Nivolumab +/− Varlilumab for Lymphoma

Not currently recruiting at 40 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunotherapy, Corticosteroids

Disqualifiers: Active CNS disease, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of the drugs nivolumab and varlilumab, used alone or together, in treating aggressive lymphoma that has either returned or not responded to standard treatments. These drugs are a type of immunotherapy that helps the body's immune system target and fight cancer cells. Suitable candidates for this trial include individuals with aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma, that have stopped responding to or returned after at least two rounds of standard treatment. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have received chemotherapy, targeted agents, or immunotherapy within 4 weeks before joining the trial. It's best to discuss your specific medications with the trial team.

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

Research has shown that using nivolumab and varlilumab together is generally safe. Studies have found that patients with advanced cancers tolerate this combination well. Trials did not identify a maximum tolerated dose for varlilumab, indicating it did not reach a level causing severe side effects.

Specifically, the combination of nivolumab and varlilumab proved tolerable at various dose levels, meaning most patients did not experience major side effects, and the treatment remained manageable. Overall, the safety data for both treatments reassures those considering joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of nivolumab and varlilumab for lymphoma because it offers a potentially powerful new way to harness the immune system. Unlike standard chemotherapy which directly targets and kills cancer cells, nivolumab is an immune checkpoint inhibitor that helps the body’s immune cells recognize and attack cancer cells more effectively. Varlilumab adds another layer by stimulating the immune system’s T-cells, enhancing their ability to fight the cancer. This dual action approach could lead to more effective and longer-lasting responses in patients compared to existing treatments.

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

Studies have shown that nivolumab, which participants in this trial may receive, can help the immune system fight aggressive B-cell lymphomas, especially when these cancers return or don't respond to treatment. Research indicates that nivolumab alone significantly reduces tumors. In this trial, some participants will receive nivolumab alone, while others will receive a combination of varlilumab and nivolumab. Lab studies have shown that varlilumab, another treatment option in this trial, can activate the immune system against cancer cells. However, combining varlilumab with nivolumab has not produced better results than using nivolumab alone in patients with aggressive B-cell lymphomas. Both treatments are generally well tolerated, with side effects similar to those caused by each drug individually. ^{1 2 4 6 7}

Who Is on the Research Team?

Stephen M Ansell

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with aggressive B-cell non-Hodgkin lymphoma that has returned or resisted treatment after two standard therapies. Participants must have a life expectancy over 12 weeks, measurable disease, good physical function (ECOG 0-1), and adequate blood counts and organ function. Pregnant or breastfeeding women, those with severe allergies to similar drugs, uncontrolled illnesses, certain autoimmune diseases, recent immunosuppressants use or other cancers being treated within the last three years are excluded.

Inclusion Criteria

My aggressive B-cell lymphoma has come back or didn't respond to treatment.

My lymphoma diagnosis fits into Category A or B of the WHO's 2016 classification.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I have not had chemotherapy, targeted therapy, or radiation in the last 4 weeks.

I still have side effects from treatment over 4 weeks ago.

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

Treatment

Patients receive nivolumab and/or varlilumab intravenously over a period of up to 2 years, with varying schedules based on group assignment

Up to 2 years

Every 2 weeks for 4 months, then every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

100 days

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Varlilumab

Trial Overview The study is testing how well nivolumab works alone or combined with varlilumab in treating recurrent or refractory aggressive B-cell lymphomas. These medications are types of immunotherapy called monoclonal antibodies which may boost the immune system's ability to fight cancer and stop tumor growth.

How Is the Trial Designed?

Group I: Group II (varlilumab, nivolumab) Experimental Treatment 2 Interventions

Patients receive varlilumab IV over 90 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes every 2 weeks for 4 months and every 4 weeks for a total of up to 2 years in the absence of disease progression or unacceptable toxicity.

Group II: Group I (nivolumab) Active Control 1 Intervention

Patients receive nivolumab IV over 30 minutes every 2 weeks for 4 months and every 4 weeks for a total of up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may cross over to Group II at the time of disease progression.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

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 study involving 51 patients with newly diagnosed advanced-stage classic Hodgkin lymphoma, nivolumab followed by a combination therapy (N-AVD) showed an impressive objective response rate of 84%, with 67% of patients achieving complete remission.

The treatment was generally well-tolerated, with 59% of patients experiencing grade 3 to 4 treatment-related adverse events, but most were manageable, and the 9-month modified progression-free survival rate was 92%, indicating strong efficacy and safety for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study. Ramchandren, R., Domingo-Domènech, E., Rueda, A., et al.[2021]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

Nivolumab, an immune checkpoint inhibitor, significantly improves overall survival and progression-free survival in patients with advanced stage squamous cell non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CHECKMATE 017 study.

