Immunotherapy for Lymphoma

Overseen By Stephen Smith

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Must be taking: CD20 antibodies

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Active infection, Autoimmune disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well a combination of immunotherapy drugs can treat certain types of lymphoma that have returned or are not responding to treatment. Researchers are using pembrolizumab (an immunotherapy drug) with either rituximab or obinutuzumab to determine if these drugs can help the immune system fight cancer cells more effectively. People with follicular lymphoma or diffuse large B cell lymphoma, whose cancer has returned or not responded to previous treatments, might be a good fit for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people, offering participants a chance to potentially benefit from cutting-edge therapies.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the trial, except for certain hormone replacement therapies.

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

Research shows that combining pembrolizumab with rituximab is generally safe for patients with relapsed follicular lymphoma. Studies have found that patients usually tolerate this combination well, experiencing only mild and expected side effects. Previous research confirms that patients can handle this treatment without major problems.

For the combination of pembrolizumab and obinutuzumab, pembrolizumab's approval for other uses indicates its relative safety. Common side effects of obinutuzumab include infusion reactions, tiredness, and low white blood cell counts, but these are usually manageable.

Overall, both treatment combinations have proven to be safe options, making them viable choices for those considering joining this trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for lymphoma because they combine pembrolizumab with either rituximab or obinutuzumab, offering a fresh approach to tackling the disease. Pembrolizumab, known for its immune checkpoint inhibition, helps the body's immune system recognize and attack cancer cells more effectively. When paired with rituximab or obinutuzumab, which are monoclonal antibodies targeting specific proteins on lymphoma cells, the combo could enhance treatment efficacy. This dual-action strategy aims to improve outcomes beyond what traditional therapies like chemotherapy or single-agent monoclonal antibodies can offer.

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

Research has shown that using pembrolizumab and rituximab together has produced mixed results in treating certain types of lymphoma, specifically relapsed or refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). This trial will evaluate the effectiveness of this combination in some participants. Some studies found that 50% of patients with FL who respond to rituximab achieved a complete response, but the treatment may be less effective for those previously treated with rituximab.

Another arm of this trial will investigate the combination of pembrolizumab with obinutuzumab, as these drugs target a protein called CD20 found on certain cancer cells. This combination aims to enhance the immune system's ability to fight cancer. While these treatments show promise, further research is needed to confirm their effectiveness. ^{5 6 7 8 9}

Who Is on the Research Team?

Stephen Smith

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for adults with relapsed or refractory follicular lymphoma or diffuse large B cell lymphoma. They must have tried certain treatments like CD20 antibody therapy, not be eligible for high-dose chemotherapy and stem cell transplant, and lack better treatment options. Participants need a minimum hemoglobin level, measurable disease, good performance status (able to carry out daily activities), adequate organ function, and agree to use contraception.

Inclusion Criteria

My DLBCL has returned or I can't have high-dose chemo and stem cell transplant.

Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 X ULN (within 28 days of cycle 1 day 1)

Be willing and able to provide written informed consent/assent for the trial

Exclusion Criteria

Hypersensitivity to pembrolizumab or any of its excipients

Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive pembrolizumab and either rituximab or obinutuzumab. Treatment repeats every 3 weeks for 4 cycles.

12 weeks

4 visits (in-person)

Extended Therapy

Patients with at least a partial response receive pembrolizumab every 3 weeks for up to 2 years. Obinutuzumab may be given on specific cycles.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Pembrolizumab
• Rituximab

Trial Overview The study tests pembrolizumab combined with either rituximab or obinutuzumab in patients whose lymphoma has returned after treatment or hasn't responded to previous therapies. Pembrolizumab is an immunotherapy drug that may help the immune system attack cancer cells; rituximab and obinutuzumab are antibodies targeting specific proteins on cancer cells.

How Is the Trial Designed?

Group I: Arm III (pembrolizumab, obinutuzumab) Experimental Treatment 3 Interventions

INDUCTION: Patients diagnosed with R/R FL receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive obinutuzumab IV on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2. EXTENDED THERAPY: Patients with at least a partial response receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years (35 cycles) in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (pembrolizumab, rituximab) Experimental Treatment 3 Interventions

INDUCTION: Patients diagnosed with R/R DLBCL receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2. EXTENDED THERAPY: Patients with at least a partial response receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years (35 cycles) in the absence of disease progression or unacceptable toxicity.

Group III: Arm I (pembrolizumab, rituximab) Experimental Treatment 3 Interventions

INDUCTION: Patients diagnosed with R/R FL receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV on days 1, 8, and 15 of cycle 1, and on day 1 of cycle 2. EXTENDED THERAPY: Patients with at least a partial response receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years (35 cycles) in the absence of disease progression or unacceptable toxicity.

