Chemotherapy + Rituximab for Acute Lymphoblastic Leukemia

Overseen By Kim Quach

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Must not be taking: Corticosteroids, Cytarabine

Disqualifiers: Burkitt lymphoma, CNS 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: 3

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of chemotherapy drugs, with or without rituximab (a type of immunotherapy), and JZP458 can effectively treat certain types of newly diagnosed acute lymphoblastic leukemia (ALL). The goal is to determine how well these treatments stop cancer cells from growing and spreading. It targets adults with B-acute lymphoblastic leukemia (ALL) or T-ALL who cannot follow a pediatric-style treatment plan, often due to older age or other concerns. Participants should have cancer cell involvement in their marrow or blood, as detected by specific testing. 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 does not specify if you need to stop taking your current medications. However, if you have taken certain treatments for ALL before, like corticosteroids or cytarabine, there are limits on how much you can have had. It's best to discuss your current medications with the trial team.

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

Previous studies have shown that the DA-EPOCH chemotherapy regimen, which includes etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, is generally well-tolerated by patients. It treats aggressive cancers and often causes expected side effects like low blood cell counts, which can be managed. Research indicates that rituximab is usually safe, even for older patients, with a very low risk of serious reactions during the first dose, though these are rare.

JZP458, a type of asparaginase, has a safety profile similar to other drugs in its class and is effective for patients who have had allergic reactions to similar treatments. While some patients stop treatment due to side effects, this is uncommon. Overall, these treatments have been studied and demonstrate a reasonable safety record, which is important for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of chemotherapy and rituximab for acute lymphoblastic leukemia because it introduces several unique elements compared to standard treatments. This approach includes the use of rituximab, a monoclonal antibody that specifically targets CD20-positive cancer cells, potentially enhancing the effectiveness of chemotherapy. Additionally, the regimen incorporates JZP458, a novel asparaginase formulation, which may offer improved tolerability and dosing flexibility over traditional asparaginase products. These features could lead to better outcomes and fewer side effects for patients, offering a promising advancement in leukemia treatment.

What evidence suggests that this trial's treatments could be effective for acute lymphoblastic leukemia?

In this trial, participants will receive the DA-EPOCH chemotherapy regimen, a combination of five drugs shown in studies to be effective and generally well-tolerated in patients with acute lymphoblastic leukemia (ALL). Early results indicate a significant reduction in the disease after just one treatment cycle. Additionally, some participants will receive rituximab, a targeted therapy that research supports for improving outcomes in ALL by attacking specific proteins on cancer cells, enhancing chemotherapy effectiveness without significant side effects. Lastly, recombinant Erwinia asparaginase (JZP458) is included in the regimen to maintain effective drug levels in the blood and has a safety profile similar to other treatments in its class. This combination of treatments shows promise in effectively targeting and killing leukemia cells in patients with ALL. ^{1 3 4 6 7}

Who Is on the Research Team?

Ryan D. Cassaday

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for patients with newly diagnosed Philadelphia chromosome-negative B-acute lymphoblastic leukemia or T-ALL. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and may need to have specific disease characteristics.

Inclusion Criteria

* In the opinion of the treating investigator, patients must be an unsuitable candidate for a pediatric-inspired regimen, reasons for which may include (but not be limited to) older age (e.g., ≥ 40 years), practical/logistical barriers to or toxicity concerns from administration of a pediatric-inspired regimen

* Marrow or blood involvement by ALL detectable by multi-parameter flow cytometry (MFC)

* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. (Performance status of 3 will be allowed if poor performance status is thought to be directly secondary to ALL.)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive DA-EPOCH chemotherapy with or without rituximab plus JZP458 for up to 8 cycles

24 weeks

Multiple visits for each cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 2 years, then every 6 months for up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Asparaginase Erwinia chrysanthemi
• Doxorubicin
• Prednisone
• Rituximab

Trial Overview The trial tests DA-EPOCH chemotherapy (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) with/without rituximab plus JZP458 in treating Ph negative B-ALL or T-ALL. It aims to see if adding these drugs can better kill cancer cells.

How Is the Trial Designed?

Group I: Treatment (DA-EPOCH, rituximab, JZP458) Experimental Treatment 13 Interventions

Patients receive etoposide IV, doxorubicin IV and vincristine IV over 96 hours on days 1-4, cyclophosphamide IV over 1 hour on day 5, prednisone PO BID on days 1-5 of each cycle. In addition, CD20 positive patients receive rituximab IV on day 1 or 5 of each cycle. Patients also receive JZP458 IM every 2-3 days on days 7-21 for up to 7 doses. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Starting on day 6, 7, or 8, patients also receive pegfilgrastim SC once or filgrastim SC QD until ANC \> 2000/uL past nadir. Patients also undergo blood sample collection and bone marrow collection throughout the study. Additionally, patients with extramedullary disease may undergo CT or PET/CT throughout the study.

Doxorubicin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Jazz Pharmaceuticals

Industry Sponsor

Trials

252

Recruited

35,100+

Bruce C. Cozadd

Jazz Pharmaceuticals

Chief Executive Officer since 2009

BA in Economics from Yale University, MBA from Stanford University

Dr. Austin

Jazz Pharmaceuticals

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Published Research Related to This Trial

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 phase II study involving 37 patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma, Rituximab was found to be well tolerated, with most adverse events being mild and decreasing with subsequent infusions.

The treatment resulted in a 57% overall response rate, with 14% achieving a complete response and 43% a partial response, indicating significant clinical activity and suggesting that extended Rituximab treatment may be effective for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Piro, LD., White, CA., Grillo-López, AJ., et al.[2022]

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]

The novel doxorubicin analogs WP744 and WP769 showed 2 to 36 times greater cytotoxicity against neuroblastoma cell lines compared to standard doxorubicin, indicating enhanced efficacy in treating this cancer.

