Pembrolizumab-Based Therapy for Hodgkin's Lymphoma

Recruiting at 2 trial locations

Overseen By Nino Mchedlishvili

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Virginia

Must not be taking: Strong CYP3A4 modulators

Disqualifiers: Nodular lymphoma, Autoimmune disease, 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: 8

44 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multi-center, open-label phase II study to assess the efficacy of a novel fitness-adapted regimen in previously untreated older patients with classical Hodgkin lymphoma. All participants will receive up to a total of 8 cycles of pembrolizumab (Q6 week dosing). The first cycle of pembrolizumab will be administered in combination with brentuximab vedotin (BV) ("lead-in treatment"). Following lead-in treatment, all participants will undergo interim PET/CT (iPET) as well as fitness testing to help inform participant level of fitness for subsequent lymphoma-directed therapies. Participants deemed "Frail" by this assessment will continue 3 additional 6 week cycles of concurrent pembrolizumab and BV ("induction therapy", each cycle is 42 days), then continue single-agent pembrolizumab to complete up to 4 additional cycles (i.e., 8 total) of therapy ("consolidation and maintenance therapy", Frail cohort). Two additional BV doses will be given as consolidation, at days 1 and 22 of pembrolizumab cycle 5. Those deemed "fit" after lead-in therapy (Fit cohort) will continue pembrolizumab and switch from BV to concurrently-administered combination chemotherapy using doxorubicin (A), vinblastine (V), and dacarbazine (D) for a total of 4 planned AVD cycles (3, 6-week pembrolizumab cycles, "induction therapy"). Chemotherapy drugs will be given at standard doses as in ABVD (no bleomycin will be given in this study) on days 1 and 15 of each 28-day cycle (C1AVD), and pembrolizumab dosing will remain every 42 days. Following end-induction PET/CT, pembrolizumab will continue every 42 days for up to 4 cycles in the consolidation/maintenance phase. Two additional BV doses will be given as consolidation, at days 1 and 22 of pembrolizumab cycle 5. Participants deemed "unfit" after lead-in therapy and by fitness assessment will continue pembrolizumab and switch from BV to concurrently administered combination chemotherapy termed "mini-avd" as induction therapy. Mini-avd consists of lower doses of conventional AVD chemotherapy (doxorubicin, vinblastine and dacarbazine) and will be administered for on days 1 and 15 of a 28 day cycle for 4 planned cycles. Pembrolizumab will continue every 42 days. Following end-induction PET/CT, pembrolizumab will continue every 42 days for up to 4 cycles in the consolidation/maintenance phase. Two additional BV doses will be given as consolidation, at days 1 and 22 of pembrolizumab cycle 5.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are taking a strong CYP3A4 modulator, you will need to stop it and complete a washout period (time without taking the medication) of 4 weeks or 5 times the half-life of the drug, whichever is shorter.

What data supports the effectiveness of the drug Pembrolizumab-Based Therapy for Hodgkin's Lymphoma?

Research shows that combining brentuximab vedotin with pembrolizumab can lead to a significant and lasting response in patients with relapsed or hard-to-treat Hodgkin's lymphoma, even when other treatments have failed. ^{1 2 3 4 5}

Is Pembrolizumab-based therapy for Hodgkin's Lymphoma safe?

Pembrolizumab and brentuximab vedotin, used in treating Hodgkin's Lymphoma, are generally well tolerated. Common side effects include peripheral neuropathy (nerve damage causing tingling or numbness) for brentuximab vedotin and immune-related side effects for pembrolizumab, which can vary and include skin rash and lung issues. ^{1 2 4 6 7}

What makes the Pembrolizumab-based therapy unique for treating Hodgkin's Lymphoma?

This treatment combines pembrolizumab, an immune checkpoint inhibitor, with other drugs like brentuximab vedotin, offering a novel approach for patients with relapsed or refractory Hodgkin's Lymphoma who have not responded to multiple therapies. It has shown promising results in achieving prolonged remission in heavily pretreated patients. ^{5 8 9 10 11}

Eligibility Criteria

This trial is for people over 60 with untreated classical Hodgkin lymphoma. They should be able to perform daily activities (ECOG status 0-2), have good organ function, and measurable disease. Prior radiation is okay under certain conditions, but no prior immune checkpoint inhibitors or systemic therapy for lymphoma except steroids.

Inclusion Criteria

I can care for myself but might not be fully active due to my lymphoma.

I am 60 years old or older.

The participant must be willing and able to provide written informed consent for the trial and participate in all planned study procedures

Exclusion Criteria

I have an immune system disorder or have been on high-dose steroids or other immune-weakening medicines recently.

I have an active tuberculosis infection.

