DA-EPOCH + Ponatinib for Acute Lymphoblastic Leukemia

Overseen By Ryan Cassaday, MD

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: 11

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of cancer-fighting drugs to determine their effectiveness in treating Philadelphia chromosome-positive acute lymphoblastic leukemia or lymphoma (Ph+ ALL). The treatment includes several chemotherapy drugs, an antibody treatment, and a specialized drug called ponatinib, a targeted therapy that may stop cancer cells from growing. The goal is to establish a safe and effective treatment plan for individuals newly diagnosed with this specific type of leukemia. Suitable candidates for this trial have been newly diagnosed with Ph+ ALL and have cancer cells in their blood or bone marrow. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants, offering them a chance to contribute to significant advancements in leukemia treatment.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, it mentions that no prior systemic therapy for ALL is allowed except to control acute symptoms. 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 found the combination of DA-EPOCH, with or without rituximab and ponatinib, to be generally safe and tolerable for treating patients with newly diagnosed Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Research shows that DA-EPOCH, which includes etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, effectively treats cancer with manageable side effects.

Ponatinib, when combined with DA-EPOCH, has been studied for its ability to block proteins that promote cancer cell growth. Although these treatments can cause side effects, they are often manageable, and the combination shows promise for treating high-risk ALL. This current trial is in Phase 2, which aims to further confirm patient tolerance and better understand the treatment's effectiveness, building on the safety demonstrated in earlier trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for acute lymphoblastic leukemia (ALL), which typically involves chemotherapy regimens like Hyper-CVAD or CALGB 10403, the DA-EPOCH + Ponatinib treatment adds a new angle by incorporating ponatinib, a targeted tyrosine kinase inhibitor. Researchers are excited because ponatinib specifically targets the BCR-ABL protein, which is known to play a role in some types of ALL, potentially offering a more precise attack on cancer cells. Additionally, this treatment combines the chemotherapy backbone of DA-EPOCH with rituximab for CD20-positive patients, offering a tailored approach that could enhance effectiveness. This combination aims to improve outcomes by both directly inhibiting cancer cell growth and modulating the immune system's response.

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

Research has shown that the DA-EPOCH treatment, which participants in this trial may receive alongside ponatinib, shows promise for treating Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). In one study, 71% of patients experienced a significant reduction in cancer cells after four treatment cycles. This combination also appears to have fewer severe side effects compared to treatments like Hyper-CVAD, potentially making it easier for patients to tolerate. The treatment uses several drugs that attack cancer cells in various ways, including inhibiting proteins that promote cancer growth. Overall, early results suggest this approach could effectively manage Ph+ ALL. ^{1 2 3 6 7}

Who Is on the Research Team?

Ryan Cassaday, MD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for newly diagnosed patients with Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoma. Participants should not have received prior treatments and must be able to undergo various chemotherapy drugs, targeted therapy, and diagnostic procedures like bone marrow biopsy and imaging tests.

Inclusion Criteria

TBili ≤ 1.5 x ULN (unless attributed to Gilbert's disease or other causes of inherited indirect hyperbilirubinemia, where TBili must be ≤ 4 x ULN)

AST/ALT ≤ 2.5 x institutional ULN (exceptions for hepatic involvement by ALL where AST/ALT must be ≤ 8 x ULN)

Calculated creatinine clearance > 30 ml/min/1.73m^2 by MDRD equation

Exclusion Criteria

Known hypersensitivity or intolerance to investigational agents

Medical or psychiatric conditions precluding safe participation

Not pregnant or nursing, with specific nursing timelines based on treatment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive DA-EPOCH with or without rituximab plus ponatinib in 21-day cycles for up to 8 cycles

24 weeks

8 cycles, each with multiple visits for IV administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

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

• Cyclophosphamide
• Doxorubicin
• Etoposide
• Ponatinib
• Rituximab

Trial Overview The trial is testing a chemotherapy regimen called DA-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) combined with rituximab plus ponatinib versus the same chemo without these additions. It aims to see if adding rituximab and ponatinib improves treatment outcomes in Ph+ ALL.

How Is the Trial Designed?

Group I: Treatment (DA-EPOCH, rituximab, ponatinib) Experimental Treatment 14 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, 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.

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Takeda

Industry Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT07224100

Dose-Adjusted EPOCH With or Without Rituximab Plus ... Giving DA-EPOCH with or without rituximab plus ponatinib may be safe, tolerable, and/or effective in treating patients with newly diagnosed Ph+ ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10357946/

Phase II Study of Dose-Adjusted EPOCH as Initial Therapy for ... All patients had ≥1 high-risk clinical feature. Measurable residual disease-negativity by multiparameter flow cytometry within 4 cycles was achieved in 71% in ...

3. withpower.com withpower.com/trial/phase-2-precursor-cell-lymphoblastic-leukemia-lymphoma-4-2026-e3b0e

DA-EPOCH + Ponatinib for Acute Lymphoblastic Leukemia Giving DA-EPOCH with or without rituximab plus ponatinib may be safe, tolerable, and/or effective in treating patients with newly diagnosed Ph+ ...

4. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/ejh.14089

Hyper‐CVAD versus dose‐adjusted EPOCH as initial ... Compared to Hyper-CVAD, DA-EPOCH is associated with fewer Grade 3 or higher adverse events and less transfusion requirements. DA-EPOCH ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2152265021002512

Clinical Outcomes of Patients With Newly Diagnosed Acute ... Five-year EFS and OS rates were 22% and 38% for patients with pre-B ALL, 24% and 44% for patients with T ALL, and 13% and 27% for patients with Ph+ ALL (Figure ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121063072

614.Acute Lymphoblastic Leukemias: Therapies, Excluding ... DA-EPOCH yields comparable response and survival rates (with manageable toxicity) as more logistically-complex therapies in primarily high-risk ALL. When TKI ...

7. researchgate.net researchgate.net/publication/369376777_Phase_II_study_of_dose-adjusted_EPOCH_as_initial_therapy_for_adults_with_high-risk_acute_lymphoblastic_leukemia

Phase II study of dose-adjusted EPOCH as initial therapy ... To address this, we performed a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) ...