Pediatric-Inspired Chemotherapy Plus Tyrosine Kinase Inhibitor in Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

NCT ID: NCT04845035

Last Updated: 2024-02-22

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-01-31
• Study Completion Date: 2029-01-31

Brief Summary

This study will combine a standard, pediatric-inspired, chemotherapy regimen with the tyrosine kinase inhibitors (TKIs) Dasatinib and Ponatinib to treat adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

There are two age groups/cohorts:

• participants aged 18 to 59 years
• participants aged 60 years and older

One tyrosine kinase inhibitor (TKI), either Dasatinib or Ponatinib, will be administered in each of the respective chemotherapy cycles. The TKI (either Dasatinib or Ponatinib) administered in a given cycle of chemotherapy will be dictated by the given cycle's standard chemotherapy, in order to minimize overlapping side effects of the chemotherapy and TKI.

The dosages of the standard chemotherapy agents, as well as the tyrosine kinase inhibitors (TKIs)--Dasatinib and Ponatinib--have been adjusted for each age group to allow continuous administration of these TKIs.

Conditions

Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

BFM + Tyrosine Kinase Inhibitor

This study has 2 cohorts: participants aged 18 - 59 years and participants aged 60 or more years. Both cohorts receive the same study intervention with dosage adjusted for age. Participants receive the Berlin-Frankfurt-Münster (BFM) protocol plus dasatinib during a two-phase induction and a delayed re-induction. Participants receive the BFM protocol plus ponatinib during post-induction consolidations and maintenance.

Group Type: EXPERIMENTAL

Dasatinib

Intervention Type: DRUG

By mouth

Ponatinib

Intervention Type: DRUG

By mouth

Berlin-Frankfurt-Münster Chemotherapy

Intervention Type: DRUG

with varied cycles, including Daunorubicin, Vincristine, Prednisone, Pegaspargase, Rituximab, Cytarabine, Mercaptopurine, Cyclophosphamide, Methotrexate, Doxorubicin, Thioguanine, and Dexamethasone

Methotrexate and Cytarabine

Intervention Type: DRUG

Intrathecal

Interventions

Dasatinib

By mouth

Intervention Type: DRUG

Ponatinib

By mouth

Intervention Type: DRUG

Berlin-Frankfurt-Münster Chemotherapy

with varied cycles, including Daunorubicin, Vincristine, Prednisone, Pegaspargase, Rituximab, Cytarabine, Mercaptopurine, Cyclophosphamide, Methotrexate, Doxorubicin, Thioguanine, and Dexamethasone

Intervention Type: DRUG

Methotrexate and Cytarabine

Intrathecal

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients ≥ 18 years of age.
• Baseline ECOG Performance Status ≤ 2, and patient is a candidate for intensive chemotherapy.
• Newly diagnosed Ph+ ALL.
• Written informed consent prior to any screening procedures. Permitted exceptions are that the diagnostic marrow exam/peripheral blood/nodal biopsy tests confirming Ph+ B-Cell ALL, as well as pre-induction cardiac workup (EKG/TTE/MUGA), may be performed prior to the patient providing written informed consent if these tests are within 14 days of enrollment.
• Patient able to give informed consent.
• B-cell Acute Lymphoblastic Leukemia with BCR-ABL1, i.e., Philadelphia chromosome-positive (Ph+) ALL.

• B-Cell lineage determined by standard flow cytometry/IHC
• Ph+ by cytogenetics (karyotype/FISH) and/or molecular (BCR-ABL1 transcripts)
• Determined in CLIA-certified laboratory
• Previously untreated, except for below allowances in a recent diagnosis and up until 48 hours after starting trial therapy:

• Corticosteroids
• Hydroxyurea
• Leukapheresis

Exclusion Criteria

• Any of the following subtypes of ALL:

• Ph-negative B-Cell ALL.
• T-Cell ALL.
• Relapsed Ph+ ALL.
• Lymphoid blast crisis of chronic myeloid leukemia (CML).
• Mature B-Cell (Burkitt's) ALL.
• Clinical signs of CNS disease.
• Active ALL in CNS or testes.
• Estimated Glomerular Filtration Rate (eGFR) by MDRD formula and calculated creatinine clearance (CrCl), based on a 24-hour urine collection, < 30 mL/min-unless related to ALL/tumor lysis syndrome and able to be corrected.
• Total Bilirubin > 2x ULN; AST/ALT > 10x ULN, unless related to ALL liver infiltration.
• Patients with known history of HIV, Hepatitis B, or Hepatitis C.
• Pre-treatment QTcF > 480 msecs.
• Left Ventricular Ejection Fraction < 45%. If an initial TTE demonstrates LVEF < 45%, a confirmatory MUGA should be performed to confirm LVEF is < 45% prior to excluding the patient. Both a TTE and a MUGA with LVEF < 45% are needed to exclude a patient. Either a TTE or MUGA alone, if LVEF is ≥ 45%, is sufficient to include a patient.
• Have significant or active cardiovascular disease, specifically including but not restricted to:

• Known prior type 1 (thrombotic) myocardial infarction (type 2 myocardial infarction/demand ischemia is not necessarily excluded).
• History of clinically significant atrial arrhythmia or any ventricular arrhythmia.
• Unstable angina within the last 12 months.
• Congestive heart failure within the last 12 months.
• Currently uncontrolled hypertension (≥ Grade 3; or systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure ≥ 100 mm Hg).
• Acute pancreatitis within the last year or a history of chronic pancreatitis.
• Have malabsorption syndrome or other gastrointestinal illness that could affect the absorption of orally administered chemotherapy.
• Ongoing uncontrolled severe nausea or vomiting.
• History of a significant bleeding disorder unrelated to ALL, including:

• Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease).
• Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).
• Taking any medications or herbal supplements that are known to be strong inhibitors or inducers of CYP3A4 within at least 7 days or 5 half-lives (whichever is longer) before the first dose of study chemotherapy on day 1 of Remission Induction Phase I (RIP1).
• Active malignancy requiring treatment, other than ALL, within two years prior to start of treatment, with the exception of basal cell or squamous cell carcinoma of the skin, colon polyp, carcinoma in situ of the cervix, or DCIS or LCIS of the breast.
• Active uncontrolled infection, any other concurrent disease, or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator.
• Pregnant women or women who are breast-feeding
• Men and women of childbearing potential must be willing to practice an effective method of birth control during treatment and up until 30 days following the end of trial therapy.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: collaborator

University of Michigan Rogel Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Patrick Burke, MD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, United States

Countries

United States

Other Identifiers

HUM00171952

Identifier Type: OTHER

Identifier Source: secondary_id

UMCC 2018.144

Identifier Type: -

Identifier Source: org_study_id