Dose-Adjusted EPOCH With or Without Rituximab Plus Ponatinib for the Treatment of Newly-Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia/Lymphoma

Phase II Study of Dose-Adjusted EPOCH ± Rituximab + Ponatinib for Adults With Newly-Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia/Lymphoma

This phase II trial tests the effect of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) with or without rituximab plus ponatinib in treating patients newly diagnosed with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia or lymphoma (ALL). Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill cancer cells. Prednisone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Doxorubicin is a drug that is used to treat many types of cancer and is being studied in the treatment of other types of cancer. Doxorubicin comes from the bacterium Streptomyces peucetius. It damages DNA and may kill cancer cells. It is a type of anthracycline antitumor antibiotic. DA-EPOCH involves a longer exposure time to doxorubicin, vincristine and etoposide compared to a higher concentration over a shorter time which may provide better tumor response. 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. Ponatinib blocks BCR::ABL1 and other proteins, which may help keep cancer cells from growing and may kill them. It may also prevent the growth of new blood vessels that tumors need to grow. Ponatinib is a type of tyrosine kinase inhibitor and a type of antiangiogenesis agent. Giving DA-EPOCH with or without rituximab plus ponatinib may be safe, tolerable, and/or effective in treating patients with newly diagnosed Ph+ ALL.

Study Overview

• Status: Recruiting
• Conditions: Lymphoblastic Lymphoma; B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; B Lymphoblastic Leukemia/Lymphoma With t(9;22)(q34.1;q11.2); BCR-ABL1
• Intervention / Treatment: Drug: Etoposide; Procedure: Biospecimen Collection; Drug: Cyclophosphamide; Drug: Prednisone; Biological: Pegfilgrastim; Drug: Vincristine; Biological: Filgrastim; Biological: Rituximab; Drug: Doxorubicin; Procedure: Positron Emission Tomography; Drug: Ponatinib; Procedure: Computed Tomography; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy

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, and prednisone orally (PO) twice daily (BID) on days 1-5 and ponatinib PO once daily (QD) on days 1-21 of each cycle. Patients receive filgrastim subcutaneously (SC) on day 6, 7, or 8 and continue until absolute neutrophil count (ANC) > 2000/µL past nadir or pegfilgrastim SC on day 6, 7, or 8 of each cycle. Patients who are CD20 positive also receive rituximab IV on day 1 or 5 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration and biopsy and computed tomography (CT) throughout the study. Additionally, patients may undergo positron emission tomography (PET)/CT at enrollment.

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

• Study Type: Interventional
• Enrollment (Estimated): 33
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ryan Cassaday, MD; Phone Number: 206-606-6744; Email: cassaday@uw.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Contact: Ryan Cassaday, MD; Phone Number: 206-606-6744; Email: cassaday@uw.edu
      • Principal Investigator: Ryan Cassaday, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults (age 18 years and older) with newly-diagnosed Ph+ B-ALL. Ph status will be determined by routine cytogenetics, fluorescence in situ hybridization (FISH), and/or reverse transcriptase-polymerase chain reaction (RT-PCR) for the BCR::ABL1 translocation
• Marrow or blood involvement by abnormal lymphoblasts detectable by multiparameter flow cytometry (MFC)

• Total bilirubin (TBili) ≤ 1.5 x upper limit of normal (ULN) (unless attributed to Gilbert's disease or other causes of inherited indirect hyperbilirubinemia, at which point TBili must be ≤ 4 x ULN)

  • (Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the TBili is ≤ 5 x ULN)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x institutional ULN

  • (Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the ALT/AST are ≤ 8 x ULN)
• Calculated creatinine clearance of > 30 ml/min/1.73m^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
• 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)
• Ability to give informed consent and comply with the protocol
• Anticipated survival of at least 3 months, independent of ALL

• Female subjects of reproductive potential must agree to use an effective method of birth control from the time of signing the consent form until one of the following:

  • For subjects not expected to receive rituximab (i.e., CD20-negative): at least 3 weeks after the last dose of ponatinib, or
  • For subjects expected to receive rituximab (i.e., CD20-positive): at least 12 months after the last dose of rituximab
  • A subject does not have reproductive potential if they are (1) surgically sterilized, or (2) postmenopausal (i.e., a female who is > 50 years old or who has not had menses for ≥ 1 year), or (3) not heterosexually active
• Male subjects must agree to use an effective method of birth control and to not donate sperm from the time of signing the consent form until at least 3 weeks after the last dose of ponatinib

Exclusion Criteria:

