Immunotherapy + Chemotherapy for Lymphoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
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
Breakthrough Therapy
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.12345
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.678910
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.89101112
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
See 10 more
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.
See 11 more
Trial 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 (Alkylating agents)
- Doxorubicin (Anti-tumor antibiotic)
- Prednisone (Corticosteroid)
- Retifanlimab (Monoclonal Antibodies)
- Rituximab and Hyaluronidase Human (Monoclonal Antibodies)
- Tafasitamab (Monoclonal Antibodies)
- Vincristine (Vinca alkaloids)
Trial OverviewThe 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
1Treatment groups
Experimental Treatment
Group I: Treatment (TRR, CHOP)Experimental Treatment15 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Fred Hutch/University of Washington Cancer ConsortiumSeattle, WA
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Who Is Running the Clinical Trial?
University of Washington
Lead Sponsor
Trials
1858
Patients Recruited
2,023,000+
References
Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. [2021]Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil) were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti-PD-L1, PD-1, and CTLA-4 mAbs) and TNF receptor agonists (OX40 and GITR ligand fusion proteins) in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti-PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti-PD-L1, increased the percentage of tumor-infiltrating CD8(+) T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity.
Synergistic chemotherapeutic effect of sorafenib-loaded pullulan-Dox conjugate nanoparticles against murine breast carcinoma. [2019]pH-Sensitive pullulan-doxorubicin conjugates encapsulating sorafenib (P-Dox/S) nanoparticles were developed as a synergistic combinatorial delivery system against murine breast carcinoma. The nanoparticles can encapsulate Dox and sorafenib with ultra-high loading capacity (65.34 wt%) through chemical conjugation and physical loading, whereas can remain stable under physiological conditions and gradually release Dox and sorafenib with the decreasing pH. These conjugates can be effectively internalized and clearly suppress 4T1 cell growth in vitro. Furthermore, research data of in vivo animal models revealed that the synergistic combinatorial P-Dox/S nanoparticles heavily accumulated in solid tumor tissue sites to maximize therapeutic efficacy; they also significantly inhibited solid tumor growth, even remarkably reduced solid tumor volume in comparison to the initial volume, and obviously diminished adverse effects. The anti-tumor therapeutic effect obviously outperformed the delivery of combinational chemotherapy of free drugs or single drug-loaded P-Dox nanoparticles at the same concentration. These promising results indicate the high-efficiency synergistic chemotherapeutic effects of these nanoparticles. Combinational chemotherapy using P-Dox/S nanoparticles has important potential in the clinical treatment of malignancy for overcoming drug resistance and heterogeneity.
The effect of adjuvant therapy with TNF-α on animal model of triple-negative breast cancer. [2022]This study tested the effect of TNF-α, a cytokine associated with inflammation, and tumor progression, on enhancing doxorubicin (Dox) tumor accumulation, and improving its therapeutic effect.
Biodistribution and antitumour efficacy of long-circulating N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin conjugates in nude mice. [2023]The aim of this study was to evaluate the influence of the molecular weight (mol. wt) of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (DOX) conjugates (P-DOX) on biodistribution and therapeutic efficacy in nu/nu mice bearing human ovarian carcinoma OVCAR-3 xenografts. Copolymerisation of HPMA, a polymerisable derivative of DOX (N-methacryloylglycylphenylalanylleucylglycyl doxorubicin) and a newly designed crosslinking agent, N(2),N(5)-bis(N-methacryloylglycylphenylalanyl-leucylglycyl)ornithine methyl ester monomers resulted in novel, high mol. wt, branched, water-soluble P-DOX containing lysosomally degradable oligopeptide sequences as crosslinks and side-chains terminated in DOX. Four conjugates with mol. wt of 22, 160, 895 and 1230 kDa were prepared. The results indicated that the half-life in blood and the elimination rate from the tumour were up to 28 times longer and 25 times slower, respectively, for P-DOX (mol. wt=1230 kDa) than for free DOX. Treatment with P-DOX (mol. wt > or = 160 kDa) inhibited tumour growth more efficiently than that of 22 kDa P-DOX or free DOX (P
Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. [2020]Cancer cells genetically modified to secrete immunoregulatory cytokines offer great promise for human cancer treatment as tumor vaccines. However, in preclinical animal studies, large established cancer burdens have appeared difficult to eradicate with such vaccines. For example, lethally-irradiated GM-CSF-secreting CT26 colon carcinoma cell vaccine therapy tends to cure only animals bearing 1 x 10(5) wild-type CT26 cells or less. For many human cancers, antineoplastic chemotherapy can often significantly reduce systemic cancer burdens. Unfortunately, for most advanced metastatic solid organ cancers, such as cancers of the breast, colon, and prostate, antineoplastic drug treatments generally fail to effect cancer cures. Treatment regimens combining genetically-modified cancer cell vaccine therapy and antineoplastic chemotherapy have the potential to increase advanced cancer cure rates if antineoplastic drugs and drug combinations that do not inhibit vaccine-induced immune responses can be identified. To assess the potential immunomodulatory properties of commonly-used antineoplastic drugs that might be used in combination with cancer vaccine treatments, we studied the effects of the drugs on antitumor immune responses manifest by animals receiving lethally-irradiated GM-CSF-secreting CT26 cell vaccines. Immunomodulatory properties of the antineoplastic drugs were evaluated i) by monitoring drug effects on the generation of tumor-specific CD8+ cytotoxic T-lymphocytes (CTLs) in response to GM-CSF-secreting CT26 vaccine administration, ii) by determining drug effects on the resistance of vaccinated animals to subsequent challenge with lethal inoculac of CT26 cells, and iii) by evaluating combination drug and vaccine treatment efficacy against established CT26 tumors. Using this approach, doxorubicin was found to possess apparent immunostimulatory activities, depending on the dose and schedule of administration, while cyclophosphamide appeared immunosuppressive. The different immunomodulatory properties of doxorubicin and cyclophosphamide may be clinically relevant: combination doxorubicin and vaccine treatment of established CT26 cancers increased cure rates over that achieved with either agent alone, while combination cyclophosphamide and vaccine treatment of animals carrying CT26 tumors was no better in curing the animals than drug treatment alone.
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]The safety and efficacy of rituximab with CODOX-M/IVAC (cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine) was retrospectively analysed in 23 patients with non-human immunodeficiency virus-related B-cell non-Hodgkin lymphoma with proliferation index >95% [14 with classical Burkitt lymphoma (BL), five with B-cell lymphoma unclassifiable, with features intermediate between diffuse large B cell lymphoma (DLBCL) and BL, and four with DLBCL]. Six (26%) low-risk (LR) patients received three cycles of CODOX-M and 17 (74%) high-risk (HR) cases were assigned to four cycles of alternating CODOX-M/IVAC. Rituximab 375 mg/m² was infused on days 1 and 10 of each cycle. Toxicity was comparable to that reported with CODOX-M/IVAC, with no treatment-related death. Two patients developed grade 3 rituximab-induced delayed neutropenia, with no adverse outcome. After completing treatment, 83% LR patients and 71% HR patients achieved CR by positron emission tomography-computerized tomography (PET-CT). Three (13%) patients received salvage treatment. At a median follow-up of 34 months (range = 18-75), 19 (83%) patients (100% LR and 74% HR) were alive, including one case undergoing salvage for late relapse. Four HR patients (17%) had died, three from primary progressive disease and one from treatment-refractory relapse 2 months after achieving CR. These results with R-CODOX-M/R-IVAC compare favourably with existing data using CODOX-M/IVAC and warrant further prospective studies. The potential pitfalls of PET-CT to assess response are highlighted.
Moving forward with new data and approaches: a fresh look at anthracyclines in non-Hodgkin's lymphoma. [2023]Anthracyclines have a central role in the management of non-Hodgkin's lymphoma (NHL). The cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment regimen has been the standard of care for more than 20 years. Further improvements have been made to the efficacy of this chemotherapy by reducing the dosing interval and adding rituximab to the regimen. A major limitation to the use of anthracyclines is the development of cardiotoxicity as a late adverse event. Strategies to reduce cardiac events include changes to the dosing schedule for doxorubicin, use of the chelating agent dexrazoxane and the use of liposome-encapsulated doxorubicin. This latter strategy has demonstrated good efficacy and reduced cardiotoxicity in patients with NHL, including those at risk of developing cardiac effects.
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]CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin-methatrexate/ifusamide, etoposide, cytarabine) chemotherapy is commonly used to treat Burkitt lymphoma and in the HIV-negative population. Rituximab is often added with suggested survival benefits. Concerns over increased toxicity in an already immunocompromized population have prevented its routine addition in people living with HIV (PLWH). This study evaluated the effect on treatment-related toxicity and efficacy of adding rituximab to CODOX-M/IVAC chemotherapy in PLWH.
Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. [2022]To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody, Rituxan (Rituximab, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy.
Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. [2022]To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL).
Novel CD20 monoclonal antibodies for lymphoma therapy. [2022]Rituximab (RTX), a monoclonal antibody (mAb) against CD20, has been widely used for lymphoma therapy. RTX in combination with cyclophosphamide /doxorubicin /vincristine /prednisone (R-CHOP) remains the standard frontline regimen for diffuse large B-cell lymphoma. However, suboptimal response and /or resistance to rituximab have remained a challenge in the therapy of B-cell non-Hodgkin's lymphoma (NHL). Novel agents are under active clinical trials. This review will summarize the latest development in new mAbs against CD20, which include second-generation mAbs, ofatumumab, veltuzumab (IMMU-106), ocrelizumab (PRO70769), and third-generation mAbs, AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutumumab).
Rituximab: clinical development and future directions. [2019]The availability of effective monoclonal antibodies (mAbs) has revolutionised the management of patients with B-cell malignancies. The most widely studied of these agents is rituximab (Rituxan, IDEC Pharmaceuticals, San Diego, CA), a chimeric anti-CD20 antibody. Using the standard 4-weekly administration schedule, rituximab induces responses in almost half of patients with relapsed follicular/low-grade (F/LG) non-Hodgkin's lymphoma (NHL) with complete remissions in 6%. Lower response rates (RRs) have been noted in chronic lymphocytic leukaemia (CLL) using the standard dose and schedule. The drug has been well tolerated in most patients with common adverse events including mild to moderate fevers and chills and rare occurrences of a serious syndrome related to cytokine release and rapid tumour clearance. This antibody is also active against aggressive NHL, mantle cell NHL, post-transplant lymphoproliferative disorder (PTLD), lymphoplasmacytic NHL and hairy cell leukaemia and is also being evaluated in autoimmune disorders. Combinations of rituximab with chemotherapy regimens such as CHOP (cyclophosphamide, adriamycin, vincristine, predinisone) may alter the therapeutic paradigm for these diseases. The future promise of this antibody is a foundation on which to develop new strategies to increase the cure of patients with lymphoid malignancies.