Brentuximab Vedotin + Nivolumab ± Ipilimumab for Hodgkin's Lymphoma

Recruiting at 530 trial locations

Overseen By Tatjana Kolevska, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Systemic corticosteroids

Disqualifiers: Autoimmune disorders, CNS involvement, 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: 17

Duration: Up to 34 months

146 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin, and how well they work in treating patients with Hodgkin lymphoma that has returned after a period of improvement (recurrent) or has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30 positive cancer cells in a targeted way and delivers vedotin to kill them. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab may kill more cancer cells.

Will I have to stop taking my current medications?

The trial requires that you stop taking any systemic corticosteroids or other immunosuppressants at least 2 weeks before starting the study treatment. If you are on replacement doses of steroids for adrenal insufficiency, you may continue those. It's best to discuss your specific medications with the study team to ensure compliance with the trial requirements.

What is known about the safety of Brentuximab Vedotin, Nivolumab, and Ipilimumab for Hodgkin's Lymphoma?

Brentuximab Vedotin is generally well tolerated but can cause side effects like peripheral neuropathy (nerve damage causing tingling or numbness) and neutropenia (low white blood cell count). Nivolumab, an anti-PD1 immunotherapy, can have unpredictable immune-related side effects such as skin rash, colitis (inflammation of the colon), and lung issues. Ipilimumab's safety profile is not detailed in the provided research, but it is known to have immune-related side effects similar to Nivolumab. ^{1 2 3 4 5}

What makes the drug combination of Brentuximab Vedotin, Nivolumab, and Ipilimumab unique for treating Hodgkin's Lymphoma?

This drug combination is unique because it combines targeted chemotherapy with immune-activating drugs to enhance the body's ability to fight Hodgkin's Lymphoma, especially in cases where the disease has returned or not responded to previous treatments. ^{6 7 8 9 10}

What data supports the effectiveness of the drug combination Brentuximab Vedotin, Nivolumab, and Ipilimumab for treating Hodgkin's Lymphoma?

Research shows that Brentuximab Vedotin, when used with other drugs, has been effective in treating Hodgkin's Lymphoma, with a high response rate in patients who had relapsed after previous treatments. Additionally, combining Brentuximab Vedotin with immune-boosting drugs like Nivolumab and Ipilimumab may enhance its effectiveness by activating the body's immune response against the cancer. ^{2 4 6 11 12}

Who Is on the Research Team?

Catherine S Diefenbach

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

Adults with recurrent or refractory classical Hodgkin lymphoma can join this trial. They must have finished previous treatments at least 21 days before, not be pregnant or breastfeeding, and agree to use contraception. Those with serious autoimmune diseases, uncontrolled infections like HIV, severe lung issues, recent monoclonal antibody therapy within 6 months (except ipilimumab in some cases), or a history of certain severe drug reactions are excluded.

Inclusion Criteria

All prior therapy must have been completed at least 21 days prior to enrollment; no concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose of treatment of lymphoma are allowed; topical steroids are allowed

Human immunodeficiency virus (HIV) positive patients are allowed on this study if they have a CD4 count > 400, and are on a stable antiviral regimen; patients with poorly controlled HIV or other chronic active viral infections will be excluded

Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids; a history of occasional (but not continuous) use of steroid inhalers is allowed

Exclusion Criteria

RANDOMIZED PHASE II (ARMS K AND L): Patients must have pathologically confirmed relapsed or refractory classical Hodgkin lymphoma (cHL); a biopsy at any relapse is acceptable; other histologies including lymphocyte predominant (LP) HL are not permitted

RANDOMIZED PHASE II (ARMS K AND L): Patients must have relapsed after first line chemotherapy; may have relapsed after autologous stem cell transplant, or have primary refractory disease; no upper limit for number of prior therapies; patient must not have received a prior allogeneic stem cell transplant (out of risk of reactivation of pulmonary graft versus host disease [GVHD])

Patients must not have grade 2 or greater peripheral sensory neuropathy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive brentuximab vedotin, nivolumab, and ipilimumab in various combinations across different arms. Treatment cycles vary between 21 and 14 days, with up to 46 cycles in total.

Up to 34 months

Regular visits every 14-21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes imaging and blood tests.

10 years

Every 3 months for 1 year, then every 6 months for 2 years, and annually thereafter

What Are the Treatments Tested in This Trial?

Interventions

• Brentuximab Vedotin
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing the combination of brentuximab vedotin and nivolumab with or without ipilimumab to see how well they work against Hodgkin lymphoma that has come back or hasn't responded to treatment. It's looking for the best dose and side effects while checking if these drugs help the immune system fight cancer more effectively.