• Burkitt lymphoma/leukemia
• No prior systemic therapy for ALL except to control acute symptoms and/or hyperleukocytosis (e.g., corticosteroids, cytarabine, etc.)
• No isolated extramedullary or known parenchymal central nervous system (CNS) disease
• History of acute pancreatitis within 1 year of enrollment or known chronic pancreatitis
• Symptomatic atherosclerotic cardiovascular disease (e.g., myocardial infarction, cerebrovascular accident, peripheral arterial disease, etc.) within 1 year of enrollment
• Active resistant hypertension, defined as having an ambulatory blood pressure above goal despite use of 3 antihypertensive medications from different classes
• Venous thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months of enrollment
• Known hypersensitivity or intolerance to any of the agents under investigation
• Other medical or psychiatric conditions that in the opinion of the investigator would preclude safe participation in the protocol
• May not be pregnant or nursing. Pregnancy test is only required in females, unless they do not have reproductive potential. For subjects not expected to receive rituximab (i.e., CD20-negative), nursing can occur 1 week after the last dose of ponatinib. For subjects expected to receive rituximab (i.e., CD20-positive), nursing can occur 6 months after the last dose of rituximab

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (DA-EPOCH, rituximab, ponatinib); Patients receive etoposide IV, doxorubicin IV, and vincristine IV over 96 hours on days 1-4, cyclophosphamide IV over 1 hour on day 5, and prednisone PO BID on days 1-5 and ponatinib PO QD on days 1-21 of each cycle. Patients receive filgrastim SC on day 6, 7, or 8 and continue until ANC > 2000/µL past nadir or pegfilgrastim SC on day 6, 7, or 8 of each cycle. Patients who are CD20 positive also receive rituximab IV on day 1 or 5 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration and biopsy and CT throughout the study. Additionally, patients may undergo PET/CT at enrollment.

