Chronic myeloid leukemia in chronic phase (CML-CP) on imatinib treatment for a minimum of 4 years with confirmed stable deep molecular response (MR4) for a minimum of 12 months prior to enrolment and no prior accelerated phase/blast crisis (AP/BC) or stem cell transplant (SCT).
Conditions
Interventions
Trade Name: Iclusig 15 mg
Product Name: Iclusig 15 mg
Pharmaceutical Form: Tablet
INN or Proposed INN: ponatinib
CAS Number: 943319-70-8
Other descriptive name: PONATINIB
Concentration unit: mg millig
Sponsors
FUNDACIÓN TEÓFILO HERNANDO
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients must meet all of the following criteria to be eligible for the study: 1 Male or female patients = 18 years of age. 2 ECOG performance status of 0, 1, or 2. 3 Patient with diagnosis of BCR-ABL positive CML-CP. 4 Patient has received a minimum of 4 years of imatinib treatment, as unique TKI therapy. 5 Patient has achieved MR4 during at least 12 months with imatinib treatment, and determined by PCR lab assessment at screening. 6 Adequate end organ function as defined by: a. Total bilirubin = 1.5 x ULN except for i) patients with documented Gilbert’s syndrome for whom any bilirubin value is allowed and ii) for patients with asymptomatic hyperbilirubinemia (liver transaminases and alkaline phosphatase within normal range), b. SGOT(AST) and SGPT(ALT) = 2.5 x ULN (upper limit of normal), c. Serum lipase and amylase = 1.5 x ULN, d. Alkaline phosphatase = 2.5 x ULN, e. Serum creatinine = 1.5 x ULN. 7 Patients must have the following electrolyte values = LLN limits or corrected to within normal limits with supplements prior to the first dose of study medication: a. Potassium, b. Magnesium, c. Total calcium (corrected for serum albumin), 8 Patients must have normal marrow function as defined below: a. Absolute neutrophil count (ANC) = 1.5 x 109/L, b. Platelets = 100 x 109/L, c. Hemoglobin > 9.0 g/dL 9 Patients with preexisting, well-controlled, diabetes are not excluded. 10 Have normal QTcF interval on screening ECG evaluation, defined as QTcF of = 450 ms in males or = 470 ms in females. 11 Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential). Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must have a negative serum pregnancy test before initiation of study treatment and must also use highly effective methods of contraception while enrolled in the study. The use of highly effective contraception should continue for at least 14 days after the last dose of study treatment or until the last day of TFR or for the duration of a monthly cycle of oral contraception, whichever is longer. 12 Be willing and able to comply with scheduled visits and study procedures. 13 Written informed consent obtained prior to any screening procedures. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Patients are not eligible for participation in the study if they meet any of the following exclusion criteria: 1 Prior AP, BC or autologous or allogenic transplant. 2 Patients with known atypical transcript. An atypical transcript is defined by the presence of any transcript in the absence of the major transcripts b3a2 (e14a2) and b2a2 (e13a2) or p210 protein. 3 CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if a testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past). 4 Are taking medications with a known risk of torsades de pointes (Appendix A) 5 Patient ever attempted to permanently discontinue imatinib or ponatinib treatment. 6 Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g., uncontrolled diabetes (defined as HbA1c > 9%), uncontrolled infection). 7 Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: a. Any history of MI, unstable angina, cerebrovascular accident, or TIA, b. Any history of peripheral vascular infarction, including visceral infarction, c. Any revascularization procedure, including the placement of a stent, d. Congestive heart failure (NYHA class III or IV) within 6 months prior to enrollment, or LVEF less than lower limit of normal, per local institutional standards, within 6 months prior to enrollment, e. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia, f. Venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 6 months prior to enrollment 8 Have uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 150 mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control. 9 Have a history of alcohol abuse. 10 History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis. 11 Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug. 12 Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer. 13 Have a history of another malignancy, other than cervical cancer in situ or no metastatic basal cell or squamous cell carcinoma of the skin; the exception is if patients have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy. 14 Have undergone surgery (with the exception of minor surgical procedures, such as catheter placement) within 14 days prior to first dose of ponatinib. 15 Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1. 16 Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. See Appendix B for a list of these medications. This list may not be comprehensive. 17 Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. These herbal medicines may include Echi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to evaluate the proportion of patients without confirmed loss of MR4 or loss of MMR (don’t require confirmation) within 52 weeks following ponatinib therapy cessation.;Secondary Objective: • To evaluate the proportion of patients without confirmed loss of MMR within 78, and 104 weeks following cessation of ponatinib therapy. • To estimate progression-free survival (PFS) from the date of ponatinib cessation to the date of the earliest of this event. • Treatment-free survival (TFS), defined as lack of any of the following: loss of MMR, confirmed loss of MR4, restart of imatinib treatment, progression of AP/BC, or death from any cause. • To estimate overall survival (OS), defined as the time from the date of cessation of ponatinib therapy to the date of death from any cause. • Proportion of patients who regain MR4 within 24 weeks of imatinib treatment re-initiation following confirmed loss of MR4 or loss of MMR in the 24 weeks subsequent to ponatinib cessation. • Kinetics of BCR-ABL transcript levels (IS) after restart of imatinib therapy.;Primary end point(s): The primary efficacy variable is the binary outcome variable, proportion of patients without confirmed loss of MR4 or loss of MMR within 52 weeks following ponatinib TFR. This variable is defined as the number of patients with no documented confirmed loss of MR4 or no loss of MMR and no restarting of imatinib therapy in the first 52 weeks after starting ponatinib TFR phase divided by the number of patients who entered ponatinib TFR phase with confirmed loss of MR4 or loss of MMR.;Timepoint(s) of evaluation of this end point: 52 weeks following ponatinib Treatment-Free Remission | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Proportion of patients without confirmed loss of MR4 or loss of MMR within 104 weeks following discontinuation of ponatinib treatment. This proportion of patients is calculated by dividing the number of patients with no documented confirmed loss of MR4 or loss MMR and no re-initiation of imatinib treatment in 104 weeks following discontinuation of ponatinib by the number of patients who attempted to cease ponatinib treatment. • Progression free survival (PFS): The estimation of PFS following ponatinib cessation will use the Kaplan-Meier (KM) method. PFS is measured from the date of cessation of ponatinib therapy to the date of the earliest of this event: progression to AP/BC or death from any cause. Patients not known to have progressed or died on or before the cut-off date for the KM analysis will have their PFS interval right-censored at the earlier of the date of their last assessment of molecular response status and the cut-off date. • Treatment-free survival: TFS is defined as lack of any of the following: loss of MMR, confirmed loss of MR4, restart of imatinib treatment, progression to AP/BC or death from any cause. TFS is measured from the date of cessation of ponatinib therapy to the date of the earliest of this event. • Overall survival (OS): OS is defined as the time from the date of cessation of ponatinib therapy to the date of death from any cause. If a patient is not known to have died, survival will be censored at the date of last contact. Similar method of analysis will be used to estimate time to regain MR4 from the date of re-start imatinib treatment. • The proportion of patients who regain MR4 within 52 weeks of imatinib treatment re- initiation following confirmed loss of MR4 or loss of MMR in the first 52 weeks subsequent to ponatinib cessation will also be calculated by dividing the number of patients who re-achieve MR4 within 52 weeks of imatinib treatment re-initiation, following confirmed loss of MR4 or loss of MMR i | — |
Countries
Spain
Contacts
Public ContactBegoña Maestro Gutiérrez
FUNDACIÓN TEÓFILO HERNANDO
Outcome results
None listed