Chemoradiotherapy + Immunotherapy for Pediatric Lymphoma

(RADICAL Trial)

Recruiting at 4 trial locations

Overseen By Mitchell Cairo, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: New York Medical College

Disqualifiers: Primary mediastinal B-cell, T-cell/histiocyte-rich large B-cell, Gray zone, Follicular, 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

Compensation: Varies

Number of Visits: Unknown

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding immunotherapy to standard chemoradiotherapy can safely and effectively treat certain types of lymphoma in children and young adults. The study focuses on two types of lymphoma: mature B-cell non-Hodgkin lymphoma and classical Hodgkin lymphoma. Different groups within the trial receive specific drug combinations, such as Bv-AVD-R (including Brentuximab Vedotin, also known as Adcetris) and Bv-NVD-R (including Brentuximab Vedotin, Vinblastine, Dacarbazine, Nivolumab, and Rituximab), to determine which works best. Those recently diagnosed with these specific types of lymphoma and meeting certain disease stage criteria might be a good fit for this trial. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group, offering participants a chance to contribute to important advancements in lymphoma treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that the treatments tested in this trial, Bv-AVD-R and Bv-NVD-R, have promising safety records from past studies.

Bv-AVD-R combines brentuximab vedotin with other drugs. Previous studies found it effective and generally well-tolerated in both adults and children with Hodgkin lymphoma. The side effects are usually manageable and similar to those of other cancer treatments, such as low blood cell counts and tiredness.

Bv-NVD-R includes nivolumab, which helps the immune system fight cancer. Studies indicate this combination is also well-tolerated, with side effects similar to other treatments.

Overall, these treatments have undergone earlier research phases, demonstrating a reasonable level of safety for participants. The trial aims to further confirm these findings in young patients with lymphoma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pediatric lymphoma because they combine innovative chemoradiotherapy with immunotherapy. Unlike traditional treatments that often rely solely on chemotherapy, these regimens incorporate polatuzumab vedotin and nivolumab, which are designed to target cancer cells more precisely. Polatuzumab vedotin is an antibody-drug conjugate that delivers chemotherapy directly to cancer cells, reducing damage to healthy cells. Nivolumab, on the other hand, is an immune checkpoint inhibitor that helps the body's immune system recognize and attack cancer cells more effectively. This dual approach aims to enhance treatment effectiveness and potentially reduce side effects compared to standard therapies.

What evidence suggests that this trial's treatments could be effective for pediatric lymphoma?

This trial will evaluate different treatment combinations for pediatric lymphoma. Studies have shown that Brentuximab Vedotin (Bv) combined with chemotherapy effectively treats classical Hodgkin lymphoma, especially in children and teenagers. In this trial, some participants will receive the Bv-AVD-R regimen, which includes Bv with doxorubicin, vinblastine, and dacarbazine (AVD). The FDA has approved this regimen for use in children, confirming its effectiveness. Other participants will receive the Bv-NVD-R regimen, which combines Bv with Nivolumab, doxorubicin, and other drugs. This combination has shown promise in controlling the cancer for a longer time. These treatments aim to reduce the use of some aggressive drugs while still managing the disease effectively. ^{3 6 7 8 9}

Who Is on the Research Team?

Mitchell S Cairo, MD

Principal Investigator

New York Medical Center

Are You a Good Fit for This Trial?

This trial is for children, adolescents, and young adults with specific types of lymphoma (MB-NHL or cHL). Participants must have newly diagnosed disease according to WHO Classification, adequate organ function, and fall into certain risk categories based on the stage of their disease. Those with other forms of lymphoma like follicular or T-cell/histiocyte-rich large B-cell are not eligible.

Inclusion Criteria

My organs are functioning well.

I am in stage III with high LDH levels or in stage IV with 5-24% bone marrow lymphoma infiltration.

I have been diagnosed with a specific type of lymphoma.

Exclusion Criteria

I have been diagnosed with a type of lymphoma called nodular lymphocyte-predominant Hodgkin.

I have been diagnosed with follicular lymphoma.

I have been diagnosed with T-cell/histiocyte-rich large B-cell lymphoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Reduction Therapy

Participants receive reduction therapy with dexamethasone, vincristine, and cyclophosphamide (DOC) to assess tumor reduction.

4 weeks

Induction and Consolidation

Participants undergo induction and consolidation therapy with various combinations of polatuzumab vedotin, rituximab, and other chemotherapeutic agents based on cohort and response.

16-24 weeks

Maintenance

Participants receive maintenance therapy with cycles of chemotherapy and immunotherapy agents.

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment.

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Bv-AVD-R
• Bv-NVD-R
• Involved Site Radiation Therapy

Trial Overview The study tests if adding targeted immunotherapy to standard chemoradiotherapy can reduce anthracycline use while maintaining control over lymphoma in young patients. It involves various treatment groups receiving different combinations of chemotherapy drugs and immunotherapies.

How Is the Trial Designed?

