Pembrolizumab + Brentuximab for T-Cell Lymphoma

Recruiting at 1 trial location

Overseen By Stephanie Ladd, BS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: HIV, Hepatitis B, Hepatitis C, 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: 35 cycles

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single arm, open label, multicenter study phase 2 study of pembrolizumab and brentuximab in subjects with relapsed/refractory CD30 positive T-cell lymphoma (including peripheral T-cell lymphoma and cutaneous T-cell lymphoma) who have received at least one prior therapy. We hypothesize that this combination is effective and will produce an overall response rate of \~55%. Pembrolizumab and brentuximab will be administered for 16 cycles in subjects with responsive disease. Pembrolizumab will be continued for an additional 19 cycles (total 35 cycles). Response assessments will occur at pre-specified intervals. For the primary endpoint the response assessment after 3 cycles will be taken into consideration. Dose adjustments for specific toxicities with either drug are detailed in the protocol. Based on statistical analysis 32 subjects will need to be accrued to evaluate for disease response based on historical control.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, it allows the concurrent use of certain medications like bexarotene or vorinostat for CTCL if the dose has been stable for 8 weeks before starting the trial. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Pembrolizumab + Brentuximab for T-Cell Lymphoma?

Research shows that Brentuximab vedotin, one of the drugs in the treatment, has been effective in improving response rates and quality of life in patients with certain types of T-cell lymphomas, such as cutaneous T-cell lymphoma, when compared to standard therapies. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and Brentuximab safe for humans?

Brentuximab vedotin has shown an acceptable safety profile in patients with certain types of lymphoma, and Pembrolizumab is generally safe but can rarely cause type 1 diabetes in 0.2% of cases. Both drugs have been studied separately and have demonstrated safety in humans for various conditions. ^{2 3 6 7 8}

What makes the drug Pembrolizumab + Brentuximab unique for T-Cell Lymphoma?

This drug combination is unique because it combines Pembrolizumab, an immunotherapy that helps the immune system attack cancer cells, with Brentuximab vedotin, a targeted therapy that specifically attacks CD30-positive cancer cells, offering a novel approach for treating T-cell lymphomas. ^{3 4 5 7 9}

Research Team

Tarsheen Sethi

Principal Investigator

Yale University

Eligibility Criteria

Adults with a confirmed diagnosis of T-cell Non-Hodgkin lymphoma, including various subtypes like PTCL and CTCL, who have CD30 positive cells and have failed at least one prior therapy. Participants must be over 18, not pregnant or breastfeeding, willing to use contraception, and have good organ function. Exclusions include those with certain other health conditions or treatments that could interfere with the trial.

Inclusion Criteria

I have a lymphoma with a detectable tumor larger than 1.5 cm.

Participant provides written informed consent for the trial

I am fully active or can carry out light work.

Exclusion Criteria

I am currently fighting an infection that needs treatment.

Known psychiatric or substance abuse disorders

History or current evidence of conditions that might interfere with the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive up to 16 cycles of brentuximab and pembrolizumab, followed by up to 19 additional cycles of pembrolizumab monotherapy

35 cycles

Response Assessment

Response assessments occur at pre-specified intervals, with primary response assessment after 3 cycles

63 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Brentuximab vedotin
• Pembrolizumab

Trial Overview The study is testing the combination of Pembrolizumab and Brentuximab Vedotin in patients with relapsed/refractory T-cell lymphoma. It's an open-label phase 2 trial where both drugs are given for up to 16 cycles if effective; Pembrolizumab may continue for a total of 35 cycles. The goal is to see if this combo can achieve around a 65% overall response rate.

Participant Groups

Group I: Brentuximab vedotin (brentuximab) and pembrolizumab Experimental Treatment 2 Interventions

All subjects are scheduled to receive up to 16 cycles of combinatorial treatment with brentuximab + pembrolizumab, followed by up to 19 additional cycles of pembrolizumab monotherapy. After receiving 35 total doses of pembrolizumab (i.e. scheduled for 16 doses in the combinatorial setting and 8 doses as monotherapy), a subject's pembrolizumab treatment will be complete.

