Parsaclisib + Standard Therapy for Non-Hodgkin's Lymphoma

Not currently recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must not be taking: Antiretrovirals

Disqualifiers: Pregnancy, CNS lymphoma, HIV, others

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

Compensation: Varies

Number of Visits: 9

Duration: 18 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best dose and assess the side effects of adding a new drug, parsaclisib, to the standard treatment for high-risk diffuse large B-cell lymphoma, a type of blood cancer. Researchers will test parsaclisib alone and with another drug, polatuzumab vedotin (an antibody-drug conjugate), to evaluate if these combinations outperform the standard treatment. The trial examines whether these new combinations can more effectively stop cancer cells from growing and spreading. It is designed for individuals recently diagnosed with this specific form of non-Hodgkin's lymphoma 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 treatment.

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, it mentions that patients receiving other treatments for lymphoma, except corticosteroids, are excluded. It's best to discuss your specific medications with the trial team.

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

Research has shown safety concerns when combining parsaclisib with the standard treatment R-CHOP. One study found that 47% of patients experienced serious side effects, with pneumonia being the most common, affecting 9% of patients. Additionally, 6% of participants faced life-threatening side effects. However, another study reported that all patients survived the follow-up period, indicating some level of safety.

When parsaclisib is combined with both R-CHOP and polatuzumab vedotin, less detailed safety information is available. While polatuzumab vedotin represents a significant advancement, it does not cure everyone, suggesting benefits but also potential risks.

As this is a Phase 1 trial, the primary goal is to assess the treatment's safety and determine the optimal dose. Early trials closely monitor side effects. Participants should consider this information when deciding whether to join the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Non-Hodgkin's Lymphoma because they incorporate parsaclisib, a novel PI3K inhibitor, which is not part of the current standard therapies like R-CHOP. Parsaclisib offers a targeted approach by interfering with the PI3K pathway, which plays a crucial role in cancer cell survival and proliferation. Additionally, one of the treatment arms includes polatuzumab vedotin, an antibody-drug conjugate that directly delivers chemotherapy to cancer cells, potentially reducing side effects. This combination of targeted action and innovative drug delivery could offer more effective and tolerable treatment options for patients.

What evidence suggests that this trial's treatments could be effective for high risk diffuse large B-cell lymphoma?

This trial will compare two treatment arms for non-Hodgkin's lymphoma. In one arm, participants will receive parsaclisib with R-CHOP. Studies have shown promising results with this combination, achieving a 97.6% overall response rate, with 90.5% of patients achieving complete remission, meaning the cancer was no longer detectable. Parsaclisib blocks certain enzymes that cancer cells need to grow, which can stop or slow the cancer. In the other arm, participants will receive parsaclisib with R-CHOP and the addition of polatuzumab vedotin. This targeted therapy delivers chemotherapy directly to cancer cells and has shown improved outcomes in similar conditions. These treatments work together to attack the cancer in multiple ways, offering hope for more effective treatment options. ^{2 4 6 7 8}

Who Is on the Research Team?

Yucai Wang

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed, high risk diffuse large B-cell lymphoma. Participants must have certain types of this cancer (non-GCB subtype or express specific proteins), be in specific stages, and have a good performance status. They need normal organ function tests and agree to use birth control if applicable. Excluded are pregnant individuals, those with uncontrolled illnesses, HIV on antiretroviral therapy, prior CNS lymphoma involvement, severe lung disease or heart failure.

Inclusion Criteria

Measurable disease as detected by computed tomography (CT) or PET/CT

Negative urine pregnancy test done =< 7 days prior to registration for persons of childbearing potential

My cancer shows high levels of Myc protein.

Exclusion Criteria

Nursing persons

I have not had a heart attack in the last 6 months.

