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

Trial Summary

What is the purpose of this trial?

To learn about the effects of brentuximab vedotin and pembrolizumab in combination with doxorubicin and dacarbazine when given to patients who have Stage II cHL with bulky mediastinal disease or advanced cHL (Stage III or IV) and who have not received treatment for the disease.

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.

What data supports the effectiveness of the drug combination Brentuximab Vedotin, Pembrolizumab, and Chemotherapy for Hodgkin's Lymphoma?

Research shows that Brentuximab Vedotin, when used with other chemotherapy drugs, has been effective in treating Hodgkin's Lymphoma, especially in patients who have not responded to standard treatments. In trials, it showed high response rates and significant tumor reduction in patients with relapsed Hodgkin's Lymphoma. ^{1 2 3 4 5}

Is the combination of Brentuximab Vedotin, Pembrolizumab, and Chemotherapy safe for humans?

Brentuximab Vedotin has been generally well tolerated in trials for Hodgkin lymphoma, with common side effects including peripheral neuropathy (nerve damage causing pain or numbness) and neutropenia (low white blood cell count). Rare but serious side effects like diabetic ketoacidosis (a serious diabetes complication) have been reported. The combination with chemotherapy drugs like doxorubicin and dacarbazine has shown manageable toxicity, but it is contraindicated with bleomycin due to lung toxicity. ^{1 2 3 6 7}

What makes the drug combination of Brentuximab, Pembrolizumab, and Chemotherapy unique for treating Hodgkin's Lymphoma?

This treatment combines Brentuximab Vedotin, which targets CD30-positive cancer cells, with Pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer, and traditional chemotherapy. This combination aims to enhance the effectiveness of treatment by using different mechanisms to target the cancer cells. ^{1 6 8 9 10}

Research Team

Hun Lee, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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 am 18 years old or older.

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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 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 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]

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 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]

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]

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]

References

1. 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]

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

Diabetic Ketoacidosis and Profound Insulin Resistance From Brentuximab Vedotin. [2023]

3. 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]

4. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of front-line treatments for advanced Hodgkin lymphoma: a systematic literature review. [2021]

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

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

6. England 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. [2023]

7. England pubmed.ncbi.nlm.nih.gov

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

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

Inhibition of MDR1 Overcomes Resistance to Brentuximab Vedotin in Hodgkin Lymphoma. [2021]

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

Cost-Effectiveness Analysis of Brentuximab Vedotin With Chemotherapy in Newly Diagnosed Stage III and IV Hodgkin Lymphoma. [2019]

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]