Immunotherapy + Chemotherapy for Lymphoma

Overseen By Stephen Smith

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Washington

Must not be taking: Systemic corticosteroids, Anti-PD-1/PD-L1

Disqualifiers: Immunodeficiency, CNS metastases, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 9

35 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with untreated diffuse large B-cell lymphoma. It seeks to determine if adding immunotherapy drugs, which help the immune system attack cancer cells, to standard chemotherapy can more effectively kill cancer cells. Participants receive various combinations of these treatments, including Retifanlimab, an immunotherapy drug. This trial suits those diagnosed with diffuse large B-cell lymphoma or similar conditions who have not yet received treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop taking my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on systemic corticosteroids above 10 mg/day of prednisone or equivalent, you may need to adjust your dosage. It's best to discuss your current medications with the trial team.

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

Research has shown that tafasitamab, retifanlimab, and rituximab are under study for their safety in treating diffuse large B-cell lymphoma. Tafasitamab can cause serious side effects, with 26% of patients experiencing infections, including pneumonia in 7%. Retifanlimab is typically used for skin cancer, but its safety in children remains unclear. Rituximab, when combined with hyaluronidase human, carries several safety warnings.

The chemotherapy drugs cyclophosphamide, doxorubicin, vincristine, and prednisone have a long history of use. Cyclophosphamide is effective against many cancers but can also be carcinogenic. Doxorubicin can cause severe tissue damage if it leaks during injection. Vincristine may also cause tissue damage if it leaks from the vein, and prednisone can weaken the immune system, increasing infection risk.

This trial is in its early stages, focusing mainly on safety. Although these drugs have known side effects, their common use in cancer treatment suggests a level of expected tolerance. However, close monitoring for side effects remains crucial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination of immunotherapy and chemotherapy for lymphoma because it introduces innovative elements not seen in traditional treatments. Unlike standard therapies that often rely solely on chemotherapy drugs like CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), this treatment incorporates novel immunotherapy agents such as tafasitamab and retifanlimab. Tafasitamab is an antibody that targets CD19 on B-cells, enhancing the immune system's ability to attack cancer cells, while retifanlimab is a PD-1 inhibitor that helps the immune system recognize and destroy cancer cells more effectively. These additions aim to improve the efficacy of treatment and potentially lead to better outcomes for patients with lymphoma.

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

Research has shown that combining the drugs tafasitamab, retifanlimab, and rituximab may help treat diffuse large B-cell lymphoma. Studies have found that tafasitamab, when used with another drug, led to a high rate of positive responses and long-term benefits for patients with this type of cancer. Retifanlimab has demonstrated a strong ability to stop cancer growth. Rituximab effectively targets B-cells, which are often involved in lymphoma. When combined with standard chemotherapy, these three drugs might better destroy cancer cells and improve patient outcomes. ^{6 7 8 9 10}

Who Is on the Research Team?

Stephen Smith

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

Adults with untreated diffuse large B-cell lymphoma or grade 3B follicular lymphoma, who have not received prior therapy for lymphoma. Participants must have adequate organ function, no severe allergies to monoclonal antibodies, and agree to use contraception. Excluded are those with certain infections (HIV, Hepatitis B/C), active central nervous system metastases, other progressing cancers requiring treatment, or conditions that could interfere with the trial.

Inclusion Criteria

My heart pumps blood effectively.

I can take care of myself and am up and about more than half of my waking hours.

Be willing and able to provide written informed consent/assent for the trial

Exclusion Criteria

Currently participating in another study with investigational agents or devices

I have had an organ transplant.

I am on high doses of steroids, with some exceptions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Prephase Therapy

Patients receive tafasitamab, rituximab, and retifanlimab as a prephase treatment

6 weeks

3 visits (in-person) per cycle

Combination Therapy

Patients receive TRR in combination with CHOP or PolaCHP

12-18 weeks

1 visit (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Visits at 4-6 weeks, 12 weeks, then per routine care

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Doxorubicin
• Prednisone
• Retifanlimab
• Rituximab and Hyaluronidase Human
• Tafasitamab
• Vincristine

Trial Overview The trial is testing a combination of three monoclonal antibodies (tafasitamab, retifanlimab, rituximab) as prephase treatment along with standard CHOP chemotherapy in patients with diffuse large B-cell lymphoma. The goal is to see if this combination can more effectively kill cancer cells than current treatments.