Group I: Cohort 2b Experimental Treatment 4 Interventions

COHORT IIb (Classical Hodgkin lymphoma, HIGH RISK) Cohort IIb patients will receive 2 cycles of brentuximab vedotin (Bv), doxorubicin, vinblastine, dactinomycin, and rituximab (Bv-AVD-R 1 and 2). Response assessment will be performed with FDG-PET scan after 2 cycles of Bv-AVD-R. Rapid early responders (RER) will continue therapy with 4 cycles of Bv, vinblastine, dactinomycin, nivolumab, and rituximab (Bv-NVD-R 1, 2, 3, and 4). RERs will not receive radiation therapy. Patients deemed to be Slow Early Responders (SER) after 2 cycles of Bv-AVD-R will receive 2 cycles of Bv, nivolumab, doxorubicin, vinblastine, dactinomycin, and rituximab (Bv-NAVD-R 1 and 2), followed by 4 cycles of Bv, vinblastine, dactinomycin, nivolumab, and rituximab (Bv-NVD-R 1, 2, 3, and 4). Radiation therapy will be given at completion of therapy only for SER patients NOT achieving complete remission at the end of chemoimmunotherapy.

Group II: Cohort 2a Experimental Treatment 3 Interventions

Classical Hodgkin lymphoma, INTERMEDIATE RISK will receive 2 cycles of brentuximab vedotin (Bv), doxorubicin, vinblastine, dactinomycin, and rituximab (Bv-AVD-R 1 and 2). Response assessment with FDG-PET scan after 2 cycles of Bv-AVD-R. Rapid early responders (RER) will continue therapy with 2 cycles of Bv, vinblastine, dactinomycin, nivolumab, and rituximab (Bv-NVD-R 1 and 2). RERs will not receive radiation therapy. Patients deemed to be Slow Early Responders (SER) after 2 cycles of Bv-AVD-R will continue therapy with 4 cycles of Bv-NVD-R (Bv-NVD-R 1, 2, 3, and 4). Radiation therapy will be given at completion of therapy only for SER patients NOT achieving complete remission at the end of chemoimmunotherapy.

Group III: Cohort 1b Experimental Treatment 8 Interventions

MB NHL, GROUP C will receive reduction therapy with DOC. Patients with \< 20% tumor reduction will be off protocol. Patients with ≥ 20% tumor reduction get Induction 1 and 2 with cyclophosphamide, doxorubicin, dexamethasone, high dose methotrexate, polatuzumab vedotin, and triple intrathecal chemotherapy (M8A30D CPR) 1 and 2, then Consolidation 1 with Pv-R-CYVE 1. If no residual disease, they get Consolidation 2 (Pv-R-CYVE 2), followed by Maintenance (M) 1 with M8A30D CP, M 2 with Pv-cytarabine/etoposide, M 3 with cyclophosphamide, doxorubicin, dexamethasone and polatuzumab vedotin (A30D CP), and M 4 with Pv-cytarabine/etoposide. Cohort Ib patients with CNS disease will receive additional intrathecal chemotherapy and high dose methotrexate during Consolidation.

Group IV: Cohort 1a Experimental Treatment 3 Interventions

Mature B-cell Non-hodgkin Lymphoma \[MB NHL\], GROUP B will receive reduction therapy with dexamethasone, vincristine and cyclophosphamide (DOC), then undergo disease assessment. If tumor reduction ≥ 20%, will get induction 1 and 2 with polatuzumab vedotin, cyclophosphamide, vincristine, methotrexate, rituximab, doxorubicin (Pv-COM3RA25D) 1 and 2, then Consolidation 1 with rituximab, cytarabine, methotrexate (R-CYM) . Patients will undergo disease assessment post Consolidation 1. If no residual disease, they proceed to receive Consolidation 2 with Pv-R-CYM (R-CYM 2). Cohort Ia patients with \< 20% tumor reduction post DOC will be assigned to Cohort Ib starting at Induction 1. Cohort Ia patients with residual disease post Consolidation 1 will be assigned to Cohort Ib starting at Consolidation 1 polatuzumab vedotin, rituximab, high dose cytarabine, cytarabine, high dose methotrexate, etoposide (Pv-R-CYVE 1).

Bv-AVD-R is already approved in United States, European Union for the following indications:

Approved in United States as Adcetris for:

• Classical Hodgkin Lymphoma
• Systemic Anaplastic Large Cell Lymphoma
• Primary Cutaneous Anaplastic Large Cell Lymphoma
• CD30-expressing Peripheral T-cell Lymphomas

Approved in European Union as Adcetris for:

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

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

Published Research Related to This Trial

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 (BV) is an effective treatment for relapsed or refractory classical Hodgkin lymphoma, showing a 75% overall response rate and a median remission duration of 20 months in pivotal Phase II studies.

BV has a manageable safety profile, with peripheral neuropathy being the most significant side effect, which is mostly reversible, making it a preferred option for patients who have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of brentuximab vedotin in the treatment of relapsed or refractory Hodgkin lymphoma. Siddiqi, T., Thomas, SH., Chen, R.[2021]

In a study of 136 patients with relapsed/refractory Hodgkin lymphoma who were ineligible for autologous stem cell transplant, brentuximab vedotin (BV) showed a high overall response rate of 74%, indicating its effectiveness in this population.