The safety and tolerability of nivolumab are favorable, and interestingly, the expression of the PD-L1 ligand does not predict treatment outcomes, suggesting that other factors may influence the effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of metastatic squamous non-small cell lung cancer: a review of the evidence. Lim, JS., Soo, RA.[2018]

Nivolumab, an immune checkpoint inhibitor targeting PD-1, has shown effectiveness in treating various cancers, including Hodgkin lymphoma, as evidenced by a partial response in a 75-year-old patient after multiple treatments.

The case highlights a potential risk where discontinuation of nivolumab led to the emergence and progression of new malignancies, suggesting that while ICIs can be effective, they may also uncover or allow the growth of other cancers in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two primary cancers appeared after discontinuation of nivolumab in the course of treating Hodgkin lymphoma: a case report. Potluri, LB., Nanjareddy, S., Al Sbihi, A., et al.[2023]

In a phase 1b trial involving 137 patients with relapsed/refractory lymphoid malignancies, the combination of nivolumab with ipilimumab or lirilumab showed significant activity in classical Hodgkin lymphoma, with overall response rates of 74% and 76%, respectively.

However, the combination therapies did not demonstrate a meaningful improvement in efficacy compared to single-agent nivolumab, and the combination with ipilimumab resulted in higher rates of severe treatment-related adverse events (29%) compared to lirilumab (15%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies. Armand, P., Lesokhin, A., Borrello, I., et al.[2021]

Nivolumab, a PD-1 inhibitor used for advanced lung adenocarcinoma, can cause significant skin toxicity, as observed in a 60-year-old male patient who developed worsening skin rashes after treatment.

Early detection and treatment of immune-related skin toxicity with steroids led to alleviation of symptoms, suggesting that prompt management can improve patient outcomes while maintaining stable lung disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment-related Skin Toxicity Caused by Programmed Death-1 Inhibitor Nivolumab: A Case Report]. Gao, L., Yu, Y., Lu, S.[2020]

In a phase 2 trial involving 92 patients with relapsed or refractory follicular lymphoma, nivolumab showed a low objective response rate of only 4%, indicating limited efficacy as a monotherapy for this condition.

The study found that responders had a higher presence of CD3+ T cells in their tumors, suggesting that immune response characteristics may play a role in treatment outcomes, while the safety profile of nivolumab remained consistent with previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma. Armand, P., Janssens, A., Gritti, G., et al.[2021]

In a meta-analysis of five studies involving 2399 patients, nivolumab was found to significantly lower the risk of hematological toxicities such as anemia, neutropenia, and leukopenia compared to other treatments.

The relative risks for these conditions were notably low, indicating that nivolumab may be a safer option regarding hematological side effects, which is important for clinicians when considering treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The risks of hematological toxicities of nivolumab in cancer patients: A PRISMA-compliant meta-analysis. Shi, Z., Liu, X., Chen, M., et al.[2023]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

A retrospective analysis of adverse events related to PD-1/PD-L1 inhibitors revealed a significant association between Pembrolizumab and hepatitis B reactivation (HBVr), with a reporting odds ratio of 2.32, indicating a higher risk compared to other treatments.

No cases of HBVr were reported with Ipilimumab or Avelumab, suggesting that not all immune checkpoint inhibitors carry the same risk, highlighting the need for further prospective studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. Burns, EA., Muhsen, IN., Anand, K., et al.[2023]

Citations

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Results of the DIAL study (NCI 10089), a randomized ... Dual immunomodulatory therapy did not enhance anti-tumor activity in patients with aggressive B-NHL compared to nivolumab alone.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03038672

Nivolumab With or Without Varlilumab in Treating Patients ... This phase II trial studies how well nivolumab with or without varlilumab works in treating patients with aggressive B-cell lymphomas that have come back ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118595082

A Randomized Phase 2 Study of CDX-1127 (Varlilumab) in ... Varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9364417/

Safety, tolerability and efficacy of agonist anti-CD27 antibody ... Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.TPS7570

A randomized phase 2 study of CDX-1127 (varlilumab) in ... Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least ...

6. ashpublications.org ashpublications.org/bloodadvances/article/4/9/1917/454777/Safety-and-activity-of-varlilumab-a-novel-and

Safety and activity of varlilumab, a novel and first-in-class ... The anti-CD27 agonist antibody varlilumab was well tolerated in lymphoma patients with no maximum tolerated dose identified.

7. firstwordpharma.com firstwordpharma.com/story/3760856

Celldex Therapeutics Presents Favorable Safety Profile ... "The combination of varlilumab and nivolumab demonstrated acceptable tolerability across all dose levels of varlilumab, showing that immune ...