ViPOR-P for B-Cell Lymphoma

Overseen By Christopher J Melani, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Active CNS lymphoma, HIV, Pregnancy, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

Duration: 18 weeks

55 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of six drugs, including Ibrutinib (Imbruvica), to determine their safety and effectiveness in treating certain types of B-cell lymphomas, which are cancers of the blood and lymphatic system. The goal is to assist individuals whose lymphoma has returned after treatment or has not responded to previous treatments. Participants will receive the treatment in cycles over several months and will be monitored for five years. This trial suits adults with B-cell lymphoma that is resistant to or has returned after at least one prior treatment. 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 combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does exclude participants who need to use warfarin or certain other medications due to potential interactions. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

A previous study found that venetoclax caused some serious side effects. When combined with other drugs for chronic lymphocytic leukemia, about 9% of patients developed pneumonia. Researchers tested ibrutinib on patients with marginal zone lymphoma and large B-cell lymphoma, and 70.7% experienced severe side effects, though it was generally well-tolerated. Obinutuzumab often led to low white blood cell counts and reactions during infusions, with serious side effects, including neutropenia, seen in about 80.3% of patients.

Polatuzumab, when used with other drugs for certain lymphomas, may lower blood cell counts and cause nerve damage, resulting in tingling or numbness. Lastly, lenalidomide often caused low white blood cell counts and fever in patients with B-cell lymphoma.

As this is a Phase 1 trial, the main goal is to determine safe dosages and monitor side effects. These studies show the drugs have known side effects but are generally well-researched. Safety in this combination is still being assessed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for B-cell lymphoma, which typically involve chemotherapy and monoclonal antibodies, the combination of ibrutinib, obinutuzumab, polatuzumab, prednisone, Revlimid, and venetoclax offers a targeted multi-drug approach. This regimen is unique as it aims to maximize effectiveness by using both oral and intravenous medications with varied mechanisms, such as venetoclax's ability to inhibit BCL-2 proteins, which are crucial for cancer cell survival. Researchers are particularly excited about the potential to determine the maximum tolerated doses (MTD) of polatuzumab and venetoclax, which could enhance treatment efficacy while minimizing side effects. This approach could offer a more personalized and potentially more effective treatment for patients with B-cell lymphoma.

What evidence suggests that this trial's treatments could be effective for B-cell lymphoma?

Research has shown that each drug tested in this trial holds potential for treating B-cell lymphomas. Venetoclax, which blocks the BCL-2 protein, has helped some patients with recurring lymphoma live longer without disease progression for several months. Ibrutinib, another key drug in this trial, has successfully treated various B-cell cancers and can extend patient survival. Obinutuzumab has achieved high success rates in slow-growing lymphomas, with some studies reporting response rates up to 100%. Polatuzumab has proven effective in treating aggressive B-cell lymphoma that has returned or not responded to treatment, showing significant success rates. Lastly, lenalidomide has demonstrated clear benefits in treating large B-cell lymphoma, with high success rates in clinical studies. This trial tests these drugs together in different treatment arms to determine if their combined effects can better treat both aggressive and slow-growing B-cell lymphomas. ^{5 6 7 8 9}

Who Is on the Research Team?

Christopher J Melani, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults over 18 with B-cell lymphoma that has come back or didn't respond to treatment can join. They must have tried at least one cancer therapy, be in good health otherwise, and agree to use birth control. People with certain types of lymphoma like MCL or active CNS involvement, pregnant women, those with liver disease or HIV, and anyone on conflicting medications are excluded.

Inclusion Criteria

My lymphoma is an aggressive type, such as DLBCL or Burkitt.

My B-cell lymphoma didn't respond or came back after treatment with an anti-CD20 drug.

My aggressive B-cell lymphoma didn't respond to or came back after treatment with an anthracycline.

Exclusion Criteria

Evidence of active tumor lysis syndrome

You are allergic to xanthine oxidase inhibitors and rasburicase or any of the study drugs.

I do not have any unmanaged ongoing illnesses.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for assessments and tests

Treatment

Participants receive a combination of venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide, and polatuzumab over 6 cycles, each lasting 21 days

18 weeks

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits for 5 years

5 years

Follow-up visits every 3-6 months

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Obinutuzumab
• Polatuzumab
• Prednisone
• Revlimid
• Venetoclax

Trial Overview

The trial tests a drug combo (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Revlimid & Polatuzumab) for B-cell lymphomas resistant to standard treatments. Participants will take some drugs orally and receive others through IV for up to six cycles lasting 21 days each.

How Is the Trial Designed?

Group I: Arm 2: Dose Expansion Experimental Treatment 6 Interventions

Venetoclax (PO) at the MTD days 2-14, ibrutinib (PO) 560mg on days 1-14, prednisone (PO) 100mg on days 1-7, obinutuzumab 1000mg (IV) on days 1 and 2, lenalidomide (PO) 15mg on days 1-14, and polatuzumab (IV) at the MTD of each 21-day cycle (maximum 6 cycles)

Group II: Arm 1: Dose Escalation Experimental Treatment 6 Interventions

Venetoclax (PO) 800mg at escalating doses (2 dose levels) on days 2-14, ibrutinib (PO) 560mg on days 1-14, prednisone (PO) 100mg on days 1-7, obinutuzumab 1000mg (IV) on days 1 and 2, lenalidomide (PO) 15mg on days 1-14, and polatuzumab (IV) at escalating doses (2 dose levels) on day 2 of each 21-day cycle (maximum 6 cycles) to determine MTD of polatuzumab and venetoclax

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

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 3 trial involving 879 patients with untreated intermediate-risk or high-risk diffuse large B-cell lymphoma (DLBCL), the modified regimen pola-R-CHP (which replaces vincristine with polatuzumab vedotin) showed a significantly higher progression-free survival rate at 2 years (76.7%) compared to the standard R-CHOP regimen (70.2%).

