Brentuximab Vedotin + Nivolumab for Hodgkin's Lymphoma

Recruiting at 416 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Interstitial lung disease, Uncontrolled illness, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: Unknown

Duration: 8-16 weeks

1875 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether adding immunotherapy drugs, brentuximab vedotin and nivolumab, to standard chemotherapy and possibly radiation can improve survival for people with stage I or II classical Hodgkin lymphoma. Brentuximab vedotin targets and destroys cancer cells, while nivolumab helps the immune system attack the cancer. The trial includes different groups testing these combinations to determine which works best. Individuals with newly diagnosed, untreated stage I or II classical Hodgkin lymphoma and measurable disease might be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on corticosteroids or other immunosuppressive medications, you may need to stop them 14 days before enrolling, unless they are for specific conditions like adrenal insufficiency or Hodgkin lymphoma symptoms.

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

Research shows that the combination of brentuximab vedotin and nivolumab is generally well-tolerated by patients with Hodgkin's lymphoma. Studies have found this combination safe, with manageable side effects. For instance, one study found that using both drugs together was effective and well-tolerated, especially as a first treatment after other treatments failed.

Common side effects include tiredness, nausea, and low blood counts, but these were mostly mild to moderate. Serious side effects were less common. Overall, evidence from these studies suggests that brentuximab vedotin and nivolumab are safe options for treating patients, providing reassurance about their use in clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Brentuximab Vedotin and Nivolumab for Hodgkin's Lymphoma because these drugs offer a new approach compared to standard treatments like ABVD (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine). Brentuximab Vedotin is an antibody-drug conjugate that specifically targets CD30, a protein found on Hodgkin's lymphoma cells, delivering chemotherapy directly to the cancer cells. Nivolumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells more effectively. This combination aims to enhance treatment effectiveness by directly targeting cancer cells and boosting the immune response, potentially offering better outcomes for patients.

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

Research has shown that using brentuximab vedotin with nivolumab is promising for treating Hodgkin's lymphoma. In this trial, some participants will receive this combination, which studies have found to greatly improve survival rates. Brentuximab vedotin targets and kills cancer cells directly, while nivolumab helps the immune system fight the cancer. This combination has effectively helped patients live longer without the cancer worsening. Overall, these treatments are considered a strong option for improving outcomes in Hodgkin's lymphoma. ^{1 2 3 4 6}

Who Is on the Research Team?

Kara M. Kelly

Principal Investigator

Roswell Park Cancer Institute

Are You a Good Fit for This Trial?

This trial is for patients aged 5-60 with newly diagnosed, untreated classical Hodgkin lymphoma stages I or II. They must have proper kidney and liver function, no severe lung conditions, not be on high-dose steroids or immunosuppressants, and not have other active serious illnesses. Pregnant women and those who haven't agreed to use effective contraception are excluded.

Inclusion Criteria

I am 17 or younger with a moderate ability to carry out daily activities.

ALT =< 3 x ULN

I am between 5 and 60 years old.

Exclusion Criteria

I have a weak immune system that is not well-managed.

Patients with uncontrolled intercurrent illnesses that would jeopardize safety

I haven't taken steroids or immunosuppressants in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ABVD chemotherapy regimen on days 1 and 15 of each 28-day cycle, followed by stratification into different arms based on risk status and response.

8-16 weeks

Multiple visits for chemotherapy administration and imaging

Immunotherapy

Participants in certain arms receive brentuximab vedotin and nivolumab, with or without involved site radiation therapy (ISRT).

8-16 weeks

Regular visits for immunotherapy administration and imaging

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups every 3 months for the first year, then every 6 months for the next two years, and annually up to 12 years.

12 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Brentuximab Vedotin
• Cyclophosphamide
• Etoposide
• Nivolumab
• Vincristine Sulfate

Trial Overview

The study compares standard chemotherapy (with drugs like doxorubicin and prednisone) plus radiation against the same treatment combined with immunotherapy drugs Brentuximab Vedotin and Nivolumab. The goal is to see if adding these two drugs improves survival rates.

How Is the Trial Designed?

Group I: Arm H (ABVD, brentuximab vedotin, nivolumab, ISRT) Experimental Treatment 13 Interventions

Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive treatment and imaging, and may undergo blood sample collection as in arm D.

Group II: Arm G (ABVD, eBEACOPP or eBPDac, ISRT) Experimental Treatment 18 Interventions

Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive treatment and imaging, and may undergo blood sample collection as in arm C.

Group III: Arm F (ABVD, brentuximab vedotin, nivolumab) Experimental Treatment 12 Interventions

Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive treatment as in arm B. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial.

Group IV: Arm E (ABVD, AVD) Experimental Treatment 10 Interventions

Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive AVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, vinblastine IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial.

Group V: Arm D (ABVD, brentuximab vedotin, nivolumab, ISRT) Experimental Treatment 13 Interventions

Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive brentuximab vedotin IV and nivolumab IV as in arm B followed by ISRT. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial.

Group VI: Arm C (ABVD, eBEACOPP or eBPDac, ISRT) Experimental Treatment 18 Interventions

See Detailed Description.

Group VII: Arm B (ABVD, brentuximab vedotin, nivolumab) Experimental Treatment 12 Interventions

Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 30 minutes once during each treatment cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial.

Group VIII: Arm A (ABVD) Active Control 10 Interventions

Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or MRI and are identified as RER or SER. Patients then receive ABVD IV for an additional 2 cycles on study. Each cycle lasts 28 days and ABVD is administered on days 1 and 15 of each cycle in the absence of disease progression or unacceptable toxicity. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial.