Obinutuzumab is already approved in United States, European Union for the following indications:

Approved in United States as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Approved in European Union as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

Obinutuzumab, combined with bendamustine, significantly prolonged progression-free survival (PFS) in patients with indolent non-Hodgkin's lymphoma, particularly benefiting those with follicular lymphoma, as shown in the phase III GADOLIN study.

The treatment was generally well-tolerated, with mild to moderate infusion-related reactions being the most common side effects, while neutropenia was the most frequent severe adverse event, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma. Dhillon, S.[2018]

The Phase IIIb GREEN trial demonstrated that obinutuzumab (GA101) has a manageable toxicity profile in both first-line and relapsed/refractory chronic lymphocytic leukaemia (CLL) patients, with no new safety signals identified in the final analysis involving 630 first-line and 341 relapsed/refractory patients.

Common serious adverse events included neutropenia and thrombocytopenia, but the safety profile remained consistent with existing risk management strategies, while efficacy analyses indicated that certain treatment combinations, like obinutuzumab with fludarabine and cyclophosphamide, may lead to better outcomes in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of obinutuzumab alone or with chemotherapy in previously untreated or relapsed/refractory chronic lymphocytic leukaemia patients: Final analysis of the Phase IIIb GREEN study. Stilgenbauer, S., Bosch, F., Ilhan, O., et al.[2021]

Obinutuzumab (GA101) is an effective treatment for non-Hodgkin's lymphoma and is currently undergoing phase 3 clinical trials to further evaluate its efficacy.

A case report of a 62-year-old patient revealed a significant side effect, a widespread lichenoid eruption, highlighting the need for further investigation into the safety profile of GA101.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GA101 (a Novel Anti-CD20 Monoclonal Antibody)-Induced Lichenoid Eruption. Bakkour, W., Coulson, IH.[2022]

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]

In a phase II study involving 37 patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma, Rituximab was found to be well tolerated, with most adverse events being mild and decreasing with subsequent infusions.

The treatment resulted in a 57% overall response rate, with 14% achieving a complete response and 43% a partial response, indicating significant clinical activity and suggesting that extended Rituximab treatment may be effective for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Piro, LD., White, CA., Grillo-López, AJ., et al.[2022]

In a study of 56 patients with relapsed/refractory follicular lymphoma, obinutuzumab combined with chemotherapy (either G-CHOP or G-FC) resulted in high response rates of 93% to 96%, indicating strong efficacy for this treatment approach.

The safety profile was acceptable, with most adverse events being mild infusion-related reactions; however, G-FC was associated with more adverse events compared to G-CHOP, suggesting that while both regimens are effective, G-CHOP may be better tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Radford, J., Davies, A., Cartron, G., et al.[2022]

Citations

1. ashpublications.org ashpublications.org/blood/article/146/15/1782/546730/Treatment-of-relapsed-and-refractory-follicular

Treatment of relapsed and refractory follicular lymphoma A 5-year update demonstrated 5-year OS rates for R2 vs rituximab of 83.2% (95% confidence interval [CI], 76.3-88.3) vs 77.3% (95% CI, 70.1-83.1) ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11976689/

Relapsed/Refractory Follicular Lymphoma: Current ... This review provides a comprehensive overview of current standard treatments for relapsed or refractory (R/R) FL, including chemoimmunotherapy and stem cell ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S000649712501938X

Treatment of relapsed and refractory follicular lymphoma A 5-year update demonstrated 5-year OS rates for R2 vs rituximab of 83.2% (95% confidence interval [CI], 76.3-88.3) vs 77.3% (95% CI, 70.1-83.1) ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.7519

Interim results of an on open-label, phase II study. Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: Interim results of an on open- ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/jha2.1029

A phase 2 study of frontline pembrolizumab in follicular ... We developed a phase 2 study to evaluate the efficacy of pembrolizumab as the initial treatment for indolent B-cell lymphoma.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf

Keytruda - accessdata.fda.gov KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin ... Safety data are available for the first 203 ...

7. gazyva.com gazyva.com/content/dam/gene/gazyva/global/pdfs/GAZYVA-relapsed-refractory-FL-patient-brochure.pdf

R/R Follicular Lymphoma The most common side effects seen with GAZYVA in a study that included relapsed or refractory FL patients were infusion-related reactions, fatigue, low white ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12167646/

Follicular Lymphoma: Current Therapeutic Landscape and ... Summary of efficacy and safety data for BsAbs in relapsed‐refractory FL. BsAbs, Prior lines, No. of FL patients, Delivery, ORR, CR, Median PFS ...

9. keytrudahcp.com keytrudahcp.com/prescribing-information/

Prescribing Information - KEYTRUDA® (pembrolizumab) Safety data are available for the first 203 patients who received KEYTRUDA and ... Adults with relapsed or refractory cHL received KEYTRUDA 200 mg ...