day 1, prednisone PO BID on days 1-5, etoposide IV on days 1-4, doxorubicin IV on days 1-4, and cyclophosphamide IV on day 5. Patients also receive filgrastim SC 24-72 hours after the last dose of each treatment cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MUGA scan or echocardiography during screening and FDG PET, CT scan, bone marrow biopsy and aspiration and blood sample collection throughout the study.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

In a multi-institutional study of 69 patients with untreated diffuse large B-cell lymphoma, the DA-EPOCH-R treatment showed high rates of progression-free survival (81%) and overall survival (84%) after a median follow-up of 62 months.

The treatment was well-tolerated, with no significant grade 4 non-hematologic toxicities reported, confirming its safety and efficacy across different subtypes of diffuse large B-cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Wilson, WH., Jung, SH., Porcu, P., et al.[2022]

In a study of 20 patients with untreated poor prognosis diffuse large B-cell lymphoma (DLBCL), the two-weekly dose-adjusted EPOCH-like chemotherapy (DA-EDOCH14-R) showed a promising three-year progression-free survival (PFS) rate of 95%, compared to 74% in a previous trial with a three-weekly regimen.

The treatment was well-tolerated with manageable toxicity and no therapy-related deaths, highlighting its safety, especially for patients with a high-risk prognosis (age-adjusted International Prognostic Index of 3), where PFS reached 100% compared to just 30% in the previous trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. García-Suárez, J., Flores, E., Callejas, M., et al.[2015]

Chemotherapy for non-Hodgkin lymphoma in hemodialysis patients requires careful dose adjustments and timing due to the unique pharmacokinetics of drugs and their metabolites, which can lead to either overdose or undertreatment.

An extensive review of 48 studies involving 66 hemodialysis patients undergoing 71 chemotherapy regimens provided valuable insights and recommendations for managing chemotherapy in this population, highlighting the importance of individualized treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy for non-Hodgkin lymphoma in the hemodialysis patient: A comprehensive review. Yasuda, H., Yasuda, M., Komatsu, N.[2021]

In a study of 50 patients treated with R-CHOP-14 for aggressive B-cell lymphoma, 82% achieved a complete or improved response, indicating high efficacy of this treatment regimen.

Despite its effectiveness, R-CHOP-14 was associated with significant toxicities, including grade 3-4 neutropenia in 32% of patients and peripheral neuropathy in 45%, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with biweekly CHOP plus rituximab chemoimmunotherapy for the treatment of aggressive B-cell non-Hodgkin lymphoma. Aguiar Bujanda, D., Aguiar Morales, J., Bohn Sarmiento, U., et al.[2021]

In a pooled analysis of 150 patients with HIV-associated aggressive B-cell non-Hodgkin lymphoma, those treated with R-EPOCH showed significantly better event-free survival (EFS) and overall survival (OS) compared to those receiving R-CHOP, particularly in patients with a CD4 count ≥100/μL.

Patients with CD4 counts <50/μL experienced a much higher rate of treatment-related deaths (37% vs 6%), indicating that lower immune function increases the risk of lethal toxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Barta, SK., Lee, JY., Kaplan, LD., et al.[2022]

A systematic review of 62 randomized controlled trials found that the five-year overall survival rates for ABVD and BEACOPP regimens in advanced-stage Hodgkin lymphoma were 60-97% and 84-99%, respectively, indicating high efficacy for both treatments.

The new treatment A+AVD showed improved efficacy compared to ABVD while maintaining an acceptable tolerability profile, suggesting it may be a more manageable option for patients with advanced-stage Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of front-line treatments for advanced Hodgkin lymphoma: a systematic literature review. Dalal, M., Gupta, J., Price, K., et al.[2021]

In a study of 60 previously untreated patients with intermediate- or high-grade non-Hodgkin's lymphomas, the combination chemotherapy regimen CEOP-B/VIMB achieved a high complete remission rate of 77% and a 48-month overall survival rate of 70%.

The treatment demonstrated mild toxicity, making it a favorable option compared to third-generation regimens, while patient outcomes were significantly influenced by factors such as serum LDH levels and performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CEOP-B alternated with VIMB in intermediate-grade and high-grade non-Hodgkin's lymphoma: a pilot study. De Lena, M., Ditonno, P., Lorusso, V., et al.[2017]

This study analyzed over 7.5 million reports from the FDA Adverse Event Reporting System and found that conventional doxorubicin (DOX) has a higher incidence of adverse events compared to liposomal formulations, particularly in terms of myelosuppression and cardiotoxicity.

Liposomal DOX, especially the PEGylated version, showed lower reporting odds ratios for serious side effects like myelosuppression and cardiotoxicity, but a higher risk for palmar-plantar erythrodysesthesia (PPE), indicating the need for careful monitoring when using these formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. Fukuda, A., Tahara, K., Hane, Y., et al.[2022]

A phase 3 study involving 407 treatment-naïve patients with diffuse large B-cell lymphoma demonstrated that HLX01, a biosimilar to rituximab, has comparable efficacy to the reference drug, with overall response rates of 94.1% for HLX01 and 92.8% for rituximab, falling within the pre-defined equivalence margin.

