Polatuzumab Vedotin + Chemotherapy for Richter Syndrome

Recruiting at 3 trial locations

Overseen By Katherine Greig, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Weill Medical College of Cornell University

Must not be taking: BTKi, Venetoclax, PI3K

Disqualifiers: HIV, Active hepatitis, Cardiovascular disease, 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: 24

Duration: 18 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of polatuzumab vedotin (an antibody-drug conjugate) with chemotherapy to evaluate its safety and effectiveness in treating Richter Syndrome. This condition occurs when chronic lymphocytic leukemia (CLL) transforms into a more aggressive form called diffuse large B-cell lymphoma (DLBCL). Participants will receive up to six cycles of treatment and undergo close monitoring to track safety and outcomes. Suitable candidates for this trial have a confirmed diagnosis of CLL or small lymphocytic lymphoma (SLL) that has transformed into Richter Syndrome, specifically into the DLBCL subtype. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial allows continuation of certain targeted therapies like BTKi, venetoclax, or PI3K up to 72 hours before starting the study. Steroid therapy equivalent to 40mg of Dexamethasone daily can be continued up to 24 hours before the study treatment. Other medications are not specified, so it's best to discuss with the trial team.

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

Research has shown that Polatuzumab vedotin, combined with standard chemoimmunotherapy (including rituximab, etoposide, prednisone, cyclophosphamide, and hydroxydaunorubicin), has been tested for safety in people. Previous patients have generally tolerated this combination well, though some side effects have been reported. Common side effects include low blood cell counts, tiredness, and nausea. These side effects are typical for chemotherapy and can usually be managed with supportive care.

The study phase suggests some confidence in the safety of this combination, but more data is being collected to confirm this. Prospective participants can be assured that safety remains a top priority, and health professionals will monitor participants closely throughout the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Richter Syndrome?

Polatuzumab vedotin is unique because it combines a targeted approach with traditional chemotherapy, offering a new strategy for tackling Richter Syndrome. Unlike standard treatments that primarily rely on chemotherapy alone, polatuzumab vedotin is an antibody-drug conjugate. This means it specifically targets cancer cells with a monoclonal antibody, delivering the drug directly to the tumor, potentially reducing damage to healthy cells. Researchers are excited about this treatment because it could enhance the effectiveness of chemotherapy while minimizing side effects, addressing a significant challenge in treating this aggressive condition.

What evidence suggests that Polatuzumab Vedotin plus chemotherapy could be an effective treatment for Richter Syndrome?

In this trial, participants will receive Polatuzumab vedotin combined with R-EPCH, a type of chemoimmunotherapy, which has shown promising results for treating Richter Syndrome. Research indicates that in a study with 35 patients, 50% experienced a reduction or disappearance of their cancer. Specifically, 39% of these patients achieved a complete response, with all signs of cancer gone. This treatment combines Polatuzumab vedotin with other drugs like rituximab, known to aid in aggressive B-cell cancers. The combination targets cancer cells more effectively, potentially leading to better patient outcomes. ^{1 6 7 8 9}

Who Is on the Research Team?

John Allan, M.D.

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

Adults diagnosed with chronic B-cell leukemia or Richter's Syndrome, who have a life expectancy of at least 24 weeks and are in relatively good health (ECOG ≤2). They must have normal organ function and bone marrow activity. Women of childbearing age must use effective contraception, as must men, who should also not donate sperm during the trial.

Inclusion Criteria

I agree to follow strict birth control measures or remain abstinent during and for 5 months after treatment.

Subject must have adequate organ function: Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (Subjects with Gilbert's disease will be granted exception to this rule), Creatinine clearance >30 ml/min/1.73m2 as calculated by the MDRD equation, Ejection fraction ≥ 50% measured by transthoracic echocardiogram or MUGA scan

Subject must be able to sign informed consent

Exclusion Criteria

I have not had major surgery in the last 4 weeks, except for minor lymph node biopsies.

I do not have any major health issues that could interfere with the study.

I am HIV positive.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Polatuzumab vedotin in combination with R-EPCH for up to six 21-day cycles

18 weeks

Weekly visits (in-person) during treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

Weekly visits until end of treatment, then every 12 weeks

Long-term follow-up

Participants are followed for survival outcomes and next line of treatments

104 weeks

Assessments every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Etoposide
• Hydroxydaunomycin
• Polatuzumab Vedotin
• Prednisone
• Rituximab

Trial Overview The trial is testing Polatuzumab Vedotin combined with chemotherapy drugs (rituximab, etoposide, prednisone, cyclophosphamide, hydroxydaunorubicin) for treating Richter's Transformation. Patients will undergo six cycles of treatment over 21 days each and be monitored weekly until end of treatment followed by long-term follow-ups.

