Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin (DA-EPOCH) With or Without Rituximab Plus Recombinant Erwinia Asparaginase (JZP458) for the Treatment of Newly Diagnosed Ph Negative B-Acute Lymphoblastic Leukemia or T Acute Lymphoblastic Leukemia

Phase 2

Not yet recruiting

• Conditions: B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative; T Acute Lymphoblastic Leukemia
• Interventions: Drug: Asparaginase Erwinia chrysanthemi; Procedure: Biospecimen Collection; Procedure: Bone Marrow Collection; Procedure: Computed Tomography; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Etoposide; Biological: Filgrastim; Biological: Pegfilgrastim; Procedure: Positron Emission Tomography; Drug: Prednisone; Biological: Rituximab; Drug: Vincristine

• Registration Number: NCT06738368
• Lead Sponsor: University of Washington

Brief Summary

This phase II trial tests how well etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH) with or without rituximab plus recombinant Erwinia asparaginase (JZP458) works in treating patients with newly diagnosed Philadelphia chromosome (Ph) negative B-acute lymphoblastic leukemia (ALL) or T-ALL. Chemotherapy drugs, such as etoposide, vincristine, cyclophosphamide and doxorubicin, 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. Anti-inflammatory drugs, such as prednisone, lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. JZP458 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving DA-EPOCH with or without rituximab plus JZP458 may kill more cancer cells in patients with newly diagnosed Ph negative B-ALL or T-ALL.

Detailed Description

OUTLINE:

Patients receive etoposide intravenously (IV), doxorubicin IV and vincristine IV over 96 hours on days 1-4, cyclophosphamide IV over 1 hour on day 5, prednisone orally (PO) twice daily (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 intramuscularly (IM) once 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 subcutaneously (SC) once or filgrastim SC once daily (QD) until absolute neutrophil count (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 computed tomography (CT) or positron emission tomography (PET)/CT throughout the study.

After completion of study treatment, patients are followed up every 3 months for 2 years then every 6 months for up to 3 years.

Study Timeline

• Status Verified: 2024-12
• Study First Submitted: 2024-12-12
• Study First Submitted QC: 2024-12-12
• Last Update Submitted: 2024-12-12
• Study First Posted: 2024-12-17
• Last Update Posted: 2024-12-17
• Study Start: 2025-06-01
• Primary Completion: 2027-12-31
• Study Completion: 2028-06-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Adults (age 18 years and older) with newly-diagnosed Ph- B-ALL or T-ALL
• 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.)
• Total bilirubin ≤ 2.0 x upper limit of normal (ULN) (unless attributed to Gilbert's disease or other causes of inherited indirect hyperbilirubinemia, at which point total bilirubin must be ≤ 4.0 x ULN) (Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the total bilirubin is ≤ 5.0 x ULN and alanine aminotransferase [ALT]/aspartate aminotransferase [AST] are ≤ 8.0 x ULN.)
• AST (serum glutamic oxaloacetic transaminase [SGOT])/ALT (serum glutamic pyruvic transaminase [SGPT]) ≤ 5.0 x institutional ULN. (Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the total bilirubin is ≤ 5.0 x ULN and ALT/AST are ≤ 8.0 x ULN.)
• Calculated creatinine clearance of ≥ 60 ml/min/1.73 m^2, as measured by the Modification of Diet in Renal Disease (MDRD) equation, will be eligible
• As patients with ALL frequently have cytopenias, no hematologic parameters will be required for enrollment or to receive the first cycle of treatment. However, adequate recovery of blood counts will be required to receive subsequent cycles
• Ability to give informed consent and comply with the protocol
• Anticipated survival of at least 3 months, independent of ALL
• Female subjects of childbearing potential should use effective non-hormonal contraceptive methods during treatment with JZP458 and for 3 months after the last dose of study drug. Male subjects with female partners of childbearing potential must agree to use an effective method of birth control from the time of signing the consent form until at least 3 months after the last dose of study drug

Exclusion Criteria

• Prior systemic therapy for ALL except to control acute symptoms and/or leukocytosis (e.g., corticosteroids, cytarabine, etc.). Cytarabine 500 mg/m^2 per dose up to 2 doses and/or the equivalent of prednisone 50 mg/m^2/day for up to 2 days are permitted

• Burkitt lymphoma/leukemia

• Isolated extramedullary or known parenchymal central nervous system (CNS) disease

• Known hypersensitivity or intolerance to any of the agents under investigation

• Known history of grade 3+ pancreatitis or chronic pancreatic insufficiency

• Known active chronic liver disease including, but not limited to, non-alcoholic steatohepatitis, cirrhosis, or non-alcoholic fatty liver disease

• Other medical or psychiatric conditions that in the opinion of the investigator would preclude safe participation in the protocol

• Pregnant or nursing

  • Pregnancy test is only required in women, unless they are highly unlikely to conceive (defined as [1] surgically sterilized, or [2] postmenopausal [i.e., a woman who is > 50 years old or who has not had menses for ≥ 1 year], or [3] not heterosexually active)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (DA-EPOCH, rituximab, JZP458)	Pegfilgrastim	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Asparaginase Erwinia chrysanthemi	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Doxorubicin	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Biospecimen Collection	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Bone Marrow Collection	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Computed Tomography	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Cyclophosphamide	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Etoposide	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Filgrastim	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Positron Emission Tomography	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Prednisone	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Rituximab	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.
Treatment (DA-EPOCH, rituximab, JZP458)	Vincristine	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.

Primary Outcome Measures

Name	Time	Method
Measurable residual disease (MRD) negativity	After 4 cycles of treatment (cycle length = 21 days)	Will be measured by multi-parameter flow cytometry (MFC). Will be assessed according to the National Comprehensive Cancer Network response criteria.

Secondary Outcome Measures

Name	Time	Method
MRD negativity	After 1 cycle of study therapy (cycle length = 21 days)	Will be measured by MFC. Will be assessed descriptively, using means, medians, and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures.
Incidence of grade 3 or higher non-hematologic adverse events (AEs)	Up to 30 days after last dose of study treatment	Will be assessed descriptively, using means, medians, and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures. The incidence of AEs will be reported as ratios or percentages.
Event-free survival (EFS)	Up to 5 years	Will be assessed descriptively, using means, medians, and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures. Kaplan-Meier curves will be used to depict EFS.
Relapse-free survival (RFS)	Up to 5 years	Will be assessed descriptively, using means, medians, and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures. Kaplan-Meier curves will be used to depict RFS.
Overall survival (OS)	Up to 5 years	Will be assessed descriptively, using means, medians, and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures. Kaplan-Meier curves will be used to depict OS.

Trial Locations

Locations (1)

Fred Hutch/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States