Combination Antibody Therapy for Large B-Cell Lymphoma

(PACIFIC Trial)

Overseen By Ranjit Nair

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anthracyclines, HAART

Disqualifiers: Uncontrolled hypertension, Diabetes, HIV, 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: 9

31 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of brentuximab vedotin and nivolumab alone and in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone in treating patients with untreated, stage I-IV primary mediastinal large B-cell lymphoma. Brentuximab vedotin is a monoclonal antibody, called brentuximab, linked to a toxic agent, called vedotin. Brentuximab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD30 receptors, and delivers vedotin to kill them. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Rituximab is a type of antibody therapy, which targets and attaches to the CD20 protein found on the surface of blood cells with cancer and some healthy blood cells. Chemotherapy drugs, such as cyclophosphamide, and doxorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells, or by stopping them from dividing. Prednisone is a steroid, a hormone (chemical messengers) with multiple roles, notably in the immune system and inflammation reduction. Steroids are poisonous to lymphocytes (white blood cells from which lymphomas develop). Giving brentuximab vedotin and nivolumab in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone may help to control the disease and be a less harmful regimen than standard chemotherapy in patients with primary mediastinal large B-cell lymphoma.

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, if you are on glucocorticoids, you must stop them before starting the trial.

What data supports the effectiveness of the drug combination for large B-cell lymphoma?

Research shows that rituximab, when combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), is highly effective in treating diffuse large B-cell lymphoma, improving survival rates compared to CHOP alone. ^{1 2 3 4 5}

What safety data exists for Brentuximab Vedotin in treating lymphoma?

Brentuximab Vedotin has been shown to increase the risk of certain side effects in lymphoma patients, including nerve damage, fever, nausea, vomiting, diarrhea, and hair loss. However, it was generally well tolerated in trials, with nerve damage being the most common side effect, and about half of those affected experienced complete recovery. ^{6 7 8 9 10}

What makes the combination antibody therapy for large B-cell lymphoma unique?

This treatment is unique because it combines multiple drugs, including Brentuximab Vedotin and Nivolumab, which are not typically part of the standard R-CHOP regimen for large B-cell lymphoma. Brentuximab Vedotin targets a specific protein on cancer cells, and Nivolumab helps the immune system attack cancer, offering a novel approach compared to traditional therapies. ^{1 2 4 11 12}

Research Team

Ranjit Nair

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults diagnosed with primary mediastinal large B-cell lymphoma (PMBL) who haven't been treated yet, except possibly a short course of steroids or limited-field radiotherapy. They must have measurable disease, be in stages I-IV (stage I tumors must be at least 5 cm), and have adequate organ function. Participants need to agree to use effective birth control and can't join if they're pregnant, have HIV with active viremia, hepatitis B or C viremia, other recent cancers, significant neuropathy, uncontrolled major diseases, or known allergies to the drugs tested.

Inclusion Criteria

My kidneys are functioning well enough, with a creatinine clearance of at least 30 ml/min.

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN or < 5 x ULN if hepatic metastases are present

I am willing to receive blood transfusions.

Exclusion Criteria

I do not have any severe health conditions that my doctor thinks could make the trial unsafe for me.

I have not had major surgery or unhealed wounds in the last 4 weeks.

I am allergic to specific cancer drugs like brentuximab vedotin or nivolumab.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Immune Lead-in

Participants receive 2 cycles of Brentuximab vedotin and Nivolumab (A-O) to assess initial response and safety

6 weeks

2 visits (in-person)

Combination Treatment

Participants receive A-O with R-CHP for cycles 3 and 4, followed by additional cycles based on response

12-24 weeks

4-8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months for 1 year, then every 4 months for 1 year

Treatment Details

Interventions

• Brentuximab Vedotin
• Cyclophosphamide
• Doxorubicin
• Nivolumab
• Prednisone
• Rituximab

Trial Overview The trial is testing brentuximab vedotin and nivolumab alone and combined with rituximab, cyclophosphamide, doxorubicin, and prednisone for treating PMBL. Brentuximab vedotin targets cancer cells specifically; nivolumab boosts the immune system's response against cancer; rituximab attaches to specific proteins on cancerous blood cells; chemotherapy aims to kill or stop the division of cancer cells; prednisone helps reduce inflammation.

Participant Groups

Group I: Treatment (brentuximab vedotin, nivolumab, R-CHP) Experimental Treatment 7 Interventions

Patient will receive an immune lead-in of 2 cycles of Brentuximab vedotin and Nivolumab (A-O) (cycles 1 and 2), which has an appropriate futility rules in place to close early if efficacy targets are not met. At cycle 3 and 4, patients will receive A-O with R-CHP. Patients who will have achieved complete response (CR) at PET/CT before cycle 5 will receive 2 more cycles of A-O-R-CHP (cycle 5 and 6) and A-O only for cycle 7 and 8. If these patients still present CR at PET/CT after cycle 8, they will have completed therapy and will be followed up. In case of stable disease or progressive disease at PET/CT after cycle 4, the patient will be taken off the trial. Patients who present further response but no CR, at PET/CT before cycle 5 will receive 4 more cycles A-O-R-CHP (cycles 5-8). If they reach CR at PET/CT after cycle 8, they will have completed therapy and will be followed up. All patients will receive a total of 8 cycles of A-O. The cycle duration is 21 days.

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+

Findings from Research

Rituximab (RTX) is a widely used monoclonal antibody for treating diffuse large B-cell lymphoma, often combined with other drugs in the R-CHOP regimen, but some patients experience suboptimal responses or resistance.

New developments in CD20-targeting monoclonal antibodies, including second- and third-generation agents like ofatumumab and obinutumumab, are being actively researched to improve treatment outcomes for B-cell non-Hodgkin's lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel CD20 monoclonal antibodies for lymphoma therapy. Cang, S., Mukhi, N., Wang, K., et al.[2022]

In a randomized trial involving 399 elderly patients with diffuse large-B-cell lymphoma, the addition of rituximab to the standard CHOP chemotherapy significantly increased the complete response rate from 63% to 76%.

Patients receiving CHOP plus rituximab experienced significantly better event-free and overall survival rates compared to those receiving CHOP alone, without a notable increase in treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. Coiffier, B., Lepage, E., Briere, J., et al.[2022]

In a study of 18 elderly patients with non-Hodgkin's lymphoma, the combination of rituximab and CHOP showed a high response rate of 91%, indicating its potential effectiveness as a treatment option.

While the overall survival and disease-free survival rates were slightly better in the rituximab plus CHOP group (91%) compared to CHOP alone (83% overall survival), the differences were not statistically significant, suggesting that further research is needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of rituximab in combination with conventional chemotherapy for the treatment of non-Hodgkin's lymphoma of the head and neck. Manolopoulos, L., Gomatos, IP., Leandros, E., et al.[2015]

Rituximab is the first monoclonal antibody approved for treating B-cell lymphomas, showing significant effectiveness in conditions like follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma.

The combination of rituximab with standard chemotherapy agents (cyclophosphamide, doxorubicin, vincristine, and prednisone) has achieved the highest efficacy reported for treating diffuse large B-cell lymphoma and follicular lymphoma, while maintaining low toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. Traullé, C., Coiffier, BB.[2015]

The CHOEA-7 chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine, etoposide, and ara-C, has shown excellent results in treating patients with CD 20-positive non-Hodgkin's lymphoma.

Adding rituximab to the CHOEA-7 regimen (RCHOEA-7) further enhances treatment efficacy, indicating a promising approach for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. Uzuka, Y., Saitou, Y., Saitou, K., et al.[2015]

In a review of 2225 lymphoma patients from 4 randomized controlled trials, brentuximab vedotin was found to significantly increase the risk of all-grade adverse events (AEs) and high-grade AEs compared to non-brentuximab vedotin treatments.

Specific AEs associated with brentuximab vedotin included a higher risk of peripheral sensory neuropathy, pyrexia, nausea, vomiting, diarrhea, and alopecia, with particularly high risks for high-grade sensory neuropathy and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of adverse events in lymphoma patients treated with brentuximab vedotin: a systematic review and meta-analysis. Gao, S., Zhang, M., Wu, K., 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]

Brentuximab vedotin is an antibody-drug conjugate that combines an anti-CD30 antibody with a powerful cytotoxic agent, showing promise in treating Hodgkin lymphoma and anaplastic large cell lymphoma.

The drug is currently under investigation in North America and Europe, highlighting its potential as a targeted therapy for specific types of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin. [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 targeted therapy for relapsed or refractory systemic anaplastic large cell lymphoma (ALCL), showing high response rates in patients who have not responded to previous chemotherapy treatments.

The treatment is associated with manageable side effects, primarily myelosuppression and peripheral neuropathy, making it a viable option for patients with CD30(+) lymphomas like ALCL and Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin in anaplastic large cell lymphoma. Skarbnik, AP., Smith, MR.[2019]

The combination of bendamustine and rituximab showed promising therapeutic efficacy in treating lymphoproliferative diseases, achieving an overall response rate of 65% in chronic lymphocytic leukemia (CLL) and 96% in indolent lymphoma among 71 patients studied.

However, the treatment was associated with significant hematotoxicity, with severe neutropenia and thrombocytopenia occurring in 33% and 18% of patients, respectively, and a notable risk of severe infections in aggressive lymphoma and CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Routine use of bendamustine and rituximab combination therapy in consecutive patients with lymphoproliferative diseases: a survey from Tyrolean hospitals. Waldthaler, C., Stauder, R., Schnallinger, M., et al.[2021]

Ad35K++ is a newly developed recombinant protein that safely depletes CD46 from the surface of tumor cells, enhancing the effectiveness of rituximab in treating CD20-positive B-cell malignancies, as shown in preclinical studies with mice and nonhuman primates.

The treatment regimen using Ad35K++ not only increased the killing of tumor cells by rituximab but also allowed for the measurement of shed serum CD46 as a potential biomarker to monitor treatment efficacy in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic. Richter, M., Yumul, R., Saydaminova, K., et al.[2020]

References

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

Novel CD20 monoclonal antibodies for lymphoma therapy. [2022]

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

CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. [2022]

3. Greece pubmed.ncbi.nlm.nih.gov

Use of rituximab in combination with conventional chemotherapy for the treatment of non-Hodgkin's lymphoma of the head and neck. [2015]

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

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. [2015]

5. Japan pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. [2015]

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

Risk of adverse events in lymphoma patients treated with brentuximab vedotin: a systematic review and meta-analysis. [2021]

7. 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]

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

Brentuximab vedotin. [2021]

9. 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]

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

Brentuximab vedotin in anaplastic large cell lymphoma. [2019]

11. Austria pubmed.ncbi.nlm.nih.gov

Routine use of bendamustine and rituximab combination therapy in consecutive patients with lymphoproliferative diseases: a survey from Tyrolean hospitals. [2021]

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

Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic. [2020]