I have or had hepatitis B or C, but if B, I'm not currently infectious.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in Treatment

Participants receive the first cycle of pembrolizumab in combination with brentuximab vedotin (BV)

6 weeks

1 visit (in-person)

Induction Therapy

Participants receive pembrolizumab with either BV, AVD, or mini-AVD based on fitness assessment

18 weeks

3 visits (in-person)

Consolidation and Maintenance Therapy

Participants continue pembrolizumab for up to 4 additional cycles, with additional BV doses for consolidation

24 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Brentuximab vedotin
• Dacarbazine
• Doxorubicin
• Pembrolizumab
• Vinblastine

Trial Overview The study tests a pembrolizumab-based treatment combined with brentuximab vedotin (BV) or chemotherapy drugs doxorubicin, vinblastine, and dacarbazine (AVD). Participants are assessed for fitness after initial treatment to determine their subsequent therapy path in this phase II trial.

Participant Groups

Group I: Fit Cohort Experimental Treatment 5 Interventions

Three 6-week cycles of 400 mg intravenous pembrolizumab + intravenous AVD (q 2 weeks).

Group II: Frail Cohort Active Control 5 Interventions

Three 6-week cycles of 400 mg intravenous pembrolizumab and concurrent (q 3 week) intravenous brentuximab vedotin (BV).

Group III: Unfit Cohort Active Control 5 Interventions

Three 6-week cycles of 400 mg intravenous pembrolizumab and mini-AVD (q 2 weeks).

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?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

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]

In the ECHELON-1 study involving 1334 patients with stage III or IV classical Hodgkin lymphoma, the A+AVD treatment (brentuximab vedotin combined with standard chemotherapy) demonstrated a significantly better 5-year progression-free survival rate of 82.2% compared to 75.3% for the ABVD treatment, indicating its superior efficacy.

The safety profile of A+AVD was consistent, with fewer secondary malignancies reported compared to ABVD, and while more patients experienced ongoing peripheral neuropathy with A+AVD, the condition improved over time, suggesting a manageable side effect profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Straus, DJ., Długosz-Danecka, M., Connors, JM., et al.[2022]

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]

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]

A patient with relapsed/refractory Hodgkin's lymphoma showed a remarkable and durable response to the combination of brentuximab-vedotin and pembrolizumab, even after failing multiple previous treatments.

This case highlights the potential of combining novel agents like BV and immune checkpoint inhibitors to improve treatment outcomes in difficult-to-treat Hodgkin's lymphoma, suggesting further research is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged Remission by Pembrolizumab and Brentuximab-Vedotin Combination Therapy in Heavily-Pretreated Relapsed/Refractory Hodgkin's Lymphoma. Yu, TY., Dai, MS.[2020]

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, 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 patients with relapsed and refractory classical Hodgkin's lymphoma who have previously failed treatment with brentuximab vedotin, pembrolizumab significantly improves progression-free survival (PFS) compared to standard of care, with hazard ratios indicating a much lower risk of disease progression.

The study involved a systematic literature review and comparisons of outcomes from pembrolizumab's KEYNOTE-087 trial against an observational study of standard care, confirming that pembrolizumab is a more effective treatment option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus the standard of care for relapsed and refractory classical Hodgkin's lymphoma progressing after brentuximab vedotin: an indirect treatment comparison. Keeping, S., Wu, E., Chan, K., et al.[2019]

Brentuximab vedotin (BV) and immune checkpoint inhibitors (CPIs) like nivolumab and pembrolizumab show promising efficacy when added to standard chemotherapy for advanced classical Hodgkin lymphoma (cHL), indicating their potential in frontline treatment.

Pembrolizumab has demonstrated superior effectiveness over BV in treating relapsed/refractory classical Hodgkin lymphoma (RRHL) in patients who have either relapsed after autologous stem cell transplant (ASCT) or are ineligible for ASCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequencing novel agents in the treatment of classical hodgkin lymphoma. Ferhanoglu, B., Ozbalak, M.[2023]

In a phase 3 study involving 304 patients with relapsed or refractory classical Hodgkin lymphoma, pembrolizumab demonstrated a median progression-free survival of 13.2 months, significantly longer than the 8.3 months observed with brentuximab vedotin, indicating its superior efficacy.

While both treatments had associated adverse events, pembrolizumab's safety profile was consistent with previous studies, with serious treatment-related events occurring in 16% of patients, supporting its use as a preferred option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. Kuruvilla, J., Ramchandren, R., Santoro, A., et al.[2021]

In a phase II study involving 210 patients with relapsed or refractory classic Hodgkin lymphoma, pembrolizumab showed a high overall response rate of 69%, indicating its effectiveness as a treatment option.

The safety profile of pembrolizumab was consistent with previous studies, suggesting it is a well-tolerated therapy for patients with this challenging form of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. Chen, R., Zinzani, PL., Fanale, MA., et al.[2022]

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. England pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. [2022]

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. 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]

5. Canada pubmed.ncbi.nlm.nih.gov

Prolonged Remission by Pembrolizumab and Brentuximab-Vedotin Combination Therapy in Heavily-Pretreated Relapsed/Refractory Hodgkin's Lymphoma. [2020]

6. 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]

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

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

8. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus the standard of care for relapsed and refractory classical Hodgkin's lymphoma progressing after brentuximab vedotin: an indirect treatment comparison. [2019]

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

Sequencing novel agents in the treatment of classical hodgkin lymphoma. [2023]

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

Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. [2021]

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

Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. [2022]