How Is the Trial Designed?

Group I: Treatment (TRR, CHOP) Experimental Treatment 15 Interventions

PREPHASE THERAPY: Patients receive tafasitamab IV over 30 minutes on days 1, 8, and 15 of each cycle, rituximab and hyaluronidase human SC on day 1 of each cycle, and retifanlimab IV over 30 minutes on day 8 of each cycle. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity. COMBINATION THERAPY: After completion of prephase therapy or if patients progress during prephase therapy, patients receive tafasitamab IV over 30 minutes, retifanlimab IV over 30 minutes, rituximab and hyaluronidase human SC, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1 of each cycle. Patients with an IPI score of 2-5 may receive polatuzumab vedotin IV in place of vincristine at investigator discretion. Patients also receive prednisone PO on days 1-5 of each cycle. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

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 study of 40 patients with low-grade or follicular B-cell non-Hodgkin's lymphoma, the combination of Rituxan (Rituximab) and CHOP chemotherapy resulted in a high overall response rate of 95%, with 55% achieving complete remission.

The combination therapy showed promising safety, with common side effects being manageable, and it also indicated potential for clearing minimal residual disease, as evidenced by the conversion of the bcl-2 translocation from positive to negative in several patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. Czuczman, MS., Grillo-López, AJ., White, CA., et al.[2022]

The pH-sensitive pullulan-doxorubicin-sorafenib nanoparticles demonstrated a high drug loading capacity and effectively released their contents in acidic tumor environments, leading to significant suppression of breast cancer cell growth in vitro.

In vivo studies showed that these nanoparticles not only accumulated in tumor tissues but also significantly inhibited tumor growth and reduced tumor volume compared to traditional chemotherapy methods, suggesting a promising approach for overcoming drug resistance in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic chemotherapeutic effect of sorafenib-loaded pullulan-Dox conjugate nanoparticles against murine breast carcinoma. Sui, J., Cui, Y., Cai, H., et al.[2019]

Anthracyclines, particularly doxorubicin, are crucial in treating non-Hodgkin's lymphoma (NHL), with the CHOP regimen being the standard for over 20 years, but they carry a risk of cardiotoxicity as a late side effect.

Using liposome-encapsulated doxorubicin has shown to be effective in treating NHL while significantly reducing the risk of cardiotoxicity, making it a safer option for patients, especially those at higher risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving forward with new data and approaches: a fresh look at anthracyclines in non-Hodgkin's lymphoma. Amadori, D.[2023]

In a study of 91 people living with HIV and Burkitt lymphoma, adding rituximab to CODOX-M/IVAC chemotherapy did not increase severe treatment-related toxicities, indicating it is a safe option for this population.

The addition of rituximab significantly improved both overall survival (72% vs. 55%) and progression-free survival (81% vs. 55%) compared to chemotherapy alone, suggesting it enhances treatment efficacy without added risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding rituximab to CODOX-M/IVAC chemotherapy in the treatment of HIV-associated Burkitt lymphoma is safe when used with concurrent combination antiretroviral therapy. Alwan, F., He, A., Montoto, S., et al.[2022]

Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown to induce responses in nearly 50% of patients with relapsed follicular/low-grade non-Hodgkin's lymphoma, with complete remissions occurring in 6% of cases, highlighting its efficacy in treating this type of cancer.

The drug is generally well tolerated, with common side effects being mild to moderate fevers and chills, and it is also effective against various other B-cell malignancies, suggesting its potential for broader applications in both cancer treatment and autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. Cheson, BD.[2019]

In a study of 33 patients with aggressive non-Hodgkin's lymphoma, the combination of Rituxan (rituximab) and CHOP chemotherapy resulted in a high overall response rate of 94%, with 61% achieving a complete response.

The treatment was well-tolerated, with common side effects like fever and chills, and did not hinder the completion of the full six-course regimen, indicating both safety and efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. Vose, JM., Link, BK., Grossbard, ML., et al.[2022]

In a study using 4T1 murine breast cancer cells in mice, TNF-α did not enhance the anticancer effects of doxorubicin (Dox) in vitro, indicating that it may not improve treatment efficacy in laboratory settings.