I do not have any uncontrolled illnesses.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive parsaclisib with R-CHOP or with polatuzumab vedotin and R-CHP for up to 6 cycles

18 weeks

6 cycles, each 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months during year 1, every 4 months during year 2

Long-term follow-up

Participants who experience disease progression are followed up every 6 months until 5 years after registration

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Doxorubicin Hydrochloride
• Parsaclisib
• Pegfilgrastim
• Polatuzumab Vedotin
• Prednisone
• Rituximab
• Vincristine Sulfate

Trial Overview The trial is testing the effectiveness of parsaclisib with or without polatuzumab vedotin plus standard R-CHOP therapy against R-CHOP alone. Parsaclisib inhibits enzymes for cell growth; polatuzumab delivers chemo directly to cancer cells; R-CHOP includes rituximab and various chemotherapy drugs aimed at stopping cancer spread.

How Is the Trial Designed?

Group I: Arm I (parsaclisib, R-CHOP) Experimental Treatment 7 Interventions

Patients receive parsaclisib PO QD on days 1-10 or 1-14, rituximab IV or biosimilar substitute, cyclophosphamide IV over 30 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV over 15 minutes on day 1. Patients also receive prednisone PO on days 1-5 and pegfilgrastim SC or biosimilar substitute on day 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (parsaclisib, R-CHOP, polatuzumab vedotin) Active Control 8 Interventions

Patients receive parsaclisib PO once daily QD on days 1-10 or 1-14, polatuzumab vedotin IV over 90 minutes, rituximab IV or biosimilar substitute, cyclophosphamide IV over 30 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV over 15 minutes on day 1. Patients also receive prednisone PO on days 1-5 and pegfilgrastim SC or biosimilar substitute on day 2. Treatment repeats every 21 days for up to 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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

The current standard treatment for follicular lymphoma is a combination of chemotherapy and rituximab, specifically the R-CHOP regimen, which has been widely used and is effective.

Bendamustine combined with rituximab has shown excellent efficacy and tolerability in treating low-grade lymphomas, making it a promising alternative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ongoing trials in low-grade lymphoma. Burchardt, A.[2021]

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]

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 115 patients with Waldeyer's ring diffuse large B-cell lymphoma, those treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) showed significantly better progression-free survival (PFS) and overall survival (OS) compared to those receiving standard R-CHOP treatment, with 2-year PFS rates of 90.1% versus 80.5%.

The DA-EPOCH-R treatment was associated with fewer deaths (2 out of 42 patients) compared to R-CHOP (9 out of 42 patients) during a median follow-up of 45 months, while both treatments had similar clinical responses and treatment-related toxicities, indicating that DA-EPOCH-R is a safer and more effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-adjusted EPOCH-R vs. R-CHOP in frontline management of Waldeyer's ring diffuse large B-cell lymphoma: a retrospective study from a single institution. Liang, Y., Liu, X., Yang, J., et al.[2023]

The medication instruction sheet (MIS) developed for patients receiving R-CHOP therapy effectively predicted 71% of adverse drug reactions (ADRs) during the treatment period, demonstrating its usefulness in managing these reactions.

The MIS accurately matched the onset timing of infusion reactions and peripheral neuropathy, although its effectiveness was lower for predicting thrombocytopenia-related ADRs, indicating areas for improvement in monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Medication Instruction Sheets for Patients Undergoing R-CHOP Therapy in Non-Hodgkin's Lymphoma. Uchida, M., Kawai, R., Hisamitsu, R., et al.[2022]

The CEOP chemotherapy regimen, which substitutes epirubicin for doxorubicin, demonstrated a high efficacy with a complete remission rate of 64.3% in 186 patients with intermediate- or high-grade non-Hodgkin lymphoma, particularly benefiting elderly patients.

Long-term follow-up showed that 79.8% of patients who achieved complete remission remained disease-free at a median of 86.9 months, indicating that CEOP is not only effective but also well-tolerated, with no deaths from cardiac toxicity reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of patients with intermediate or high-grade non-Hodgkin lymphoma treated with a combination of cyclophosphamide, epirubicin, vincristine, and prednisone. Rossini, F., Terruzzi, E., Perego, D., et al.[2015]

In a study of 675 patients aged 65 and older with follicular lymphoma, those who received the R-CHOP treatment as their first line of therapy had significantly longer overall survival compared to those who received it as a second line treatment.