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

The combination of brentuximab vedotin (BV) with ifosfamide-carboplatin-etoposide (ICE) was found to be safe and effective as a second-line therapy for patients with refractory/relapsed classical Hodgkin lymphoma, with 61.9% achieving a complete metabolic response after 2 cycles.

With a median follow-up of 38 months, the treatment showed promising long-term outcomes, including a 3-year progression-free survival rate of 64.3% and an overall survival rate of 100%, indicating its potential as a viable alternative to other salvage therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final results of brentuximab vedotin combined with ifosfamide-carboplatin-etoposide in first refractory/relapsed Hodgkin lymphoma: a lymphoma study association phase I/II study. Stamatoullas, A., Ghesquières, H., Feugier, P., et al.[2023]

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]

In a study of 497 elderly patients with inflammatory bowel disease, those treated with vedolizumab (VDZ) had a lower incidence of mild infections (93.1 per 1000 patient-years) compared to those on 5-aminosalicylic acid (5-ASA) and chronic steroids, suggesting a potentially safer profile for VDZ.

The incidence of malignancies was similar between the VDZ and 5-ASA groups (17.6 vs. 15.6 per 1000 patient-years), while the steroid group had a higher incidence (42.6 per 1000 patient-years), indicating that VDZ may be a safer option for elderly patients with IBD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of Infections and Malignancy Among Elderly Male Patients with IBD Exposed to Vedolizumab, Prednisone, and 5-ASA Medications: A Nationwide Retrospective Cohort Study. Khan, N., Pernes, T., Weiss, A., 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]

In a meta-analysis of 46 studies involving 12,808 cancer patients treated with anti-PD-1/PD-L1 agents, the overall incidence of immune-related adverse events (irAEs) was found to be 26.82%, with severe irAEs occurring in 6.10% of patients.

The types of irAEs varied by organ system and were influenced by the specific drug and cancer type, but the occurrence of these adverse events was not related to the dosage of the PD-1 inhibitors, indicating a need for careful monitoring regardless of treatment levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis. Wang, PF., Chen, Y., Song, SY., et al.[2022]

In a study of 21 patients with relapsed and refractory classic Hodgkin lymphoma who had previously failed nivolumab treatment, the combination of nivolumab and brentuximab vedotin showed a promising overall response rate of 57%.

The treatment was found to be relatively safe, with 63% of patients experiencing any grade adverse events, and only 10% experiencing severe (grade 3-4) adverse events, suggesting that this combination therapy could be a viable option for patients after PD-1 inhibitor failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nivolumab combined with brentuximab vedotin after nivolumab monotherapy failure in patients with relapsed and refractory classic Hodgkin lymphoma. Fedorova, LV., Lepik, KV., Volkov, NP., et al.[2023]

A survey of 171 clinicians revealed that knowledge about immune-related adverse events (irAEs) was generally low, with average scores below 70%, indicating a need for improved education on diagnosing and managing these side effects of immune checkpoint inhibitors.

Experience with irAEs was linked to higher knowledge and confidence levels among oncology clinicians, suggesting that hands-on experience can enhance understanding, and highlighting the importance of developing targeted educational resources for different clinician roles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role-Specific Curricular Needs for Identification and Management of Immune-Related Adverse Events. Wesevich, A., He, G., Tomczyk, G., et al.[2023]

Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs) due to their mechanism of action, necessitating a multidisciplinary approach for effective patient management, as highlighted by 30 real-world pharmacovigilance studies.

These studies have provided valuable insights into the patterns, kinetics, and fatality rates of various irAEs, emphasizing the need for oncologists to understand both the strengths and limitations of this data for better patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance. Raschi, E., Gatti, M., Gelsomino, F., et al.[2021]

In a study involving 104 patients with advanced classical Hodgkin's lymphoma, both modified eBEACOPP regimens (BrECAPP and BrECADD) achieved high rates of complete response (86% and 88%, respectively) and complete remission, demonstrating their efficacy in treating this condition.

The BrECADD regimen showed a more favorable safety profile with fewer severe organ toxic effects compared to BrECAPP, making it a promising candidate for further testing against standard treatments in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group. Eichenauer, DA., Plütschow, A., Kreissl, S., et al.[2019]

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 study involving 65 heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma and anaplastic large-T-cell lymphoma, the combination of brentuximab vedotin and bendamustine showed a high overall response rate of 78%, indicating its efficacy as a salvage treatment.

The treatment demonstrated a favorable safety profile, with no treatment-related deaths and manageable side effects, making it a potential alternative to traditional platinum-based chemotherapy before autologous stem cell transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1-2 trial. O'Connor, OA., Lue, JK., Sawas, A., et al.[2022]

A study of 767 cancer patients receiving anti-PD-1/PD-L1 therapies found that antibiotic treatment significantly increases the risk of immune-related adverse events (irAEs), with an odds ratio of 2.12 for all cancers and 3.16 specifically for lung cancer.

The analysis of safety reports from large databases (38,705 from FAERS and 25,122 from VigiBase) confirmed that lung cancer patients on antibiotics have a heightened risk of irAEs, suggesting that the use of antibiotics should be carefully considered in these patients to mitigate potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of antibiotic treatment with immune-related adverse events in patients with cancer receiving immunotherapy. Jing, Y., Chen, X., Li, K., et al.[2022]

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]

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Brentuximab vedotin and nivolumab for untreated patients with Hodgkin lymphoma: long-term results Open Access. Clinical Trials & Observations.

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