How Is the Trial Designed?

Group I: Polatuzumab vedotin plus R-EPCH Experimental Treatment 6 Interventions

Polatuzumab vedotin will be given in conjunction with 6 cycles of R-EPCH (rituximab, etoposide, prednisone, cyclophosphamide, hydroxydaunorubicin). The dosing schedule and regimen for R-EPCH will follow established protocols. Polatuzumab vedotin will be administered on Day 1 of each 21-day cycle.

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?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

The Polatuzumab vedotin (Pola) combined with the dose-adjusted EPOCH-R regimen was found to be safe, with only 3 dose-limiting toxicities observed among 18 patients, meeting the primary safety endpoint of the trial.

The treatment showed impressive efficacy, achieving a 100% overall response rate and a 76% complete response rate, with a 12-month overall survival rate of 94%, indicating that Pola can be effectively integrated into intensified treatment regimens for aggressive large B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin with infusional chemotherapy for untreated aggressive B-cell non-Hodgkin lymphomas. Lynch, RC., Poh, C., Ujjani, CS., et al.[2023]

In a study of 69 patients with aggressive B-cell lymphoma treated with polatuzumab vedotin combined with bendamustine and rituximab, a 50% response rate was observed, with a 24% complete response rate, indicating some efficacy in a real-world setting.

However, the median progression-free survival (PFS) was only 2.0 months, and survival was 5.3 months, which is lower than what was reported in clinical trials, particularly for patients with prior refractory disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab Vedotin for Relapsed/Refractory Aggressive B-cell Lymphoma: A Multicenter Post-marketing Analysis. Smith, SD., Lopedote, P., Samara, Y., et al.[2022]

Polatuzumab vedotin (pola) was well tolerated in a phase 1 study with Japanese patients suffering from relapsed/refractory B-cell non-Hodgkin lymphoma, showing no dose-limiting toxicities and an acceptable safety profile.

The study indicated promising antitumor activity, with four out of seven patients achieving objective responses, including three complete responses, suggesting that pola could be an effective treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of polatuzumab vedotin in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma: a phase 1 dose-escalation study. Kinoshita, T., Hatake, K., Yamamoto, K., et al.[2021]

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79B, is effective for treating relapsed/refractory diffuse large B-cell lymphoma when combined with bendamustine and rituximab.

Research by Kawasaki et al. suggests potential mechanisms of resistance to polatuzumab vedotin in lymphoma cells, which could inform future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

United we stand: Double targeting of CD79B and CD20 in diffuse large B-cell lymphoma. Tarantelli, C., Bertoni, F.[2023]

Polatuzumab vedotin (POLIVY®) is an effective treatment for adult patients with diffuse large B-cell lymphoma, approved after showing significant anti-cancer activity by delivering a potent drug directly to B cells.

The incidence of anti-drug antibodies (ADA) against polatuzumab vedotin is low, likely due to its mechanism of action that targets and kills B cells, which minimizes immune response and supports a favorable benefit/risk profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrated summary of immunogenicity of polatuzumab vedotin in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Dere, RC., Beardsley, RL., Lu, D., et al.[2023]

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]

In a study of 20 patients with untreated poor prognosis diffuse large B-cell lymphoma (DLBCL), the two-weekly dose-adjusted EPOCH-like chemotherapy (DA-EDOCH14-R) showed a promising three-year progression-free survival (PFS) rate of 95%, compared to 74% in a previous trial with a three-weekly regimen.

The treatment was well-tolerated with manageable toxicity and no therapy-related deaths, highlighting its safety, especially for patients with a high-risk prognosis (age-adjusted International Prognostic Index of 3), where PFS reached 100% compared to just 30% in the previous trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. García-Suárez, J., Flores, E., Callejas, M., et al.[2015]

In a study of 60 previously untreated patients with intermediate- or high-grade non-Hodgkin's lymphomas, the combination chemotherapy regimen CEOP-B/VIMB achieved a high complete remission rate of 77% and a 48-month overall survival rate of 70%.

The treatment demonstrated mild toxicity, making it a favorable option compared to third-generation regimens, while patient outcomes were significantly influenced by factors such as serum LDH levels and performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CEOP-B alternated with VIMB in intermediate-grade and high-grade non-Hodgkin's lymphoma: a pilot study. De Lena, M., Ditonno, P., Lorusso, V., et al.[2017]

In a study of 45 patients with newly diagnosed Hodgkin's disease, 51% experienced acute hypersensitivity reactions to etoposide, typically occurring within 5 minutes of infusion, with symptoms including respiratory issues and changes in blood pressure.