Drug: Etoposide; Given IV; Other Names: Demethyl Epipodophyllotoxin Ethylidine Glucoside; EPEG; Lastet; Toposar; Vepesid; VP 16; VP 16-213; VP-16; VP-16-213; VP16; VP 16213; VP-16213; VP16213; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Asta B 518; B-518; WR-138719; B 518; B518; WR 138719; WR138719; Drug: Prednisone; Given PO; Other Names: Deltasone; Orasone; .delta.1-Cortisone; 1, 2-Dehydrocortisone; Adasone; Cortancyl; Dacortin; DeCortin; Decortisyl; Decorton; Delta 1-Cortisone; Delta-Dome; Deltacortene; Deltacortisone; Deltadehydrocortisone; Deltison; Deltra; Econosone; Lisacort; Meprosona-F; Metacortandracin; Meticorten; Ofisolona; Panafcort; Panasol-S; Paracort; Perrigo Prednisone; PRED; Predicor; Predicorten; Prednicen-M; Prednicort; Prednidib; Prednilonga; Predniment; Prednisone Intensol; Prednisonum; Prednitone; Promifen; Rayos; Servisone; SK-Prednisone; Biological: Pegfilgrastim; Given SC; Other Names: Filgrastim SD-01; filgrastim-SD/01; Fulphila; HSP-130; Jinyouli; Neulasta; Neulastim; Nyvepria; PEG-filgrastim; Pegcyte; Pegfilgrastim Biosimilar HSP-130; Pegfilgrastim Biosimilar Nyvepria; Pegfilgrastim Biosimilar Pegcyte; Pegfilgrastim Biosimilar PF-06881894; Pegfilgrastim Biosimilar Udenyca; Pegfilgrastim Biosimilar Ziextenzo; Pegfilgrastim-jmdb; PF-06881894; SD-01; SD-01 sustained duration G-CSF; Udenyca; Ziextenzo; Neupopeg; Pegylated G-CSF; Pegylated GCSF; Pegylated Granulocyte Colony Stimulating Factor; Pegfilgrastim-apgf; Pegfilgrastim-bmez; Pegfilgrastim-cbqv; Dulastin; Tripegfilgrastim; Fylnetra; G-Lasta; Pegfilgrastim-fpgk; Pegfilgrastim-pbbk; Stimufend; Drug: Vincristine; Given IV; Other Names: VCR; Leurocristine; Vincrystine; LCR; Biological: Filgrastim; Given SC; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Filgrastim-aafi; Nivestym; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; Filgrastim Biosimilar Filgrastim-sndz; Zarxio; Filgrastim XM02; Tbo-filgrastim; Granix; Nivestim; XM02; Filgrastim-sndz; Filgrastim Biosimilar Tbo-filgrastim; Filgrastim-ayow; Releuko; Neutroval; Biological: Rituximab; Given IV; Other Names: Rituxan; MabThera; ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; Monoclonal Antibody IDEC-C2B8; PF-05280586; Riabni; Rituximab ABBS; Rituximab ARRX; Rituximab Biosimilar ABP 798; Rituximab Biosimilar BI 695500; Rituximab Biosimilar CT-P10; Rituximab Biosimilar GB241; Rituximab Biosimilar IBI301; Rituximab Biosimilar JHL1101; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; Rituximab Biosimilar SAIT101; Rituximab Biosimilar SIBP-02; rituximab biosimilar TQB2303; Rituximab PVVR; Rituximab-arrx; Rituximab-pvvr; RTXM83; Ruxience; Truxima; Rixathon; Ikgdar; Mabtas; Rituximab-abbs; BI-695500; BI695500; Blitzima; IDEC 102; IDEC102; PF 05280586; PF05280586; Ritemvia; Rituximab-blit; Rituximab-rite; Rituximab-rixa; Rituximab-rixi; Riximyo; RTXM 83; RTXM-83; ABP-798; ABP798; CT P10; CTP10; GP 2013; GP-2013; GP2013; Rituximab Biosimilar GP2013; Drug: Doxorubicin; Given IV; Other Names: Adriablastin; Hydroxydaunomycin; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; Positron Emission Tomography Scan; PT; PET scan; Drug: Ponatinib; Given PO; Other Names: AP-24534; AP24534; AP 24534; Procedure: Computed Tomography; Undergo CT and PET/CT; Other Names: CT; CAT; Computed Axial Tomography; Computerized Axial Tomography; CAT scan; CT scan; Computerized Tomography (CT) scan; Diagnostic CAT Scan; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration and biopsy; Procedure: Bone Marrow Biopsy; Undergo bone marrow aspiration and biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of complete molecular response	Will be evaluated by BCR::ABL1 reverse transcriptase polymerase chain reaction.	Up to completion of 4 cycles (approximately 3 months) (cycle length = 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of non-hematologic toxicities greater than or equal to grade 3	Will be graded in severity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Will be reported as ratios/percentages. Will exclude asymptomatic grade 3 laboratory abnormalities.	Up to 30 days after last dose of study treatment
Incidence of serious adverse events	Will be graded in severity using NCI CTCAE v 5.0. Will be reported as ratios/percentages.	Up to 30 days after last dose of study treatment
Frequency of patients unable to complete one full cycle of etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin +/- rituximab + ponatinib (Feasibility)	Will be assessed descriptively, using means and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures, and either Kaplan-Meier or cumulative incidence estimates for time-to-event outcomes (depending on whether competing risks are present).	Up to 5 years after last dose of study treatment
Event-free survival	Will be assessed descriptively, using means and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures, and either Kaplan-Meier or cumulative incidence estimates for time-to-event outcomes (depending on whether competing risks are present). Kaplan-Meier curves will be used to depict survival.	Up to 5 years after last dose of study treatment
Relapse-free survival	Will be assessed descriptively, using means and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures, and either Kaplan-Meier or cumulative incidence estimates for time-to-event outcomes (depending on whether competing risks are present). Kaplan-Meier curves will be used to depict survival.	Up to 5 years after last dose of study treatment
Duration of remission	Will be assessed descriptively, using means and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures, and either Kaplan-Meier or cumulative incidence estimates for time-to-event outcomes (depending on whether competing risks are present). Kaplan-Meier curves will be used to depict survival.	Up to 5 years after last dose of study treatment
Overall survival	Will be assessed descriptively, using means and associated confidence intervals for continuous measures, simple ratios and Clopper-Pearson confidence intervals for binary measures, and either Kaplan-Meier or cumulative incidence estimates for time-to-event outcomes (depending on whether competing risks are present). Kaplan-Meier curves will be used to depict survival.	Up to 5 years after last dose of study treatment

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Takeda
• Investigators: Principal Investigator: Ryan Cassaday, MD, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2026
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2028

Study Registration Dates

• First Submitted: October 29, 2025
• First Submitted That Met QC Criteria: October 29, 2025
• First Posted (Actual): November 4, 2025

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Hemic and Lymphatic Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Carbohydrates; Alkaloids; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glucosides; Glycosides; Indoles; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Chemistry Techniques, Analytical; Spectrum Analysis; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Intercellular Signaling Peptides and Proteins; Pregnadienediols; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Anthracyclines; Naphthacenes; Aminoglycosides; Glycoproteins; Glycoconjugates; Antibodies, Monoclonal, Murine-Derived; Daunorubicin; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Rituximab; Prednisone; Cyclophosphamide; Etoposide; Doxorubicin; Vincristine; Magnetic Resonance Spectroscopy; CT-P10; Granulocyte Colony-Stimulating Factor; Filgrastim; deltacortene; prednylidene; pegfilgrastim; pegylated granulocyte colony-stimulating factor; ponatinib
• Other Study ID Numbers: RG1125799; NCI-2025-07631 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); FHIRB0021018 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No