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

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ClinicalTrials.gov Identifier: NCT04845035
Recruitment Status : Recruiting
First Posted : April 14, 2021
Last Update Posted : May 12, 2022
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
University of Michigan Rogel Cancer Center

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.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Drug: Dasatinib Drug: Ponatinib Drug: Berlin-Frankfurt-Münster Chemotherapy Drug: Methotrexate and Cytarabine Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 23 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study Using a BFM Regimen Plus Tyrosine Kinase Inhibitor in Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Estimated Study Start Date : July 2022
Estimated Primary Completion Date : March 2025
Estimated Study Completion Date : March 2028


Arm Intervention/treatment
Experimental: 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.
Drug: Dasatinib
By mouth

Drug: Ponatinib
By mouth

Drug: Berlin-Frankfurt-Münster Chemotherapy
with varied cycles, including Daunorubicin, Vincristine, Prednisone, Pegaspargase, Rituximab, Cytarabine, Mercaptopurine, Cyclophosphamide, Methotrexate, Doxorubicin, Thioguanine, and Dexamethasone

Drug: Methotrexate and Cytarabine
Intrathecal




Primary Outcome Measures :
  1. Rate of complete molecular remission (CMR) at the end of one cycle of Dasatinib + BFM [ Time Frame: Post day 36; up to day 43 ]
    CMR will be assessed by minimal residual disease (MRD)-negative status, using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) analysis from bone marrow aspirates, after 1 cycle of induction therapy with Berlin-Frankfurt-Münster (BFM) protocol and Dasatinib.


Secondary Outcome Measures :
  1. Rate of Adverse Events related to Dasatinib and Ponatinib [ Time Frame: 30 days after last treatment, up to approximately 3 years ]

    Per NCI CTCAE v5.0 toxicity data, specifically:

    • for dasatinib: pulmonary hypertension (any grade) or grade ≥ 3 serositis/volume overload.
    • for ponatinib: arterial embolism (any grade) and grade ≥ 3 venous thromboembolism, heart failure, or pancreatitis

  2. Percentage of participants who begin ponatinib post-induction that complete at least one cycle. [ Time Frame: At 18 weeks ]
    Feasibility will be assessed by the percentage, among patients who begin the ponatinib post-induction regimen, that complete at least one cycle. Completion is defined as the ability to tolerate ≥ 80% dose intensity of all prescribed anti-cancer agents per cycle of ponatinib initiated.

  3. Complete hematologic (morphologic) remission (CHR) rate after induction [ Time Frame: After Remission Induction Phase I and at end of study treatment, up to approximately 3 years ]
    Bone marrow assessed by morphologic review of both the aspirate smear and core biopsy

  4. Complete cytogenic remission (CCyR) rate post induction [ Time Frame: After Remission Induction Phase I and at end of study treatment, up to approximately 3 years ]
    Bone marrow aspirate assessed by karyotype and/or fluorescence in situ hybridization (FISH).

  5. Complete molecular remission (CMR) rate [ Time Frame: After Remission Induction Phase I and at end of study treatment, up to approximately 3 years ]
    Bone marrow aspirate analyzed by RT-qPCR.

  6. Disease-free survival (DFS) [ Time Frame: up to five years after end of study treatment (approximately 8 years) ]
    Disease-Free Survival (DFS) is defined as the duration of time from attainment of CR (morphologic remission, hematologic remission, etc) to Morphologic Relapse (Relapsed Disease) or Death.

  7. Overall survival (OS). [ Time Frame: up to five years after end of study treatment (approximately 8 years) ]
    Overall Survival (OS) is defined as the length of time from the date of diagnosis that patients diagnosed with the disease are still alive.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key 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

Key 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04845035


Locations
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United States, Michigan
University of Michigan Rogel Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Cancer AnswerLine    800-865-1125    CancerAnswerLine@med.umich.edu   
Principal Investigator: Patrick Burke, MD         
Sponsors and Collaborators
University of Michigan Rogel Cancer Center
Takeda
Investigators
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Principal Investigator: Patrick Burke, MD University of Michigan
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Responsible Party: University of Michigan Rogel Cancer Center
ClinicalTrials.gov Identifier: NCT04845035    
Other Study ID Numbers: UMCC 2018.144
HUM00171952 ( Other Identifier: University of Michigan )
First Posted: April 14, 2021    Key Record Dates
Last Update Posted: May 12, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Michigan Rogel Cancer Center:
Acute Lymphoblastic Leukemia
Dasatinib
Philadelphia chromosome
Ponatinib
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Cytarabine
Methotrexate
Dasatinib
Ponatinib
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors