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

Primary Purpose

Acute Lymphoblastic Leukemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Dasatinib
Ponatinib
Berlin-Frankfurt-Münster Chemotherapy
Methotrexate and Cytarabine
Sponsored by
University of Michigan Rogel Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring Acute Lymphoblastic Leukemia, Dasatinib, Philadelphia chromosome, Ponatinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Michigan Rogel Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BFM + Tyrosine Kinase Inhibitor

Arm Description

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.

Outcomes

Primary Outcome Measures

Rate of complete molecular remission (CMR) at the end of one cycle of Dasatinib + BFM
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

Rate of Adverse Events related to Dasatinib and Ponatinib
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
Percentage of participants who begin ponatinib post-induction that complete at least one cycle.
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.
Complete hematologic (morphologic) remission (CHR) rate after induction
Bone marrow assessed by morphologic review of both the aspirate smear and core biopsy
Complete cytogenic remission (CCyR) rate post induction
Bone marrow aspirate assessed by karyotype and/or fluorescence in situ hybridization (FISH).
Complete molecular remission (CMR) rate
Bone marrow aspirate analyzed by RT-qPCR.
Disease-free survival (DFS)
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.
Overall survival (OS).
Overall Survival (OS) is defined as the length of time from the date of diagnosis that patients diagnosed with the disease are still alive.

Full Information

First Posted
April 5, 2021
Last Updated
August 30, 2023
Sponsor
University of Michigan Rogel Cancer Center
Collaborators
Takeda
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1. Study Identification

Unique Protocol Identification Number
NCT04845035
Brief Title
Pediatric-Inspired Chemotherapy Plus Tyrosine Kinase Inhibitor in Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Official Title
A Phase II Study Using a BFM Regimen Plus Tyrosine Kinase Inhibitor in Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 2024 (Anticipated)
Primary Completion Date
January 2026 (Anticipated)
Study Completion Date
January 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Michigan Rogel Cancer Center
Collaborators
Takeda

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia
Keywords
Acute Lymphoblastic Leukemia, Dasatinib, Philadelphia chromosome, Ponatinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
23 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
BFM + Tyrosine Kinase Inhibitor
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Dasatinib
Intervention Description
By mouth
Intervention Type
Drug
Intervention Name(s)
Ponatinib
Intervention Description
By mouth
Intervention Type
Drug
Intervention Name(s)
Berlin-Frankfurt-Münster Chemotherapy
Intervention Description
with varied cycles, including Daunorubicin, Vincristine, Prednisone, Pegaspargase, Rituximab, Cytarabine, Mercaptopurine, Cyclophosphamide, Methotrexate, Doxorubicin, Thioguanine, and Dexamethasone
Intervention Type
Drug
Intervention Name(s)
Methotrexate and Cytarabine
Intervention Description
Intrathecal
Primary Outcome Measure Information:
Title
Rate of complete molecular remission (CMR) at the end of one cycle of Dasatinib + BFM
Description
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.
Time Frame
Post day 36; up to day 43
Secondary Outcome Measure Information:
Title
Rate of Adverse Events related to Dasatinib and Ponatinib
Description
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
Time Frame
30 days after last treatment, up to approximately 3 years
Title
Percentage of participants who begin ponatinib post-induction that complete at least one cycle.
Description
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.
Time Frame
At 18 weeks
Title
Complete hematologic (morphologic) remission (CHR) rate after induction
Description
Bone marrow assessed by morphologic review of both the aspirate smear and core biopsy
Time Frame
After Remission Induction Phase I and at end of study treatment, up to approximately 3 years
Title
Complete cytogenic remission (CCyR) rate post induction
Description
Bone marrow aspirate assessed by karyotype and/or fluorescence in situ hybridization (FISH).
Time Frame
After Remission Induction Phase I and at end of study treatment, up to approximately 3 years
Title
Complete molecular remission (CMR) rate
Description
Bone marrow aspirate analyzed by RT-qPCR.
Time Frame
After Remission Induction Phase I and at end of study treatment, up to approximately 3 years
Title
Disease-free survival (DFS)
Description
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.
Time Frame
up to five years after end of study treatment (approximately 8 years)
Title
Overall survival (OS).
Description
Overall Survival (OS) is defined as the length of time from the date of diagnosis that patients diagnosed with the disease are still alive.
Time Frame
up to five years after end of study treatment (approximately 8 years)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick Burke, MD
Organizational Affiliation
University of Michigan
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Michigan Rogel Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Cancer AnswerLine
Phone
800-865-1125
Email
CancerAnswerLine@med.umich.edu
First Name & Middle Initial & Last Name & Degree
Patrick Burke, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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