Polatuzumab + Rituximab for Lymphoproliferative Disorders

Overseen By Neha Mehta-shah, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must not be taking: Investigational agents

Disqualifiers: CNS involvement, Peripheral neuropathy, others

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

Compensation: Varies

Number of Visits: 1

Duration: 4-6 months

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will test polatuzumab vedotin in combination with rituximab in patients with treatment-naïve CD20-positive post-transplant lymphoproliferative disorder (PTLD) based on the established efficacy of polatuzumab vedotin in B-cell lymphomas and the inadequate response rate of PTLD to single-agent rituximab. The hypothesis is that this combination therapy will be safe, well-tolerated, and effective. If so, patients with PTLD will be able to be spared the toxicity of anthracycline-based chemotherapy. Additionally, the role of the tumor microenvironment and the role of anellovirus, a non-human pathogen virus, will be explored as prognostic markers in PTLD.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on investigational agents or have certain medical conditions, you may not be eligible to participate. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Polatuzumab + Rituximab for lymphoproliferative disorders?

Research shows that rituximab, when combined with chemotherapy like CHOP, improves survival in patients with non-Hodgkin's lymphoma and has been a significant advance in treating aggressive lymphomas. This suggests that combining rituximab with other treatments, such as Polatuzumab, could potentially enhance effectiveness in similar conditions. ^{1 2 3 4 5}

Is the combination of Polatuzumab and Rituximab safe for treating lymphoproliferative disorders?

The combination of Rituximab with chemotherapy regimens like CHOP has been studied for safety in various lymphomas. While generally well-tolerated, some studies reported mild acute toxicity and severe pulmonary complications in a few cases. The safety profile of Rituximab biosimilars was found to be comparable to the original, with similar rates of adverse events. ^{6 7 8 9 10}

What makes the drug Polatuzumab + Rituximab unique for treating lymphoproliferative disorders?

This drug combination is unique because it includes Polatuzumab Vedotin, which is an antibody-drug conjugate that specifically targets and delivers chemotherapy to cancer cells, potentially increasing effectiveness while reducing harm to normal cells. Additionally, Rituximab is a monoclonal antibody that enhances the treatment by targeting CD20+ B-cells, which are often involved in these disorders. ^{2 4 5 11 12}

Research Team

Neha Mehta-shah, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults with CD20-positive post-transplant lymphoproliferative disorder (PTLD) who haven't been treated before. They should have adequate blood counts, organ function, and be able to consent. Pregnant or breastfeeding individuals are excluded, as well as those with certain infections, heart conditions, neuropathy, or other serious health issues.

Inclusion Criteria

My blood and organ functions are within normal ranges, except for issues caused by my lymphoma.

You have an absolute neutrophil count of at least 1.0 K/cumm.

You possess the mental capacity and are willing to sign a legally binding document of consent.

Exclusion Criteria

Current ejection fraction < 40% on transthoracic echocardiogram or multigated acquisition (MUGA) scan

HIV viral load < 200 copies/mm3 by standard clinical assays

I am on a stable antiretroviral regimen.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive polatuzumab vedotin and rituximab in cycles, with additional treatment based on risk assessment

4-6 months

Multiple visits per cycle, including Day 1, Day 8, and Day 15 for initial cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• CHP
• Polatuzumab Vedotin
• Rituximab

Trial Overview The study tests polatuzumab vedotin combined with rituximab in patients with PTLD. It aims to see if this combo can avoid the toxicity of traditional chemotherapy while being safe and effective. The trial will also examine tumor environment factors and anellovirus presence as potential prognostic markers.

Participant Groups

Group I: Polatuzumab vedotin + Rituximab + CHP (Safety Lead-in High Risk/Lack of Interim Complete Remission)) Experimental Treatment 3 Interventions

* Cycle 1 (21 days) * Day 1: polatuzumab vedotin + rituximab * Day 8: rituximab * Day 15: rituximab * Cycle 2 (21 days) * Day 1: polatuzumab vedotin + rituximab * After Cycle 2, a response assessment will be performed. Patients who show anything other than a complete response (and are therefore determined to be high risk) will receive polatuzumab vedotin + rituximab + CHP (cyclophosphamide + doxorubicin + prednisone) on Day 1 of each 21-day cycle for 4 additional cycles, followed by 2 final cycles of CHP alone on Day 1 (8 cycles of treatment total).

Group II: Polatuzumab vedotin + Rituximab + CHP (Expansion High Risk/Lack of Interim Complete Remission) Experimental Treatment 3 Interventions

* Cycle 1 (21 days) * Day 1: polatuzumab vedotin + rituximab * Day 8: rituximab * Day 15: rituximab * Cycle 2 (21 days) * Day 1: polatuzumab vedotin + rituximab * After Cycle 2, a response assessment will be performed. Patients who show anything other than a complete response (and are therefore determined to be high risk) will receive polatuzumab vedotin + rituximab + CHP (cyclophosphamide + doxorubicin + prednisone) on Day 1 of each 21-day cycle for 4 additional cycles, followed by 2 final cycles of CHP alone on Day 1 (8 cycles of treatment total).

Group III: Polatuzumab vedotin + Rituximab (Safety Lead-in Low Risk/Interim Complete Remission) Experimental Treatment 2 Interventions

* Cycle 1 (21 days) * Day 1: polatuzumab vedotin + rituximab * Day 8: rituximab * Day 15: rituximab * Cycle 2 (21 days) * Day 1: polatuzumab vedotin + rituximab * After Cycle 2, a response assessment will be performed. Patients who show a complete response (and are therefore determined to be low risk) will continue to receive polatuzumab vedotin + rituximab on Day 1 of each 21-day cycle for 4 additional cycles (6 cycles of treatment total).

Group IV: Polatuzumab vedotin + Rituximab (Expansion Low Risk/Interim Complete Remission) Experimental Treatment 2 Interventions

* Cycle 1 (21 days) * Day 1: polatuzumab vedotin + rituximab * Day 8: rituximab * Day 15: rituximab * Cycle 2 (21 days) * Day 1: polatuzumab vedotin + rituximab * After Cycle 2, a response assessment will be performed. Patients who show a complete response (and are therefore determined to be low risk) will continue to receive polatuzumab vedotin + rituximab on Day 1 of each 21-day cycle for 4 additional cycles (6 cycles of treatment total).

CHP is already approved in United States, European Union for the following indications:

Approved in United States as CHP for:

• Diffuse Large B-Cell Lymphoma (DLBCL)
• High-Grade B-Cell Lymphoma (HGBL)

Approved in European Union as CHP for:

• Diffuse Large B-Cell Lymphoma (DLBCL)
• High-Grade B-Cell Lymphoma (HGBL)

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Findings from Research

In a pooled analysis of 150 patients with HIV-associated aggressive B-cell non-Hodgkin lymphoma, those treated with R-EPOCH showed significantly better event-free survival (EFS) and overall survival (OS) compared to those receiving R-CHOP, particularly in patients with a CD4 count ≥100/μL.

Patients with CD4 counts <50/μL experienced a much higher rate of treatment-related deaths (37% vs 6%), indicating that lower immune function increases the risk of lethal toxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Barta, SK., Lee, JY., Kaplan, LD., et al.[2022]

Rituximab, when added to standard chemotherapy, significantly improved survival rates in patients with non-Hodgkin's lymphoma.

In patients with chronic B-cell lymphocytic leukemia, the addition of rituximab to fludarabine-based regimens enhanced both response rates and overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of the safety and feasibility of rapid infusion of rituximab. Atmar, J.[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 involving 561 patients with chronic lymphocytic leukaemia, the standard treatment of fludarabine, cyclophosphamide, and rituximab showed a longer median progression-free survival of 55.2 months compared to 41.7 months for the bendamustine and rituximab combination, indicating that the standard therapy is more effective.

However, the bendamustine and rituximab combination was associated with significantly fewer severe side effects, such as neutropenia and infections, making it a potentially safer alternative for patients, especially those over 65 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Eichhorst, B., Fink, AM., Bahlo, J., et al.[2022]

Rituximab has revolutionized lymphoma treatment, showing effectiveness as a single agent in all types of B-cell lymphomas, both indolent and aggressive.

Combining rituximab with chemotherapy (like CHOP) significantly improves treatment outcomes for large-cell lymphomas without adding significant toxicity, establishing it as the standard of care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab and chemotherapy for aggressive lymphomas: a significant advance in therapy. Hagemeister, FB.[2015]

In a clinical trial involving 196 patients with high-risk diffuse large cell lymphoma, the addition of rituximab to the dose-dense chemotherapy regimen CEOP-14 did not significantly improve treatment outcomes compared to CEOP-14 alone, with similar complete response rates (76% vs 74%).