The safety profiles of HLX01 and rituximab were similar, with nearly identical rates of treatment-emergent adverse events (99.5% vs. 99.0%) and serious adverse events (34.0% vs. 32.5%), confirming that HLX01 is a safe alternative to rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. Shi, Y., Song, Y., Qin, Y., et al.[2021]

In a study of 40 patients with low-grade or follicular B-cell non-Hodgkin's lymphoma, the combination of Rituxan (Rituximab) and CHOP chemotherapy resulted in a high overall response rate of 95%, with 55% achieving complete remission.

The combination therapy showed promising safety, with common side effects being manageable, and it also indicated potential for clearing minimal residual disease, as evidenced by the conversion of the bcl-2 translocation from positive to negative in several patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. Czuczman, MS., Grillo-López, AJ., White, CA., et al.[2022]

Rituximab is the first monoclonal antibody approved for treating B-cell lymphomas, showing significant effectiveness in conditions like follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma.

The combination of rituximab with standard chemotherapy agents (cyclophosphamide, doxorubicin, vincristine, and prednisone) has achieved the highest efficacy reported for treating diffuse large B-cell lymphoma and follicular lymphoma, while maintaining low toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. Traullé, C., Coiffier, BB.[2015]

In a study of 38 patients with relapsed or refractory non-Hodgkin's lymphoma (NHL), a treatment regimen combining paclitaxel with other drugs resulted in a total response rate of 46%, with 26% achieving a complete response and 20% a partial response.

The regimen demonstrated a manageable safety profile, with major toxicity primarily being hematologic, and only 10% of treatment cycles leading to severe infections, indicating that it is both effective and safe for patients who have not responded to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of paclitaxel in combination with mitoxantrone and ifosfamide/mesna for patients with relapsed or refractory non-Hodgkin's lymphoma after failure to cytarabine/cisplatin combination. Romaguera, JE., Rodriguez, MA., Hagemeister, FB., et al.[2019]

The ProMACE-CytoBOM chemotherapy regimen demonstrated a 65% complete remission rate in 78 previously untreated patients with intermediate- and high-grade non-Hodgkin's lymphomas, indicating its efficacy in treating this patient population.

The treatment was found to be feasible and safe, with 84% of the 537 treatment courses administered on schedule and a low rate of fatal toxicities (6%), suggesting it can be effectively implemented in a cooperative group setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unfavorable histologies of non-Hodgkin's lymphoma treated with ProMACE-CytaBOM: a groupwide Southwest Oncology Group study. Miller, TP., Dahlberg, S., Weick, JK., et al.[2017]

In a randomized trial of 118 patients with advanced diffuse lymphocytic lymphoma, the combination of the drug VP-16-213 with doxorubicin resulted in a higher complete remission rate of 54%, compared to 39% with VP-16-213 alone and 26% with VP-16-213 combined with cyclophosphamide.

The study found that combining VP-16-213 with cyclophosphamide led to significantly lower remission rates, suggesting that doxorubicin is a more effective partner for VP-16-213 in treating this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VP-16-213 in the treatment of stage III and IV diffuse lymphocytic lymphoma of the large cell (histiocytic) variety: an interim report. Jacobs, P., King, HS., Cassidy, F., et al.[2013]

Rituximab (RTX) is a widely used monoclonal antibody for treating diffuse large B-cell lymphoma, often combined with other drugs in the R-CHOP regimen, but some patients experience suboptimal responses or resistance.

New developments in CD20-targeting monoclonal antibodies, including second- and third-generation agents like ofatumumab and obinutumumab, are being actively researched to improve treatment outcomes for B-cell non-Hodgkin's lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel CD20 monoclonal antibodies for lymphoma therapy. Cang, S., Mukhi, N., Wang, K., et al.[2022]

References

1. Italy pubmed.ncbi.nlm.nih.gov

A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. [2022]

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

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Chemotherapy for non-Hodgkin lymphoma in the hemodialysis patient: A comprehensive review. [2021]

4. Italy pubmed.ncbi.nlm.nih.gov

Clinical experience with biweekly CHOP plus rituximab chemoimmunotherapy for the treatment of aggressive B-cell non-Hodgkin lymphoma. [2021]

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

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of front-line treatments for advanced Hodgkin lymphoma: a systematic literature review. [2021]

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

CEOP-B alternated with VIMB in intermediate-grade and high-grade non-Hodgkin's lymphoma: a pilot study. [2017]

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

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. [2022]

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

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. [2021]

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

Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. [2015]

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

Phase II study of paclitaxel in combination with mitoxantrone and ifosfamide/mesna for patients with relapsed or refractory non-Hodgkin's lymphoma after failure to cytarabine/cisplatin combination. [2019]

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

Unfavorable histologies of non-Hodgkin's lymphoma treated with ProMACE-CytaBOM: a groupwide Southwest Oncology Group study. [2017]

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

VP-16-213 in the treatment of stage III and IV diffuse lymphocytic lymphoma of the large cell (histiocytic) variety: an interim report. [2013]

15. England pubmed.ncbi.nlm.nih.gov

Novel CD20 monoclonal antibodies for lymphoma therapy. [2022]