The benefit of receiving R-CHOP as a first line was particularly notable in patients aged 80 and older and those with lower histological grades (1 or 2), indicating that early treatment may be crucial for improving outcomes in these subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Impact of Sequence of Therapy for Older Patients With Follicular Lymphoma: SEER-Medicare Analysis. Xie, C., Li, R., Huang, X., et al.[2022]

In a study of 389 young patients with good-prognosis aggressive lymphoma, the high dose of CHOEP-21 did not improve event-free or overall survival compared to the standard CHOEP-21 regimen, indicating no clinical benefit from the increased dosage.

The high CHOEP regimen was associated with significantly higher toxicity, including increased rates of severe leukocytopenia, thrombocytopenia, infections, and therapy-related deaths, suggesting that the risks may outweigh any potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: II. Results of the randomized high-CHOEP trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Pfreundschuh, M., Zwick, C., Zeynalova, S., et al.[2020]

In a study of 50 patients treated with R-CHOP-14 for aggressive B-cell lymphoma, 82% achieved a complete or improved response, indicating high efficacy of this treatment regimen.

Despite its effectiveness, R-CHOP-14 was associated with significant toxicities, including grade 3-4 neutropenia in 32% of patients and peripheral neuropathy in 45%, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with biweekly CHOP plus rituximab chemoimmunotherapy for the treatment of aggressive B-cell non-Hodgkin lymphoma. Aguiar Bujanda, D., Aguiar Morales, J., Bohn Sarmiento, U., et al.[2021]

The CHOEA-7 chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine, etoposide, and ara-C, has shown excellent results in treating patients with CD 20-positive non-Hodgkin's lymphoma.

Adding rituximab to the CHOEA-7 regimen (RCHOEA-7) further enhances treatment efficacy, indicating a promising approach for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. Uzuka, Y., Saitou, Y., Saitou, K., et al.[2015]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11061660/

Frequency of Complete Remission With R-CHOP Therapy ... The majority of patients (80, 84.2%) achieved CR following R-CHOP therapy. In terms of age distribution, 43 (45.3%) patients were aged ≤45 years.

2. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper200206.html

Paper: A Phase 1/1b Study of Parsaclisib Plus Standard ... In Phase 1/1b (n=42), the overall response rate (ORR) to parsaclisib plus R-CHOP was 97.6%, and the CR rate was 90.5%.

3. withpower.com withpower.com/trial/phase-1-lymphoma-b-cell-marginal-zone-5-2020-7238b

Parsaclisib + Standard Therapy for Non-Hodgkin's ... ... lymphoma, 82% achieved a complete or improved response, indicating high efficacy of this treatment regimen. Despite its effectiveness, R-CHOP-14 was ...

4. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/3075/500110/Selective-PI3K-Inhibitor-Parsaclisib-Combined-with

Selective PI3Kδ Inhibitor Parsaclisib Combined with HDAC ... Preliminary data demonstrated that selective PI3Kδ Inhibitor parsaclisib with HDACi chidamide was tolerable and produced promising responses in r/r PTCL.

5. tandfonline.com tandfonline.com/doi/full/10.1080/10428194.2020.1832660

Phase 2 study of parsaclisib (INCB050465), a highly ... In the phase 1/2 CITADEL-101 study, parsaclisib monotherapy demonstrated an ORR of 30.4%, with a median DOR of 13.5 months (95% CI: 8.3–18.8) in ...

6. ashpublications.org ashpublications.org/blood/article/138/Supplement%201/44/477497/Efficacy-and-Safety-of-Parsaclisib-in-Patients

Efficacy and Safety of Parsaclisib in Patients with Relapsed or ... Serious TEAEs were experienced by 47.0% of pts overall, the most common was pneumonia (9.0%). 6.0% of pts experienced fatal TEAEs including ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8331102/

Recent Advances in the Management of Patients with ... As a single agent it has also demonstrated activity against 5 different subtypes of R/R non-Hodgkin lymphoma (NHL) with an ORR of 38% with 14% ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04323956

NCT04323956 | Parsaclisib Plus the Standard Drug ... It is not yet known if giving parsaclisib and R-CHOP together works better than R-CHOP alone in treating patients with high risk diffuse large B-cell lymphoma.