The overall survival rates at 2 years were similar between the pola-R-CHP and R-CHOP groups (88.7% vs. 88.6%), indicating that while pola-R-CHP may reduce the risk of disease progression, it does not significantly improve overall survival compared to the standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. Tilly, H., Morschhauser, F., Sehn, LH., et al.[2022]

The study evaluated the antibody-drug conjugate polatuzumab vedotin (pola) combined with rituximab/obinutuzumab and chemotherapy in treating B-cell non-Hodgkin lymphoma, showing that pola's pharmacokinetics were consistent and dose-proportional across different treatment cycles.

There were no significant drug-drug interactions between pola and the chemotherapy regimen (R/G-CHP), indicating that pola can be safely used in combination with these treatments for previously untreated diffuse large B-cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma. Shemesh, CS., Agarwal, P., Lu, T., et al.[2020]

In a study of 57 patients with relapsed large B-cell lymphoma after CAR T-cell therapy, polatuzumab vedotin (PV) showed a response rate of 44%, with 14% achieving complete remission, indicating its potential efficacy in this challenging patient population.

The median progression-free survival was only 10 weeks, and factors like bone marrow involvement and high lactate dehydrogenase levels were linked to shorter survival, highlighting the need for further research on treatment resistance and consolidation strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter retrospective study of polatuzumab vedotin in patients with large B-cell lymphoma after CAR T-cell therapy. Gouni, S., Rosenthal, AC., Crombie, JL., et al.[2023]

Polatuzumab vedotin is an antibody-drug conjugate that targets CD79b on B cells, delivering a cytotoxic agent (MMAE) to inhibit cell division and induce cell death, making it a promising treatment for certain blood cancers.

In June 2019, polatuzumab vedotin received accelerated FDA approval for use with bendamustine and rituximab in adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), and it is currently under review in the EU and in various stages of development for other related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab Vedotin: First Global Approval. Deeks, ED.[2023]

The combination of venetoclax, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[2021]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

In a phase 3 trial with 523 patients, the combination of ibrutinib and venetoclax significantly improved progression-free survival compared to the traditional FCR treatment, with only 12 patients experiencing disease progression or death in the ibrutinib-venetoclax group versus 75 in the FCR group.

The study also found that 65.9% of patients on ibrutinib-venetoclax achieved undetectable measurable residual disease (MRD) in bone marrow after 5 years, indicating effective disease control, although there was a higher incidence of serious cardiac adverse events in this group compared to FCR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir, T., Cairns, DA., Bloor, A., et al.[2023]

Polatuzumab vedotin (PV) is an innovative antibody-drug conjugate that has been approved by the US FDA for treating refractory/relapsed diffuse large B-cell lymphoma, particularly in patients who are not eligible for stem cell transplants.

In a pivotal Phase II trial, PV demonstrated significant efficacy and an acceptable safety profile when used in combination with bendamustine and rituximab, highlighting its potential as a valuable treatment option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin, an anti-CD79b antibody-drug conjugate for the treatment of relapsed/refractory diffuse large B-cell lymphoma. Camus, V., Tilly, H.[2021]

Polatuzumab vedotin, an antibody-drug conjugate, demonstrated an acceptable safety profile in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL), with a recommended phase 2 dose of 2.4 mg/kg showing objective responses in 23 out of 42 evaluable patients.

In contrast, the treatment was not effective for patients with chronic lymphocytic leukaemia (CLL), as no objective responses were observed, highlighting the need for further assessment of polatuzumab vedotin specifically in NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Palanca-Wessels, MC., Czuczman, M., Salles, G., et al.[2018]

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79B, is effective for treating relapsed/refractory diffuse large B-cell lymphoma when combined with bendamustine and rituximab.

Research by Kawasaki et al. suggests potential mechanisms of resistance to polatuzumab vedotin in lymphoma cells, which could inform future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

United we stand: Double targeting of CD79B and CD20 in diffuse large B-cell lymphoma. Tarantelli, C., Bertoni, F.[2023]

In a study involving 85 patients with untreated diffuse large B-cell lymphoma, the combination of polatuzumab vedotin with standard chemotherapy (R-CHP or G-CHP) showed promising preliminary efficacy, with 89% of patients achieving an overall response and 77% achieving a complete response.

The safety profile of polatuzumab vedotin was manageable, with common adverse events including neutropenia and peripheral neuropathy, leading to the establishment of a recommended phase 2 dose of 1.8 mg/kg for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Tilly, H., Morschhauser, F., Bartlett, NL., et al.[2023]

Polatuzumab vedotin (POLIVY®) is an effective treatment for adult patients with diffuse large B-cell lymphoma, approved after showing significant anti-cancer activity by delivering a potent drug directly to B cells.

The incidence of anti-drug antibodies (ADA) against polatuzumab vedotin is low, likely due to its mechanism of action that targets and kills B cells, which minimizes immune response and supports a favorable benefit/risk profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrated summary of immunogenicity of polatuzumab vedotin in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Dere, RC., Beardsley, RL., Lu, D., et al.[2023]

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