Despite the high incidence of hypersensitivity, 78% of patients were able to successfully tolerate subsequent etoposide infusions after premedication and slower administration rates, indicating that rechallenge can be safe with proper management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin's disease. Hudson, MM., Weinstein, HJ., Donaldson, SS., et al.[2017]

Epipodophyllotoxin (VP-16-213) was effective in inducing remission in all 9 patients with mycosis fungoides, with complete remission in 2 patients and partial remission in 3 patients.

However, the remissions achieved with VP-16 were not sustained, indicating that additional treatments are necessary to maintain remission after initial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epipodophyllotoxin (VP-16-213) in mycosis fungoides: A report from the Scandinavian mycosis fungoides study group. Molin, L., Thomsen, K., Volden, G., et al.[2013]

Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard treatment for relapsed diffuse large B-cell lymphoma, but the addition of rituximab has improved outcomes after first-line treatment and relapses.

The CORAL trial found no significant difference in response rates between two salvage regimens (R-ICE and R-DHAP), and identified that factors like early relapse and certain genetic markers significantly affect survival, indicating that over 70% of patients may not benefit from standard salvage therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? Gisselbrecht, C.[2022]

In a study of 17 patients with mycosis fungoides and lymph node involvement, treatment with a combination of cyclophosphamide, vincristine, and prednisone (COP) resulted in a high response rate of 76%, with 41% achieving complete remission.

The treatment was well-tolerated, showing no severe side effects, and the 5-year survival rate for patients was 64%, indicating its potential efficacy and safety in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic polychemotherapy in patients with mycosis fungoides and lymph node involvement: a follow-up study of 17 patients. Sentis, HJ., Willemze, R., Van Vloten, WA.[2015]

In a study of 24 patients with advanced mycosis fungoides, combination chemotherapy resulted in a high overall response rate of 95%, with 29% achieving complete remission.

The COP plus bleomycin regimen provided a longer median duration of remission (47 weeks) compared to adriamycin-containing therapies (22 weeks), although median survival was similar across all treatment groups at 95 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination chemotherapy for mycosis fungoides: a Southwest Oncology Group study. Grozea, PN., Jones, SE., McKelvey, EM., et al.[2015]

Citations

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Updates in the Management of Richter Transformation - PMC Recent updates with 35 patients enrolled showed an ORR of 50% and CR rate of 39%. Cytokine release syndrome (CRS) remained the most frequent ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04679012

Study Details | NCT04679012 | Polatuzumab Vedotin in ... This study evaluates the effectiveness and safety of Polatuzumab vedotin plus infusional chemoimmunotherapy containing rituximab, etoposide, prednisone, ...

3. journals.viamedica.pl journals.viamedica.pl/acta_haematologica_polonica/article/download/98365/76745

Update on management of diffuse large B-cell lymphoma ... A novel potential therapeutic option worth mentioning is polatuzumab vedotin (monomethyl-auristatin E conjugated CD79b antibody), which showed ...

4. mountsinai.org mountsinai.org/clinical-trials/polatuzumab-vedotin-in-combination-with-chemotherapy-in-subjects-with-richters-transformation

Polatuzumab Vedotin in Combination With Chemotherapy ... Summary: This study evaluates the effectiveness and safety of Polatuzumab vedotin plus infusional chemoimmunotherapy containing rituximab, etoposide, ...

5. withpower.com withpower.com/trial/phase-3-leukemia-lymphocytic-chronic-b-cell-9-2021-d4123

Polatuzumab Vedotin + Chemotherapy for Richter Syndrome Research shows that rituximab combined with chemotherapy, including drugs like cyclophosphamide and doxorubicin, has improved outcomes in aggressive B-cell ...

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Phase II study of Polatuzumab vedotin in combination with ... The purpose of this study is to find out what effects the study drug, Polatuzumab vedotin, in combination with a standard chemoimmunotherapy regimen has on ...

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Polatuzumab Vedotin in Combination With Chemotherapy in ... This study evaluates the effectiveness and safety of Polatuzumab vedotin plus infusional chemoimmunotherapy containing rituximab, etoposide, ...

8. cancer.gov cancer.gov/clinicaltrials/NCI-2022-05396

Polatuzumab Vedotin in Combination With Chemotherapy ... This study evaluates the effectiveness and safety of Polatuzumab vedotin plus infusional chemoimmunotherapy containing rituximab, etoposide, prednisone, ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT04231877

Study Details | NCT04231877 | Polatuzumab Vedotin and ... Will estimate the safety and tolerability of polatuzumab vedotin when added to dose-adjusted-etoposide, prednisone, vincristine (Oncovin), cyclophosphamide, ...