How Is the Trial Designed?

Group I: Phase II Arm II (brentuximab vedotin, nivolumab, ipilimumab) Experimental Treatment 7 Interventions

Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16, nivolumab IV over 30 minutes on day 1 of cycles 1-34, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study.

Group II: Phase II Arm I (brentuximab vedotin, nivolumab) Experimental Treatment 6 Interventions

Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and nivolumab IV over 30 minutes on day 1 of cycles 1-34. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study.

Group III: Phase I Arm III (brentuximab vedotin, nivolumab, ipilimumab) Experimental Treatment 7 Interventions

Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16, nivolumab IV over 30 minutes on day 1 of cycles 1-46, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study.

Group IV: Phase I Arm II (brentuximab vedotin, nivolumab) Experimental Treatment 6 Interventions

Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and nivolumab IV over 30 minutes on day 1 of cycles 1-46. Treatment repeats every 21 days for up to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study.

Group V: Phase I Arm I (brentuximab vedotin, ipilimumab) Experimental Treatment 6 Interventions

Patients receive brentuximab vedotin IV over 30 minutes on day 1 of cycles 1-16 and ipilimumab IV over 90 minutes on day 1 of cycles 1-4, 8, 12, and 16. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET scan throughout the trial. Patients undergo blood sample collection and may undergo tumor biopsy on study.

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

Approved in United States as Adcetris for:

• Hodgkin lymphoma
• Systemic anaplastic large cell lymphoma
• Primary cutaneous anaplastic large cell lymphoma
• CD30-expressing mycosis fungoides
• Peripheral T-cell lymphoma

Approved in European Union as Adcetris for:

• Hodgkin lymphoma
• Systemic anaplastic large cell lymphoma
• Cutaneous T-cell lymphoma

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 1/2 trial involving 64 patients with relapsed or refractory Hodgkin lymphoma, the combination of brentuximab vedotin with nivolumab showed a high overall response rate of 89%, indicating strong efficacy in treating this type of cancer.

The study also reported varying levels of treatment-related adverse events, with the triplet therapy group experiencing the highest rate of severe side effects (50%), highlighting the importance of balancing efficacy with safety in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab, nivolumab, and brentuximab vedotin combination therapies in patients with relapsed or refractory Hodgkin lymphoma: phase 1 results of an open-label, multicentre, phase 1/2 trial. Diefenbach, CS., Hong, F., Ambinder, RF., et al.[2021]

In a phase II trial involving 170 patients with early-stage unfavorable Hodgkin lymphoma, the combination of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD) resulted in a higher PET-negative response rate (82.3%) after two cycles compared to the standard ABVD treatment (75.4%).

The 2-year progression-free survival (PFS) rate was also higher in the BV-AVD group (97.3%) compared to the ABVD group (92.6%), indicating that BV-AVD may offer a more effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab Vedotin Plus AVD for First-Line Treatment of Early-Stage Unfavorable Hodgkin Lymphoma (BREACH): A Multicenter, Open-Label, Randomized, Phase II Trial. Fornecker, LM., Lazarovici, J., Aurer, I., et al.[2023]

Brentuximab vedotin (Bv) combined with bendamustine (B) showed a high overall response rate of 79% and a complete response rate of 49% in 47 patients with relapsed or refractory classic Hodgkin lymphoma, indicating its efficacy as a treatment option.

The treatment resulted in a median progression-free survival of 18 months and a 2-year overall survival rate of 72%, particularly benefiting patients who achieved a major clinical response and those who underwent stem cell transplantation afterward.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin in association with bendamustine in refractory or multiple relapsed Hodgkin lymphoma. A retrospective real-world study. Iannitto, E., Romano, A., Scalzulli, PR., et al.[2021]

Brentuximab vedotin demonstrated a high overall objective response rate of 75% in 102 patients with relapsed Hodgkin lymphoma and 86% in 58 patients with relapsed systemic anaplastic large cell lymphoma, indicating its efficacy as a targeted treatment.

The treatment was generally well tolerated, with peripheral neuropathy being the most common side effect; however, about half of the patients who experienced this side effect saw complete resolution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin: a review of its use in patients with hodgkin lymphoma and systemic anaplastic large cell lymphoma following previous treatment failure. Garnock-Jones, KP.[2021]

Brentuximab vedotin is an effective treatment for relapsed or refractory Hodgkin lymphoma, showing a manageable safety profile with common side effects like peripheral neuropathy and neutropenia.

