Brentuximab Vedotin + Chemotherapy for Hodgkin's Lymphoma

Recruiting at 13 trial locations

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Millennium Pharmaceuticals, Inc.

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Neuropathy, HIV, Hepatitis B/C, 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: 14

59 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use certain strong or moderate CYP3A4 inhibitors within 2 weeks before starting the trial treatment.

What data supports the effectiveness of the drug Brentuximab Vedotin plus chemotherapy for Hodgkin's Lymphoma?

Research shows that Brentuximab Vedotin, when combined with chemotherapy, has been effective in treating Hodgkin's Lymphoma, with high response rates in patients who have relapsed or have not responded to previous treatments. In trials, it has shown to prolong progression-free survival and reduce the risk of disease progression or death. ^{1 2 3 4 5}

Is Brentuximab Vedotin plus chemotherapy safe for treating Hodgkin's Lymphoma?

Brentuximab Vedotin combined with chemotherapy has been generally well tolerated in clinical trials for Hodgkin's Lymphoma, with common side effects including peripheral neuropathy (nerve damage causing tingling or numbness) and neutropenia (low white blood cell count). Most side effects were manageable with dose adjustments, but some patients experienced severe side effects like febrile neutropenia (fever with low white blood cell count) and one elderly patient died from neutropenic sepsis (a severe infection due to low white blood cell count). ^{1 2 5 6 7}

What makes the drug Brentuximab Vedotin unique for treating Hodgkin's Lymphoma?

Brentuximab Vedotin is unique because it is an antibody-drug conjugate that specifically targets CD30-positive cancer cells, which are common in Hodgkin's Lymphoma. It delivers a potent cytotoxic agent directly to these cells, leading to high response rates even in patients who have relapsed after other treatments. ^{1 4 5 8 9}

What is the purpose of this trial?

The purpose of this study is to assess the safety, tolerability, and anti-tumor activity, as well as confirm the recommended dose of brentuximab vedotin (ADCETRIS) in combination with a multiagent chemotherapy regimen, doxorubicin (Adriamycin), vinblastine, and dacarbazine, in pediatric participants with advanced stage newly diagnosed classical CD30+ Hodgkin Lymphoma (HL).

Research Team

Study Director

Principal Investigator

Takeda

Eligibility Criteria

This trial is for children with a new diagnosis of advanced stage Hodgkin Lymphoma, specifically stages III and IV. They should have CD30+ classical HL, not have received prior treatment, be relatively active (performance scores >=50), and have measurable disease by certain criteria. Their blood counts and kidney/liver functions must meet the study's standards.

Inclusion Criteria

My Hodgkin's lymphoma is in an advanced stage (Stage III or IV).

My Hodgkin's lymphoma is confirmed to be CD30 positive.

Your disease can be measured and seen on a scan using specific criteria.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive Brentuximab Vedotin 48 mg/m^2 in combination with doxorubicin, vinblastine, and dacarbazine to determine the recommended dose

6 months

Days 1 and 15 of each 28-day cycle

Phase 2 Treatment

Participants receive the recommended dose of Brentuximab Vedotin 48 mg/m^2 in combination with doxorubicin, vinblastine, and dacarbazine

6 months

Days 1 and 15 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 12 weeks for 12 months, then every 24 weeks

Treatment Details

Interventions

• Brentuximab vedotin
• Dacarbazine
• Doxorubicin
• Vinblastine

Trial Overview The trial is testing Brentuximab Vedotin combined with a chemotherapy regimen including Doxorubicin (Adriamycin), Vinblastine, and Dacarbazine in pediatric patients. It aims to determine the safety, tolerability, proper dosage, and effectiveness against tumors in these young participants.

Participant Groups

Group I: Phase 2: Brentuximab Vedotin 48 mg/m^2 + AVD Experimental Treatment 4 Interventions

Brentuximab vedotin 48 mg/m\^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m\^2, vinblastine 6 mg/m\^2, and dacarbazine 375 mg/m\^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.

Group II: Phase 1: Brentuximab Vedotin 48 mg/m^2 + AVD Experimental Treatment 4 Interventions

Brentuximab vedotin 48 mg/m\^2 (A), intravenous infusion, once on Days 1 and 15 of each 28-day cycle approximately 1 hour after administration of doxorubicin 25 mg/m\^2, vinblastine 6 mg/m\^2, and dacarbazine 375 mg/m\^2 (AVD), intravenous infusion, once on Days 1 and 15 of each 28-day cycle for up to 6 cycles.

Brentuximab vedotin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Adcetris for:

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

Approved in United States as Adcetris for:

• Classical Hodgkin lymphoma
• Systemic anaplastic large cell lymphoma
• Primary cutaneous anaplastic large cell lymphoma
• Mycosis fungoides

Approved in Canada as Adcetris for:

• Hodgkin lymphoma
• Systemic anaplastic large cell lymphoma

Approved in Japan as Adcetris for:

• Hodgkin lymphoma
• Anaplastic large cell lymphoma

Who Is Running the Clinical Trial?

Millennium Pharmaceuticals, Inc.

Lead Sponsor

Trials

406

Recruited

46,900+

Dr. Christophe Bianchi

Millennium Pharmaceuticals, Inc.

Chief Medical Officer since 2006

MD from University of Geneva

Dr. Deborah Dunsire

Millennium Pharmaceuticals, Inc.

Chief Executive Officer since 2005

MD from University of Witwatersrand

Takeda

Lead Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

Findings from Research

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 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 the phase III ECHELON-1 study involving 1,334 patients, older patients (aged ≥60) with classical Hodgkin lymphoma showed similar modified progression-free survival rates at 24 months when treated with brentuximab vedotin plus AVD (70.3%) compared to ABVD (71.4%).

While A+AVD demonstrated comparable efficacy to ABVD, it was associated with higher rates of grade 3/4 peripheral neuropathy (18% vs. 3%) and febrile neutropenia (37% vs. 17%), but lower rates of pulmonary toxicity, with no pulmonary-related deaths in the A+AVD group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Older patients (aged ≥60 years) with previously untreated advanced-stage classical Hodgkin lymphoma: a detailed analysis from the phase III ECHELON-1 study. Evens, AM., Connors, JM., Younes, A., et al.[2022]

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 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 phase 2 study of 34 patients with nonbulky stage I/II Hodgkin lymphoma, the combination of brentuximab vedotin and AVD (doxorubicin, vinblastine, dacarbazine) achieved a remarkable 100% complete response rate, with high progression-free survival (94%) and overall survival (97%) at a median follow-up of 38 months.

Despite the high efficacy, the treatment was associated with significant adverse effects, including high rates of peripheral sensory neuropathy (79%) and neutropenia (76%), leading to dose reductions in 38% of patients, suggesting that this regimen may not be suitable for early-stage patients with a favorable prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine for nonbulky limited-stage classical Hodgkin lymphoma. Abramson, JS., Arnason, JE., LaCasce, AS., et al.[2021]

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

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

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. Italy pubmed.ncbi.nlm.nih.gov

Older patients (aged ≥60 years) with previously untreated advanced-stage classical Hodgkin lymphoma: a detailed analysis from the phase III ECHELON-1 study. [2022]

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

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

5. 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]

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

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

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

Brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine for nonbulky limited-stage classical Hodgkin lymphoma. [2021]

8. 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]

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

Brentuximab vedotin in transplant-naive patients with relapsed or refractory hodgkin lymphoma: analysis of two phase I studies. [2021]