However, TNF-α pretreatment increased the concentration of Dox in tumors of mice, especially when combined with a micellar formulation, suggesting a potential strategy for improving drug delivery in breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of adjuvant therapy with TNF-α on animal model of triple-negative breast cancer. Greish, K., Taurin, S., Morsy, MA.[2022]

Higher molecular weight P-DOX conjugates (specifically 1230 kDa) showed significantly longer blood half-life and slower tumor elimination compared to free doxorubicin, enhancing their potential for effective cancer treatment.

P-DOX with a molecular weight of 160 kDa or greater demonstrated superior tumor growth inhibition compared to lower molecular weight P-DOX and free doxorubicin, indicating that larger conjugates can improve therapeutic efficacy in treating ovarian carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biodistribution and antitumour efficacy of long-circulating N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin conjugates in nude mice. Shiah, JG., Dvorák, M., Kopecková, P., et al.[2023]

In a study of 23 patients with aggressive B-cell non-Hodgkin lymphoma, the combination of rituximab with CODOX-M/IVAC showed promising efficacy, with 83% of low-risk and 71% of high-risk patients achieving complete remission after treatment.

The safety profile was acceptable, with no treatment-related deaths and manageable toxicity, including only two cases of grade 3 neutropenia, suggesting that this treatment combination is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in combination with CODOX-M/IVAC: a retrospective analysis of 23 cases of non-HIV related B-cell non-Hodgkin lymphoma with proliferation index >95%. Mohamedbhai, SG., Sibson, K., Marafioti, T., et al.[2015]

Doxorubicin and its liposomal form, Doxil, enhance the effectiveness of cancer immunotherapies like anti-PD-1 and CTLA-4 antibodies in mouse models, showing strong synergistic antitumor effects and improved survival rates.

Doxil appears to work better in the presence of a functional immune system, as it reduces regulatory T cells and increases CD8(+) T cells in tumors, suggesting it may help activate a stronger immune response against cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. Rios-Doria, J., Durham, N., Wetzel, L., et al.[2021]

Doxorubicin, when used in combination with genetically-modified cancer cell vaccines, showed immunostimulatory effects that enhanced cure rates in established CT26 tumors, suggesting a promising approach for advanced cancer treatment.

In contrast, cyclophosphamide was found to be immunosuppressive and did not improve cure rates when combined with the vaccine, indicating that not all antineoplastic drugs are suitable for combination therapy with cancer vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. Nigam, A., Yacavone, RF., Zahurak, ML., et al.[2020]

Citations

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A Retrospective Analysis of the Efficacy of Low-Dose ... We concluded that low-dose metronomic cyclophosphamide represents efficacious and well-tolerated treatment for low-grade NHL patients.

3. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK553087/

Cyclophosphamide - StatPearls - NCBI Bookshelf - NIH Cyclophosphamide is a medication primarily used in the management and treatment of neoplasms, including multiple myeloma, sarcoma, and breast cancer.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121033358

A Retrospective Analysis of the Efficacy of Low-Dose ... We concluded that low-dose metronomic cyclophosphamide represents efficacious and well-tolerated treatment for low-grade NHL patients.

5. dana-farber.org dana-farber.org/newsroom/news-releases/2019/high-doses-of-60-plus-year-old-chemotherapy-drug-found-to-spur-immune-system-attack-on-lymphoma

High doses of 60-plus year-old chemotherapy drug found ... The researchers demonstrate that large doses of cyclophosphamide not only kill cancer cells directly, as has been known, but also spur an immune system attack ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2025/212501s007lbl.pdf

cyclophosphamide injection - accessdata.fda.gov The safety and effectiveness of cyclophosphamide have been established in pediatric patients and information on this use is discussed throughout the labeling.

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Cyclophosphamide Injection - accessdata.fda.gov The safety and effectiveness of Cyclophosphamide Injection have been established in pediatric patients and information on this use is discussed throughout ...

8. go.drugbank.com go.drugbank.com/drugs/DB00531

Cyclophosphamide: Uses, Interactions, Mechanism of Action Cyclophosphamide is a nitrogen mustard used to treat lymphomas, myelomas, leukemia, mycosis fungoides, neuroblastoma, ovarian adenocarcinoma, retinoblastoma ...

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Cyclophosphamide - 15th Report on Carcinogens - NCBI - NIH Cyclophosphamide is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

10. macmillan.org.uk macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/cyclophosphamide

Cyclophosphamide Cyclophosphamide is a type of chemotherapy. It is used to treat breast cancer, lung cancer, leukaemia, lymphoma, myeloma, ovarian cancer and Ewing sarcoma.