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

NCT04845035 | Withdrawn Phase 2 FDA Drug

• 2 other identifiers: UMCC 2018.144HUM00171952
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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

Keywords

Acute Lymphoblastic Leukemia; Dasatinib; Philadelphia chromosome; Ponatinib

Outcome Measures

Primary Outcomes (1)

• 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.

  Post day 36; up to day 43

Secondary Outcomes (7)

• Rate of Adverse Events related to Dasatinib and Ponatinib

  30 days after last treatment, up to approximately 3 years

• Percentage of participants who begin ponatinib post-induction that complete at least one cycle.

  At 18 weeks

• Complete hematologic (morphologic) remission (CHR) rate after induction

  After Remission Induction Phase I and at end of study treatment, up to approximately 3 years

• Complete cytogenic remission (CCyR) rate post induction

  After Remission Induction Phase I and at end of study treatment, up to approximately 3 years

• Complete molecular remission (CMR) rate

  After Remission Induction Phase I and at end of study treatment, up to approximately 3 years

Study Arms (1)

BFM + Tyrosine Kinase Inhibitor

EXPERIMENTAL

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; Drug: Ponatinib; Drug: Berlin-Frankfurt-Münster Chemotherapy; Drug: Methotrexate and Cytarabine

Interventions

Dasatinib DRUG

By mouth

BFM + Tyrosine Kinase Inhibitor

Ponatinib DRUG

By mouth

BFM + Tyrosine Kinase Inhibitor

Berlin-Frankfurt-Münster Chemotherapy DRUG

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

BFM + Tyrosine Kinase Inhibitor

Methotrexate and Cytarabine DRUG

Intrathecal

BFM + Tyrosine Kinase Inhibitor

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• University of Michigan Rogel Cancer Center: lead
• Takeda: collaborator

Study Sites (1)

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Philadelphia Chromosome

Interventions

Dasatinib; ponatinib; Methotrexate; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Translocation, Genetic; Chromosome Aberrations; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Cytidine; Pyrimidine Nucleosides; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Patrick Burke, MD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 5, 2021
• First Posted: April 14, 2021
• Study Start: January 1, 2024
• Primary Completion: January 1, 2026
• Study Completion (Estimated): January 1, 2029
• Last Updated: February 22, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)