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

Trial Summary

What is the purpose of this trial?

This phase I/II trial tests the safety of tafasitamab, retifanlimab, and rituximab (TRR) as a prephase treatment and in combination with standard therapy consisting off cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or polatuzumab vedotin, cyclophosphamide, doxorubicin, and prednisone (PolaCHP) in patients with untreated diffuse large B-cell lymphoma. Tafasitamab, retifanlimab, and rituximab are monoclonal antibodies. Tafasitamab binds to a protein called CD19, which is found on B-cells (a type of white blood cell) and some types of cancer cells. Rituximab binds to a protein called CD20, which is also found on B-cells and some cancer cells. These monoclonal antibodies may help the immune system kill cancer cells. Immunotherapy with other monoclonal antibodies, such as retifanlimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as CHOP and PolaCHP, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving TRR in combination with CHOP or PolaCHP may kill more cancer cells.

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.

What evidence supports the effectiveness of the drugs used in the Immunotherapy + Chemotherapy for Lymphoma trial?

Research shows that doxorubicin, a component of the treatment, can enhance the immune system's response to cancer therapies, leading to stronger antitumor effects and increased survival in animal models. This suggests that combining doxorubicin with immunotherapy could improve treatment outcomes. ^{1 2 3 4 5}

Is the combination of immunotherapy and chemotherapy safe for treating lymphoma?

The combination of immunotherapy (like Rituximab) and chemotherapy (such as CHOP or CODOX-M/IVAC) has been studied for safety in treating lymphoma. While generally safe, some patients may experience side effects like delayed neutropenia (low white blood cell count) and cardiotoxicity (heart damage). Strategies like adjusting drug doses and using protective agents can help reduce these risks. ^{6 7 8 9 10}

What makes this lymphoma treatment unique?

This treatment combines immunotherapy with chemotherapy, using a mix of drugs like rituximab and tafasitamab, which target specific proteins on cancer cells, potentially improving effectiveness compared to standard chemotherapy alone. The inclusion of retifanlimab, an immune checkpoint inhibitor, may enhance the immune system's ability to fight cancer, offering a novel approach for patients with lymphoma. ^{8 9 10 11 12}

Research Team

Stephen Smith

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

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

I have had an organ transplant.

Currently participating in another study with investigational agents or devices

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. [2021]

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

Synergistic chemotherapeutic effect of sorafenib-loaded pullulan-Dox conjugate nanoparticles against murine breast carcinoma. [2019]

3. England pubmed.ncbi.nlm.nih.gov

The effect of adjuvant therapy with TNF-α on animal model of triple-negative breast cancer. [2022]

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

Biodistribution and antitumour efficacy of long-circulating N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin conjugates in nude mice. [2023]

5. Greece pubmed.ncbi.nlm.nih.gov

Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. [2020]

6. England 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%. [2015]

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

8. England 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. [2022]

9. United States 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. [2022]

10. United States 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. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Novel CD20 monoclonal antibodies for lymphoma therapy. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. [2019]