The drug is contraindicated with bleomycin due to the risk of pulmonary toxicity, and ongoing trials will help clarify its role in frontline therapy and its potential to replace radiation in early-stage disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A safety evaluation of brentuximab vedotin for the treatment of Hodgkin lymphoma. Oak, E., Bartlett, NL.[2019]

In a review of 2225 lymphoma patients from 4 randomized controlled trials, brentuximab vedotin was found to significantly increase the risk of all-grade adverse events (AEs) and high-grade AEs compared to non-brentuximab vedotin treatments.

Specific AEs associated with brentuximab vedotin included a higher risk of peripheral sensory neuropathy, pyrexia, nausea, vomiting, diarrhea, and alopecia, with particularly high risks for high-grade sensory neuropathy and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of adverse events in lymphoma patients treated with brentuximab vedotin: a systematic review and meta-analysis. Gao, S., Zhang, M., Wu, K., et al.[2021]

Brentuximab vedotin, a targeted therapy for Hodgkin lymphoma, is effective for patients at high risk of recurrence or relapse, but it can cause significant side effects, particularly peripheral neuropathy.

For patients who relapse after brentuximab vedotin, anti-PD1 immunotherapy (nivolumab or pembrolizumab) is an option, though it carries unpredictable immune-related side effects, highlighting the need for careful management in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Toxicity of targeted therapies and immunotherapy with checkpointinhibitors in Hodgkin lymphoma]. Michot, JM., Lazarovici, J.[2023]

In a phase 1 trial involving 7 patients with HIV-associated classical Hodgkin lymphoma, the combination of brentuximab vedotin and AVD was well tolerated at a dose of 1.2 mg/kg, with no dose-limiting toxicities identified and a 100% progression-free survival rate at 25 months.

The study highlighted the importance of avoiding strong CYP3A4 inhibitors during treatment, as one patient who took ritonavir experienced severe adverse events, underscoring the need for careful medication management in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin with AVD shows safety, in the absence of strong CYP3A4 inhibitors, in newly diagnosed HIV-associated Hodgkin lymphoma. Rubinstein, PG., Moore, PC., Rudek, MA., et al.[2020]

In a phase 2 trial involving 46 older patients with untreated Hodgkin lymphoma, the combination of brentuximab vedotin and nivolumab showed an overall response rate of 61%, indicating its potential efficacy in this population, particularly those with comorbidities.

The treatment was generally well tolerated, although 48% of patients experienced peripheral neuropathy, and there were some serious adverse events, including one treatment-related death, suggesting that while the regimen is promising, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. Cheson, BD., Bartlett, NL., LaPlant, B., et al.[2020]

In a phase 3 trial with 1334 patients, brentuximab vedotin combined with chemotherapy (A+AVD) showed a 4.9% higher 2-year modified progression-free survival rate (82.1%) compared to the standard ABVD treatment (77.2%), indicating superior efficacy for advanced-stage Hodgkin's lymphoma.

While A+AVD had a higher incidence of peripheral neuropathy (67% vs. 43% in ABVD), most patients in the A+AVD group experienced resolution or improvement of symptoms, and the treatment was associated with lower rates of severe pulmonary toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. Connors, JM., Jurczak, W., Straus, DJ., et al.[2023]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Ipilimumab, nivolumab, and brentuximab vedotin combination therapies in patients with relapsed or refractory Hodgkin lymphoma: phase 1 results of an open-label, multicentre, phase 1/2 trial. [2021]

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

Brentuximab Vedotin Plus AVD for First-Line Treatment of Early-Stage Unfavorable Hodgkin Lymphoma (BREACH): A Multicenter, Open-Label, Randomized, Phase II Trial. [2023]

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

Brentuximab vedotin in association with bendamustine in refractory or multiple relapsed Hodgkin lymphoma. A retrospective real-world study. [2021]

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

Brentuximab vedotin: a review of its use in patients with hodgkin lymphoma and systemic anaplastic large cell lymphoma following previous treatment failure. [2021]

5. England pubmed.ncbi.nlm.nih.gov

A safety evaluation of brentuximab vedotin for the treatment of Hodgkin lymphoma. [2019]

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

Risk of adverse events in lymphoma patients treated with brentuximab vedotin: a systematic review and meta-analysis. [2021]

7. France pubmed.ncbi.nlm.nih.gov

[Toxicity of targeted therapies and immunotherapy with checkpointinhibitors in Hodgkin lymphoma]. [2023]

8. France pubmed.ncbi.nlm.nih.gov

[Brentuximab vedotin: new treatment for CD30+ lymphomas]. [2019]

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

Brentuximab vedotin in systemic T-cell lymphoma. [2022]

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

Brentuximab vedotin with AVD shows safety, in the absence of strong CYP3A4 inhibitors, in newly diagnosed HIV-associated Hodgkin lymphoma. [2020]

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

Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. [2020]

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

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. [2023]