Brentuximab + Pembrolizumab + Chemotherapy for Hodgkin's Lymphoma

Overseen By Hun Lee, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Antineoplastics, Corticosteroids, others

Disqualifiers: Other malignancy, Active infection, Autoimmune, 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: Unknown

Duration: 12-24 weeks

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of four drugs—brentuximab vedotin, pembrolizumab, doxorubicin, and dacarbazine—to evaluate their effectiveness against Hodgkin's Lymphoma, a type of blood cancer. The trial targets patients with specific stages of this cancer (Stage II with bulky disease, or Stage III/IV) who have not yet received treatment. Eligible participants should have a diagnosis of these specific stages of Hodgkin's Lymphoma and measurable disease on scans. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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 be on other systemic anti-cancer treatments or certain immunosuppressive medications close to the start of 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 shows that the drugs brentuximab vedotin and pembrolizumab hold promise for treating Hodgkin's lymphoma. Studies have found that brentuximab vedotin helped up to 86% of patients with relapsed Hodgkin's lymphoma. Additionally, pembrolizumab improved quality of life compared to using brentuximab vedotin alone in similar patients.

Both treatments are generally well-tolerated, but like most cancer treatments, they can cause side effects. Common side effects of brentuximab vedotin include nerve damage and low blood cell counts. Pembrolizumab might cause tiredness and skin reactions. Importantly, these drugs have been used in various studies, and the side effects are usually manageable.

This trial uses these drugs together with chemotherapy (doxorubicin and dacarbazine). Participants should discuss potential risks with their healthcare provider. This combination aims to enhance treatment effectiveness while closely monitoring safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Brentuximab Vedotin, Pembrolizumab, and chemotherapy for Hodgkin's Lymphoma because it offers a novel approach to treatment that differs from standard options like ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine). While traditional treatments primarily rely on chemotherapy, Brentuximab Vedotin targets a protein called CD30 on cancer cells, delivering a potent anti-cancer agent directly to the tumor. Pembrolizumab, an immune checkpoint inhibitor, works by unleashing the body's immune system to fight cancer more effectively. This combination aims to enhance treatment efficacy and potentially improve outcomes by using targeted therapy and immunotherapy alongside traditional chemotherapy.

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

Research shows that combining brentuximab vedotin with pembrolizumab may offer promise for treating Hodgkin's lymphoma. In this trial, participants in Part A will receive pembrolizumab and brentuximab vedotin alongside chemotherapy. Studies have found that pembrolizumab helps patients live longer without disease progression compared to brentuximab vedotin alone in cases where Hodgkin's lymphoma has returned or is difficult to treat. Additionally, combining brentuximab vedotin with chemotherapy has led to better outcomes over three years compared to chemotherapy alone. This suggests these treatments could be highly effective for individuals with advanced or untreated Hodgkin's lymphoma. While more research is needed, early results are encouraging for these new treatments. ^{1 2 5 6 7}

Who Is on the Research Team?

Hun Lee, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with untreated classic Hodgkin Lymphoma (cHL) at stage II with bulky disease or advanced stages III/IV. Participants must have measurable disease, be in good physical condition (ECOG 0-1), and have normal organ function. They should not be pregnant/breastfeeding and agree to use effective contraception. People with severe allergies, certain lung or liver diseases, neuropathy, heart conditions, HIV, recent infections or other cancers are excluded.

Inclusion Criteria

I agree to use two forms of birth control during and for 7 months after the study if there's any chance of causing pregnancy.

I, or my legal representative, have given written consent to participate.

I have a tumor larger than 1.5 cm that shows up on scans and is active on PET.

Exclusion Criteria

I have been treated with brentuximab vedotin before.

I am not allergic to ingredients in my cancer drugs.

I have received an organ or stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Brentuximab vedotin and pembrolizumab in combination with doxorubicin and dacarbazine

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Brentuximab Vedotin
• Dacarbazine
• Doxorubicin
• Pembrolizumab

Trial Overview The study tests the combination of brentuximab vedotin and pembrolizumab with doxorubicin and dacarbazine in patients who haven't been treated for Stage II cHL with bulky mediastinal disease or advanced cHL (Stage III/IV). It aims to understand the effects of this drug combo on these specific lymphoma stages.

How Is the Trial Designed?

Group I: Part C: Standard Risk Arm Experimental Treatment 4 Interventions

Group II: Part B: De-Escalation Experimental Treatment 4 Interventions

Group III: Part A: Pembrolizumab and Brentuximab +AD Experimental Treatment 4 Interventions

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Seagen Inc.

Industry Sponsor

Trials

212

Recruited

73,800+

Founded

1997

Headquarters

Bothell, USA

Known For

Antibody-Drug Conjugates

Top Products

Adcetris (brentuximab vedotin), Tukysa (tucatinib), Padcev (enfortumab vedotin-ejfv), Tivdak (tisotumab vedotin-tftv)

Dr. Roger Dansey

Seagen Inc.

Chief Medical Officer since 2018

MD from University of Witwatersrand

David R. Epstein

Seagen Inc.

Chief Executive Officer since 2022

BSc in Pharmacy from Rutgers University, MBA from Columbia University

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

Brentuximab vedotin is an effective treatment for Hodgkin's lymphoma that has not responded to standard chemotherapy, as it specifically targets cancer cells expressing CD30 markers with a cytotoxic agent.