Both treatment regimens showed comparable long-term outcomes, with 5-year tumor-progression-free survival (TTP) rates of 74% for CEOP-R and 72% for CEOP-14, indicating that while the dense-dose regimen is well tolerated, rituximab does not enhance efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose dense (CEOP-14) vs dose dense and rituximab (CEOP-14 +R) in high-risk diffuse large cell lymphoma. Avilés, A., Nambo, MJ., Neri, N., et al.[2019]

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 100 lymphoma patients receiving either R-CHOP or CHOP treatment, severe pulmonary complications were observed more frequently in the R-CHOP group (18.3%) compared to CHOP (13.8%), although this difference was not statistically significant.

Continuous steroid use for conditions other than lymphoma significantly increased the risk of pulmonary infections, highlighting the need for careful monitoring of patients during lymphoma treatment to manage potential pulmonary complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe pulmonary adverse effects in lymphoma patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen plus rituximab. Lim, KH., Yoon, HI., Kang, YA., et al.[2022]

A phase 3 study involving 407 treatment-naïve patients with diffuse large B-cell lymphoma demonstrated that HLX01, a biosimilar to rituximab, has comparable efficacy to the reference drug, with overall response rates of 94.1% for HLX01 and 92.8% for rituximab, falling within the pre-defined equivalence margin.

The safety profiles of HLX01 and rituximab were similar, with nearly identical rates of treatment-emergent adverse events (99.5% vs. 99.0%) and serious adverse events (34.0% vs. 32.5%), confirming that HLX01 is a safe alternative to rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. Shi, Y., Song, Y., Qin, Y., et al.[2021]

In a study of 250 patients with indolent non-Hodgkin lymphomas, both R-CVP and R-CHOP regimens followed by rituximab maintenance showed similar efficacy in terms of event-free survival and progression-free survival after a median follow-up of over 5 years.

R-CVP demonstrated significantly lower rates of severe adverse events compared to R-CHOP, making it a safer option for induction treatment in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line R-CVP versus R-CHOP induction immunochemotherapy for indolent lymphoma with rituximab maintenance. A multicentre, phase III randomized study by the Polish Lymphoma Research Group PLRG4. Walewski, J., Paszkiewicz-Kozik, E., Michalski, W., et al.[2020]

A 56-year-old man developed dilated cardiomyopathy after receiving rituximab and bendamustine for chronic lymphocytic leukemia, highlighting a potential serious cardiovascular side effect of rituximab.

Despite the adverse reaction, the patient fully recovered after treatment with medications for cardiomyopathy and supportive care, emphasizing the importance of monitoring for such effects in patients undergoing rituximab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversible Cardiomyopathy after Rituximab Treatment in a Chronic Lymphocytic Leukemia Patient. Girkar, N., Zaki, S., Pawar, S., et al.[2022]

Rituximab, a targeted therapy for B-lineage lymphoma, can increase the risk of opportunistic infections like Pneumocystis jiroveci pneumonia (PCP), particularly during periods of neutropenia, as seen in two reported cases.

Despite the rarity of PCP in lymphoma patients treated with rituximab, timely diagnosis and management can lead to successful treatment, highlighting the need for vigilance regarding this potential complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pneumocystis jiroveci pneumonia in patients with non-Hodgkin's lymphoma receiving chemotherapy containing rituximab. Chang, H., Yeh, HC., Su, YC., et al.[2019]

References

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

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. [2022]

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

Review of the safety and feasibility of rapid infusion of rituximab. [2022]

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

Rituximab: clinical development and future directions. [2019]

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

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. [2022]

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

Rituximab and chemotherapy for aggressive lymphomas: a significant advance in therapy. [2015]

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

Dose dense (CEOP-14) vs dose dense and rituximab (CEOP-14 +R) in high-risk diffuse large cell lymphoma. [2019]

7. 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]

8. Korea (South) pubmed.ncbi.nlm.nih.gov

Severe pulmonary adverse effects in lymphoma patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen plus rituximab. [2022]

9. England pubmed.ncbi.nlm.nih.gov

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. [2021]

10. England pubmed.ncbi.nlm.nih.gov

First-line R-CVP versus R-CHOP induction immunochemotherapy for indolent lymphoma with rituximab maintenance. A multicentre, phase III randomized study by the Polish Lymphoma Research Group PLRG4. [2020]

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

Reversible Cardiomyopathy after Rituximab Treatment in a Chronic Lymphocytic Leukemia Patient. [2022]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Pneumocystis jiroveci pneumonia in patients with non-Hodgkin's lymphoma receiving chemotherapy containing rituximab. [2019]