WP744 demonstrated a unique ability to significantly increase sensitivity in neuroblastoma cells with MYCN amplification, suggesting it may be particularly effective for tumors with this genetic alteration and those resistant to conventional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WP744 is a novel anthracycline with enhanced activity against neuroblastoma. Inge, TH., Harris, NL., Wu, J., et al.[2018]

In a clinical phase II study involving 70 patients with refractory or early relapse acute lymphoblastic leukemia (ALL) and T-cell lymphoblastic non-Hodgkin's lymphoma (NHL), 78% achieved complete remission with the combination of high-dose idarubicin and high-dose cytosine-arabinoside, indicating strong antileukemic activity.

The treatment was well-tolerated, with limited non-hematologic side effects primarily related to infections, suggesting that this regimen could be a feasible option for patients while still allowing for potential bone marrow transplantation afterward.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single high dose of idarubicin combined with high-dose ABA-C (MSKCC ALL-3 protocol) in adult and pediatric patients with acute lymphoblastic leukemia. Experience at the University La Sapienza of Rome. Testi, AM., Moleti, ML., Giona, F., et al.[2013]

In a study of 112 patients under 65 years old with diffuse large B-cell lymphoma, the combination of rituximab and high-dose sequential chemotherapy led to an impressive 80% clinical remission rate, demonstrating its efficacy in treating this aggressive cancer.

At a median follow-up of 48 months, 78% of patients remained alive and 73% were in continuous remission, indicating that this treatment significantly improves life expectancy compared to conventional chemotherapy for younger patients with higher risk scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). Tarella, C., Zanni, M., Di Nicola, M., et al.[2022]

The combination of Doxil (40 mg/m2) and vinorelbine (30 mg/m2) was found to be effective in treating metastatic breast cancer in a phase I study involving 30 women, with a recommended schedule for further testing.

This combination therapy demonstrated a favorable toxicity profile, with minimal severe side effects like neutropenia and a low incidence of significant nausea, vomiting, or hair loss, making it a promising option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of Doxil and vinorelbine in metastatic breast cancer. Burstein, HJ., Ramirez, MJ., Petros, WP., et al.[2020]

This study analyzed over 7.5 million reports from the FDA Adverse Event Reporting System and found that conventional doxorubicin (DOX) has a higher incidence of adverse events compared to liposomal formulations, particularly in terms of myelosuppression and cardiotoxicity.

Liposomal DOX, especially the PEGylated version, showed lower reporting odds ratios for serious side effects like myelosuppression and cardiotoxicity, but a higher risk for palmar-plantar erythrodysesthesia (PPE), indicating the need for careful monitoring when using these formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. Fukuda, A., Tahara, K., Hane, Y., et al.[2022]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

Dexrazoxane (DZR) effectively protects against doxorubicin (DOX)-induced cardiotoxicity in both young and mature rats, showing significant cardioprotective activity at all time points examined during the study.

The study demonstrated that DZR mitigates adverse effects on liver and kidney weights, as well as serum cholesterol and triglycerides, indicating its potential safety and efficacy in reducing the harmful side effects of DOX treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protection against doxorubicin-induced cardiotoxicity in weanling rats by dexrazoxane. Della Torre, P., Mazué, G., Podestà, A., et al.[2013]

In a clinical phase II study involving 70 patients with refractory or early relapse acute lymphoblastic leukemia (ALL) and T-cell non-Hodgkin's lymphoma (NHL), the combination of high-dose idarubicin and high-dose cytosine-arabinoside (ARA-C) resulted in a complete remission rate of 78%.

The treatment was well-tolerated, with limited non-hematologic side effects primarily related to infections, suggesting that this regimen could be a feasible option for patients with difficult-to-treat leukemia without compromising future bone marrow transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single high dose of idarubicin combined with high-dose ARA-C (MSKCC ALL-3 protocol) in adult and pediatric patients with acute lymphoblastic leukemia. Experience at the University "La Sapienza" of Rome. Testi, AM., Moleti, ML., Giona, F., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10651770/

Recombinant Erwinia asparaginase (JZP458) in acute ... Intramuscular JZP458 at 25/25/50 mg/m2 M/W/F was effective in patients with ALL/LBL, with a safety profile similar to other asparaginases.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2473952924006268

Recombinant Erwinia asparaginase (JZP458) in ALL/LBL Recombinant Erwinia asparaginase JZP458 maintains therapeutic serum asparaginase activity levels via multiple IM and IV dosing schedules.

3. aetna.com aetna.com/cpb/medical/data/800_899/0864.html

Asparaginase Erwinia Chrysanthemi (Recombinant)-rywn ... Emadi et al (2014) stated that asparaginases are among the most effective agents against acute lymphoblastic leukemia (ALL) and are Food and Drug Administration ...

4. haematologica.org haematologica.org/article/view/11165

the amazing journey of the therapeutic anti-leukemia ... In 2023, Maese et al. reported that this recombinant Erwinia c. ASNase was efficacious at 25/25/50 mg/m when given IM on a MondayWednesday- ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.6521

Recombinant Erwinia asparaginase (JZP458) in acute ... Primary efficacy and safety data have been reported; here, we report on adverse events of interest (AEIs: allergic reaction, pancreatitis, ...

6. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1498/501397/Efficacy-and-Safety-of-Recombinant-Erwinia

Efficacy and Safety of Recombinant Erwinia Asparaginase ... It is used in treatment of patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT07133997

Recombinant Erwinia Asparaginase and Venetoclax in ... Giving asparaginase Erwinia chrysanthemi and venetoclax in combination with blinatumomab may be safe, tolerable, and/or effective in treating ...