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?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Sethi

Lead Sponsor

Trials

2

Recruited

70+

Tarsheen Sethi

Lead Sponsor

Trials

2

Recruited

70+

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

Brentuximab vedotin significantly reduced symptom burden in patients with CD30-expressing cutaneous T-cell lymphoma compared to physician's choice treatments, with a mean maximum reduction in symptom scores of -27.96 versus -8.62, exceeding the minimally important difference.

Quality of life measures, including FACT-G and EQ-5D scores, remained comparable between brentuximab vedotin and physician's choice, indicating that the treatment did not adversely affect patients' overall well-being, even in those experiencing peripheral neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported quality of life in patients with relapsed/refractory cutaneous T-cell lymphoma: Results from the randomised phase III ALCANZA study. Dummer, R., Prince, HM., Whittaker, S., et al.[2020]

In a phase 3 trial involving 131 patients with CD30-positive cutaneous T-cell lymphomas, brentuximab vedotin demonstrated a significantly higher objective response rate lasting at least 4 months (56.3%) compared to conventional therapies (12.5%), indicating its superior efficacy.

While brentuximab vedotin was associated with a higher incidence of peripheral neuropathy (67% of patients), the overall safety profile was comparable to conventional therapies, with similar rates of grade 3-4 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Prince, HM., Kim, YH., Horwitz, SM., et al.[2019]

In the international phase III ALCANZA trial, brentuximab vedotin, a CD30-directed antibody-drug conjugate, showed significantly better clinical responses in patients with cutaneous T-cell lymphomas compared to standard treatments like methotrexate or bexarotene.

This study highlights the efficacy of brentuximab vedotin as a more effective treatment option for patients with this type of lymphoma, suggesting a promising advancement in targeted cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab Beats Standard Therapies for CTCL. [2019]

The ECHELON-2 trial demonstrated that the combination of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone (A+CHP) significantly improved progression-free survival in patients with CD30-positive peripheral T-cell lymphomas, with a median of 48.2 months compared to 20.8 months for the standard CHOP regimen.

The safety profile of A+CHP was manageable, with similar rates of adverse events like febrile neutropenia and peripheral neuropathy compared to CHOP, indicating that A+CHP is a viable and effective front-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Horwitz, S., O'Connor, OA., Pro, B., et al.[2022]

A phase 2 study demonstrated promising efficacy of brentuximab vedotin, an antibody-drug conjugate, in treating patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

The results suggest that BV could be a valuable treatment option for patients who have not responded to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time has come for immunotherapy in PTCL. Bachy, E., Coiffier, B.[2021]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Brentuximab vedotin, an antibody-drug conjugate, does not cause significant prolongation of the QT/QTc interval, indicating a favorable cardiac safety profile in patients with CD30-positive hematologic malignancies.

In a phase 1 study involving 52 patients, brentuximab vedotin was well tolerated, with no clinically meaningful changes in cardiac repolarization and a response rate consistent with previous trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies. Han, TH., Chen, R., Advani, R., et al.[2021]

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]

Brentuximab vedotin (BV) is an effective targeted therapy for CD30-positive primary cutaneous T-cell lymphoma (CTCL), showing response rates over 75% in clinical trials, including a Phase III trial that demonstrated significant improvements compared to standard treatments.

While BV is associated with manageable adverse effects, including frequent peripheral neuropathy, it does not increase the risk of severe adverse effects, making it a promising option for patients with refractory CTCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin therapy for CD30-positive cutaneous T-cell lymphoma: a targeted approach to management. Scarisbrick, JJ.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Patient-reported quality of life in patients with relapsed/refractory cutaneous T-cell lymphoma: Results from the randomised phase III ALCANZA study. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. [2019]

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

Brentuximab Beats Standard Therapies for CTCL. [2019]

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

Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. [2022]

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

Time has come for immunotherapy in PTCL. [2021]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies. [2021]

8. 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]

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

Brentuximab vedotin therapy for CD30-positive cutaneous T-cell lymphoma: a targeted approach to management. [2019]