The median progression-free survival (PFS) and overall survival (OS) were 15.1 months and 17.8 months, respectively, with peripheral neuropathy reported in 9.6% of patients, highlighting the treatment's safety profile in elderly or frail patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma who are Ineligible for autologous stem cell transplant: A Germany and United Kingdom retrospective study. Bröckelmann, PJ., Zagadailov, EA., Corman, SL., et al.[2019]

In a phase II study involving 30 patients aged 1 to 30 years with newly diagnosed classic Hodgkin's lymphoma, the combination of brentuximab vedotin, rituximab, and risk-adapted chemotherapy resulted in a 100% complete response rate and 100% event-free and overall survival rates after a median follow-up of 62 months.

The treatment was found to be safe, with only mild toxicities reported, such as grade III mucositis (3%) and peripheral neuropathy (6%), indicating a significant reduction in the need for more toxic chemotherapy and radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk-adapted chemoimmunotherapy using brentuximab vedotin and rituximab in children, adolescents, and young adults with newly diagnosed Hodgkin's lymphoma: a phase II, non-randomized controlled trial. Hochberg, J., Basso, J., Shi, Q., et al.[2022]

In a study of 34 patients with nonbulky stage I-II Hodgkin lymphoma, the combination of brentuximab vedotin (BV) and AVD resulted in a 100% overall response rate and a 97% complete response rate, with a 5-year progression-free survival of 91%.

The treatment showed an improved safety profile compared to traditional ABVD, with no cases of grade-4 neutropenia or neutropenic fever, and most adverse events were mild, primarily grade 1 peripheral neuropathy, indicating a potentially safer alternative for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin plus doxorubicin and dacarbazine in nonbulky limited-stage classical Hodgkin lymphoma. Abramson, JS., Bengston, E., Redd, R., et al.[2023]

Brentuximab vedotin (BV) has shown promising efficacy in treating refractory CD30+ non-Hodgkin lymphomas (NHL), as demonstrated in two cases where patients responded positively to BV-based regimens after failing multiple standard treatments.

Both patients, one with anaplastic large cell lymphoma and the other with diffuse large B-cell lymphoma, experienced significant responses to novel BV combinations, suggesting that these regimens are effective and have manageable side effects, warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Brentuximab Vedotin Combination Therapies Show Promising Activity in Highly Refractory CD30+ Non-Hodgkin Lymphoma: A Case Series and Review of the Literature. Delacruz, W., Setlik, R., Hassantoufighi, A., et al.[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 a study of 44 patients receiving concurrent brentuximab vedotin (BV) and radiation therapy (RT), 20% experienced new grade 2 or higher hematologic toxicity, particularly linked to higher radiation doses (median 35 Gy for those with toxicity).

The combination of BV and RT was generally well tolerated, with 57% of patients achieving local control and 23% remaining disease-free at last follow-up, suggesting it can be an effective treatment option for patients needing both local and systemic control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Concurrent Radiation Therapy With Brentuximab Vedotin in the Treatment of Lymphoma. Wu, SY., Fang, PQ., Wang, EB., et al.[2023]

Citations

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2. clinicaltrials.gov clinicaltrials.gov/study/NCT06201507?term=lymphoma%20AND%20children&viewType=Table&rank=7

BV-AVD-R Treatment Children Hodgkin's Lymphoma The goal of this clinical trial is to use modified Brentuximab Vedotin+doxorubicin+vinblastine+dacarbazine+Rituximab(BV-AVD-R) regimen in Chinese Classical ...

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FDA approves brentuximab vedotin in combination with ... FDA approves brentuximab vedotin in combination with chemotherapy for pediatric patients with classical Hodgkin lymphoma · FDA: Coronavirus ...

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Pediatric and Adolescent Hodgkin Lymphoma: Paving the ... Frontline clinical trials for pediatric and adolescent classic Hodgkin lymphomas before and after the introduction of novel immune-oncology ...

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HLHR13: Adcetris (Brentuximab Vedotin), Combination ... In other studies, this drug was effective in patients whose Hodgkin lymphoma returned after treatment. We thought it might also work well against high-risk ...

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FOR FIRST-LINE STAGE III/IV cHL ADULTS Discover ADCETRIS® (brentuximab vedotin)+AVD for adult patients with previously untreated cHL. See full Prescribing Information, including BOXED WARNING.

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Adcetris, INN-brentuximab vedotin - EMA ADCETRIS is indicated for adult patients with previously untreated CD30+ Stage III or IV Hodgkin lymphoma (HL) in combination with doxorubicin, vinblastine and ...

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Brentuximab vedotin plus AVD for Hodgkin lymphoma With longer follow-up of ECHELON-1, BV + AVD demonstrated a superior 6-year overall survival (OS) of 93.9% compared with 89.4% of the previous standard of care: ...

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Adcetris (Brentuximab Vedotin) The E-R safety dataset contained data from 26 pediatric patients with PK data aged 3 and older in Study AHOD1331 who were scheduled to receive 1.8 mg/kg IV ...