Patient case: 4-year-old female with leukemia; genetic feature: ABL1

Clinical trial: Therapies in Combination or Sequentially With Tyrosine Kinase Inhibitors (TKIs) in Chronic Phase Chronic Myelogenous Leukemia Patients in CCR (ACTIW)

Summary: Patients will be randomized in phase II trials to continue on the same TKI versus one of the alternative treatment approaches. If a patient is not eligible for one of the treatments, he (she) will be randomized between the options for which he (she) is eligible.
  The trial will start with current available treatment options (experimental arms). New available treatment options may be open at any times later on. Authorized TKIs are imatinib, nilotinib, dasatinib, bosutinib and ponatinib.
  For all options the treatment duration is for a minimum of 12 months and will be continued in the absence of adverse events following investigator decision. Each therapeutic option will be detailed in term of combination modalities, dose, dose adaptation, specific warnings, specific exclusion and inclusion criteria. The decision to introduce a new option will depend on the general pace of recruitment and on the assessment of the potential efficacy and safety of the new treatment, and will be implemented after scientific review by a protocol amendment.
  Primary objective:
  A. To select molecules in combination or sequentially with imatinib, nilotinib, dasatinib, bosutinib or ponatinib potentially able to produce a 25% increase in the Cumulative Incidence of MR4.5 as compare to control.
  Secondary objectives:
  A. To determine the safety of selected therapies
  B. To determine the rate of MR4 by 12, 24, 36, 48 months in experimental and control arms
  C. To determine the rates of MR4.5 by 24, 36, 48 months in experimental and control arms
  D. To determine the rate of undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, 48 months in experimental and control arms
  E. To estimate treatment free remission (TFR) in patients eligible for discontinuation studies
  F. To investigate the relationship between biological activity and the clinical efficacy of the selected therapies
  G. To assess the effects of the treatments on the number and clonogenicity of CML stem cells and other biological markers of interest
  H. To estimate duration of response, progression-free survival, event free survival and overall survival.

Detailed description: Patients will be randomised to continue on TKI (same daily dose) versus one of the X alternative novel treatment approaches. If a patient is not eligible for one of the treatments, he will be randomised between the options for which he is eligible.
  All treatment options may be open at all times.
  The first available treatment arms will be:
  1. TKI alone same daily dose (control arm)
  2. TKI in combination with pioglitazone
  Planned treatment arms for the future may be :
  1. TKI in combination with pegylated interferon
  2. TKI in combination with arsenic trioxide
  3. TKI in combination with Homoharringtonine
  4. TKI in combination with anti-PD-L1 antibody
  For all options the treatment plan is for at least 12 months depending on each molecule tested.
  New treatment options will be introduced over time. The decision to introduce a new option will depend on the general pace of recruitment and the assessment of the potential efficacy and safety of the new treatment in this patient population, and will be implemented after scientific review by a protocol amendment.
  Protocol plan:
  1. Control arm (Imatinib, nilotinib, dasatinib, bosutinib or ponatinib):
  Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months
  2. Pioglitazone arm TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months
  PIOGLITAZONE (Actos®):
  30 mg per day for 12 months. The dose will be increased to 45 mg per day after 2 months in the absence of grade >1 related AE.
  3. Other experimental arm TKI : Daily dose and schedule identical to the daily dose and schedule administered during the last 3 months
  -  Arsenic trioxide : to be determined after amendment
  -  Pegylated Interferon : to be determined after amendment
  -  Anti-PD-L1 antibody : to be determined after amendment
  -  Homoharringtonine : to be determined after amendment
  -  Drug X
  -  Drug Y
  After 12 Months :
  Continue TKI at the same daily dose. Continue experimental drug if indicated.

Eligibility: Inclusion Criteria:
  1. Patient aged 18y or more
  2. Signed informed consent
  3. Patient with Philadelphia chromosome positive chronic phase CML and M BCR-ABL1 transcript positivity
  4. Treatment with imatinib, nilotinib, dasatinib, bosutinib or ponatinib for more than 2 years overall
  5. No switch between tyrosine kinase inhibitors within the last 3 months
  6. No dose modification within the last 3 months
  7. Complete cytogenetic response or BCR-ABLIS ≤ 1%
  8. Detectable BCR-ABL1 with BCR-ABLIS > 0.0032% (less than MR4.5)
  9. ECOG grade 0 to 2
  10. ASAT and ALAT ≤ 2.5 N
  11. Bilirubin in serum ≤ 2.5 N
  12. Women of childbearing potential must be using an adequate method of contraception
  Exclusion Criteria:
  1. Pregnant or lactating women,
  2. Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment,
  3. Patient requiring anti-diabetic medication
  4. Prior history of hematopoietic stem cell transplantation (autologous or allogenic)
  5. Cardiovascular disease:
  -  Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure.
  -  Myocardial infarction within the previous 6 months
  -  Symptomatic cardiac arrhythmia requiring treatment
  6. Grade III or IV fluid retention
  7. Known BCR-ABL kinase domain mutation
  8. CML patient not in chronic phase at diagnosis
  9. Individuals with an active malignancy
  10. Kown HIV-positivity

Relevance to patient case: not relevant