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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of antibody therapies and chemotherapy for treating primary mediastinal large B-cell lymphoma, a type of blood cancer. The study evaluates the effectiveness of brentuximab vedotin (an antibody-drug conjugate) and nivolumab (an immunotherapy drug), both alone and with other drugs like rituximab and prednisone, in controlling the disease. These treatments aim to target cancer cells and boost the immune system while potentially being less harsh than traditional chemotherapy. The trial seeks participants who have not received prior treatment for this cancer and have a tumor showing at least 1% of the CD30 protein. Participants should have a tumor size of at least 5 cm and meet other specific health requirements. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in cancer therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that the combination of brentuximab vedotin and nivolumab has a manageable safety profile, with most participants tolerating it well and experiencing expected, non-severe side effects. No new safety issues emerged, even after three years of follow-up.

Research indicates that the R-CHP regimen, which includes rituximab, cyclophosphamide, doxorubicin, and prednisone, is generally well-tolerated. Rituximab targets cancer cells, while the other drugs help stop cancer growth. These treatments have been used in other cancer therapies, and their safety is well-documented.

Overall, available evidence suggests that both treatment combinations have been safe for most patients in previous studies. However, as with any treatment, individual reactions may vary. It is important to consult a healthcare provider to understand what these findings might mean for individual circumstances. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Brentuximab vedotin combined with nivolumab, cyclophosphamide, doxorubicin, prednisone, and rituximab is unique because it pairs targeted antibody therapy with immune checkpoint inhibition, offering a dual approach to fighting large B-cell lymphoma. While traditional treatments like R-CHOP focus on chemotherapy and the CD20-targeting rituximab, this combination also includes brentuximab vedotin, which targets CD30 on lymphoma cells, and nivolumab, which unleashes the immune system to attack cancer by blocking the PD-1 pathway. Researchers are excited because this novel combination could enhance treatment effectiveness and improve patient outcomes by tackling the cancer from multiple angles simultaneously.

What evidence suggests that this trial's treatments could be effective for large B-cell lymphoma?

This trial will evaluate a combination treatment for large B-cell lymphoma. Participants will receive brentuximab vedotin and nivolumab, which studies have shown attach to specific parts of cancer cells and help the immune system attack and stop cancer cells from growing. The trial will also include rituximab, which targets other parts of cancer cells, in combination with chemotherapy drugs like cyclophosphamide and doxorubicin. Rituximab has been effective in stopping cancer cell growth when used with these chemotherapy drugs. Prednisone, a steroid included in the trial, helps reduce swelling and can harm certain cancer cells. Early findings suggest this combination could be a strong treatment for primary mediastinal large B-cell lymphoma. ^{5 6 7 8 9}

Who Is on the Research Team?

Ranjit Nair

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS7589

Brentuximab vedotin and nivolumab alone and then ... We are conducting a phase II, open-label, single-center clinical trial combining BV-Nivolumab alone and then combined with rituximab, cyclophosphamide, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04745949

NCT04745949 | PACIFIC: Primary Mediastinal Large B-cell ... Giving brentuximab vedotin and nivolumab in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone may help to control the disease and be a ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8168499/

Brentuximab vedotin in combination with rituximab ... We conducted a phase I/II multicenter trial using six cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and ...

4. journals.lww.com journals.lww.com/hemasphere/fulltext/2022/06003/p1222__pacific__brentuximab_vedotin_and_nivolumab.1108.aspx

p1222: pacific: brentuximab vedotin and nivolumab alone ... We aim to evaluate the efficacy, safety, and quality of life of PMBL patients treated in the PACIFIC trial with BV and Nivolumab alone and then combined with ...

5. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2020-0686.html

A Phase II Study to Determine the Response Kinetics ... This phase II trial studies the effect of brentuximab vedotin and nivolumab alone and in combination with rituximab, cyclophosphamide, doxorubicin, and ...

6. ashpublications.org ashpublications.org/bloodadvances/article/7/18/5272/496496/Nivolumab-combined-with-brentuximab-vedotin-for-R

Nivolumab combined with brentuximab vedotin for R/R ... Nivolumab + BV showed durable safety and efficacy as salvage in patients with R/R PMBL after 3-year follow-up, with no new safety signals.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8619646/

Efficacy and safety of nivolumab combined with ... The aim of this study was to evaluate the efficacy and safety of the combination of nivolumab with brentuximab vedotin (Nivo + BV) after nivolumab monotherapy ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6864847/

Efficacy and Safety From the Phase II CheckMate 436 Study In patients with R/R PMBL, the combination of nivolumab plus BV represents a promising option, with high antitumor activity and a manageable safety profile.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT02572167

NCT02572167 | A Study of Brentuximab Vedotin ... The purpose of this study is to assess the safety profile and antitumor activity of brentuximab vedotin administered in combination with nivolumab in ...