However, it can cause serious adverse effects, including rare cases of diabetic ketoacidosis and profound insulin resistance, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diabetic Ketoacidosis and Profound Insulin Resistance From Brentuximab Vedotin. Thakkar, K., Khurana, S., Sun, Y., et al.[2023]

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 phase 2 study involving 41 patients with untreated HIV-associated classical Hodgkin lymphoma, brentuximab vedotin combined with AVD showed a high complete response rate of 100% among those who completed therapy, with a 2-year progression-free survival rate of 87%.

The treatment was generally well-tolerated, with the most common serious side effects being neutropenia and peripheral sensory neuropathy, indicating that brentuximab vedotin-AVD is a promising and safe option for patients with HIV-cHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin with AVD for stage II-IV HIV-related Hodgkin lymphoma (AMC 085): phase 2 results from an open-label, single arm, multicentre phase 1/2 trial. Rubinstein, PG., Moore, PC., Bimali, M., et al.[2023]

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]

A systematic review of 62 randomized controlled trials found that the five-year overall survival rates for ABVD and BEACOPP regimens in advanced-stage Hodgkin lymphoma were 60-97% and 84-99%, respectively, indicating high efficacy for both treatments.

The new treatment A+AVD showed improved efficacy compared to ABVD while maintaining an acceptable tolerability profile, suggesting it may be a more manageable option for patients with advanced-stage Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of front-line treatments for advanced Hodgkin lymphoma: a systematic literature review. Dalal, M., Gupta, J., Price, K., et al.[2021]

Brentuximab vedotin, an antibody-drug conjugate, shows a high response rate of 75% in relapsed/refractory Hodgkin lymphoma, but resistance often develops due to upregulation of the MDR1 protein.

Combining brentuximab vedotin with cyclosporine A (CsA) effectively restores sensitivity to the drug in resistant cases, achieving a 75% overall response rate and 42% complete response rate in a phase I trial, indicating a promising new strategy to overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of MDR1 Overcomes Resistance to Brentuximab Vedotin in Hodgkin Lymphoma. Chen, R., Herrera, AF., Hou, J., 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 doxorubicin, vinblastine, and dacarbazine (AVD+BV) improves clinical outcomes in adults with stage III or IV Hodgkin lymphoma, providing an increase of 0.56 quality-adjusted life-years (QALYs) compared to standard ABVD therapy.

However, the use of BV significantly raises lifetime healthcare costs, resulting in an incremental cost-effectiveness ratio (ICER) of $317,254 per QALY, indicating that it is unlikely to be cost-effective at current pricing without substantial price reductions for BV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness Analysis of Brentuximab Vedotin With Chemotherapy in Newly Diagnosed Stage III and IV Hodgkin Lymphoma. Huntington, SF., von Keudell, G., Davidoff, AJ., et al.[2019]

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]

Brentuximab vedotin is an effective treatment for relapsed or refractory classical Hodgkin lymphoma, showing high response rates and durable outcomes in both clinical trials and real-world settings.

In the phase 3 AETHERA trial, brentuximab vedotin significantly prolonged progression-free survival compared to placebo after autologous stem cell transplant, reducing the risk of disease progression or death by 43% over a median follow-up of 30 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab Vedotin: A Review in CD30-Positive Hodgkin Lymphoma. Scott, LJ.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8791579/

Quality-of-life analysis of pembrolizumab vs brentuximab ... Key Points. Pembrolizumab improved health-related quality of life over brentuximab vedotin in patients with relapsed/refractory cHL.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02684292

NCT02684292 | Study of Pembrolizumab (MK-3475) vs. ... The purpose of this study is to evaluate pembrolizumab (MK-3475) in the treatment of participants with relapsed or refractory Classical Hodgkin Lymphoma.

3. merck.com merck.com/news/mercks-keytruda-pembrolizumab-significantly-improved-progression-free-survival-compared-with-brentuximab-vedotin-in-patients-with-relapsed-or-refractory-classical-hodgkin-lymphoma-ch/

Merck's KEYTRUDA® (pembrolizumab) Significantly ... KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in PFS compared with brentuximab vedotin (BV) in this patient ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8869808/

Brentuximab Vedotin and Pembrolizumab Combination in ... The BV and pembrolizumab combination is a very effective bridge treatment to ASCT for high-risk R/R HL patients. Keywords: Hodgkin lymphoma, ...

5. ashpublications.org ashpublications.org/bloodadvances/article/8/11/2740/515346/Brentuximab-vedotin-and-chemotherapy-in-relapsed

Brentuximab vedotin and chemotherapy in relapsed/refractory ... In patients with relapsed disease, the BV cohort showed a significantly better 3-year PFS than the chemotherapy cohort of 79.9% (95% CI, 74-87) vs 69.7% (95% ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05180097

NCT05180097 | Pembrolizumab and Brentuximab Vedotin ... This study is being done to determine if two new drugs can shrink or eliminate classical Hodgkins lymphoma. Detailed Description. Treatment given to ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3627331/

Safety and efficacy of brentuximab vedotin in patients with ... In phase II studies, brentuximab vedotin induced overall response rates of 75% and 86% in relapsed or refractory Hodgkin lymphoma and anaplastic large cell ...