Chronic Phase Chronic Myeloid Leukemia MedDRA version: 18.0 Level: LLT Classification code 10054352 Term: Chronic phase chronic myeloid leukemia System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Iclusig
Product Name: ponatinib
Product Code: AP24534
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Ponatinib
CAS Number: 943319-70-8
Current Sponsor code: AP24534
Other des
Sponsors
ARIAD Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: All patients must meet all of the following inclusion criteria for study entry: 1. Have chronic phase CML and are resistant to at least two prior tyrosine kinase inhibitors. a. The diagnosis of CML will be made using standard hematopathologic and cytogenetic criteria. Chronic phase CML will be defined by all of the following: i 95% Ph+) or failure to achieve CHR ii Six months after the initiation of prior TKI therapy: Less than a minor cytogenetic response (> 65% Ph+) iii Twelve months after the initiation of prior TKI therapy: Less than a PCyR (> 35% Ph+) iv At any time after the initiation of prior TKI therapy, the development of new BCR-ABL kinase domain mutations in the absence of MCyR v At any time after the initiation of prior TKI therapy, the development of new clonal evolution in the absence of MCyR vi At any time after the initiation of prior TKI therapy, the loss of any cytogenetic response (from complete [0%] or partial [1% to 35%] to anything less than a partial response; or from minor [36% to 65%], or minimal [66% to 95%] to a response at least 1 grade worse), confirmed in at least 2 consecutive analyses separated by at least 4 weeks 2. Be male or female patients = 18 years old. 3. Have an ECOG performance status of 0, 1, or 2. 4. Have adequate renal function as defined by the following criterion: a. Serum creatinine = 1.5 × ULN for institution 5. Have adequate hepatic function as defined by the following criteria: a. Total serum bilirubin = 1.5 × ULN, unless due to Gilbert’s syndrome b. ALT = 2.5 × ULN, or = 5 × ULN if leukemic involvement of the liver is present c. AST = 2.5 × ULN, or = 5 × ULN if leukemic involvement of the liver is present 6. Have normal pancreatic status as defined by the following criterion: a. Serum lipase and amylase = 1.5 × ULN 7. Have normal QTcF interval on screening ECG evaluation, defined as QTcF of = 450 ms in males or = 470 ms in females. 8. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential). 9. Agree to use an effective form of contraception with sexual partners throughout study participation (for female and male patients who are fertile). 10. Provide written informed consent. 11. Be willing and able to comply with scheduled visits and study procedures. 12. Have fully recovered (= grade 1, returned to baseline, or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug. 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 330 F.1.3 Elderly (>=6
Exclusion criteria
Exclusion criteria: Patients are not eligible for participation in the study if they meet any of the following exclusion criteria: 1. Have used any approved TKIs or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is longer, prior to receiving study drug. 2. Received interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib, or have not recovered (> grade 1 by NCI CTCAE, v4.0) from AEs (except alopecia), due to agents previously administered. 3. Have undergone autologous or allogeneic SCT 90 mmHg; systolic > 150 mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control. 11. Have poorly controlled diabetes, defined as HbA1c values over the previous year of > 7.5% (59 mmol/mol) on more than 3 occasions; patients with preexisting, well-controlled, diabetes are not excluded. 12. Have a significant bleeding disorder unrelated to CML. 13. Have a history of alcohol abuse. 14. Have a history of either acute pancreatitis within 1 year of study or of chronic pancreatitis. 15. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug. 16. Have a history of another malignancy, other than cervical cancer in situ or nonmetastatic 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. 17. Are pregnant or lactating. 18. Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement) within 14 days prior to first dose of ponatinib. 19. Have an ongoing or active infection; this includes, but is not limited to, the requiremen
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 30 mg, and 15 mg daily) in patients with chronic phase CML who are resistant to at least two tyrosine kinase inhibitors (TKIs), as measured by major cytogenetic response by 12 months.;Secondary Objective: To characterize, according to ponatinib starting dose, the rates of Vascular Occlusive Events (VOEs), AEs (Adverse Events), and serious AEs (SAEs). To evaluate safety differences according to ponatinib starting dose among the 3 starting dose cohorts, particularly for VOEs. To characterize the exposure-response and exposure-toxicity relationships between PK parameters and selected safety and efficacy measures. To characterize, according to ponatinib starting dose, the rates of cytogenetic responses and molecular responses; durability will be assessed by evaluating molecular response (MR)2 and major molecular response (MMR) at 12, 18, and 24 months. To characterize, according to ponatinib starting dose, the rate of discontinuation, dose reductions, and interruptions. To characterize, according to ponatinib starting dose, the rates of hematologic responses. To evaluate, according to ponatinib starting dose, time to response, duration of response, and survival outcomes.;Primary end point(s): MCyR by 12 months for each dose cohort (MCyR is defined as PCyR, CCyR, or = 1% BCR-ABLIS (eg, MR2), which is equivalent to CCyR);Timepoint(s) of evaluation of this end point: After 12 months of treatment and the final analysis will be done at the end of the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety: a. Rate of VOEs in each dose cohort b. Rate of AEs in each dose cohort c. Rate of SAEs in each dose cohort Exposure-response and exposure-toxicity relationships of AUC and Cmax at steady state on efficacy outcomes (including MCyR, MR2, and MMR) and safety outcomes (VOEs and AEs that occur in at least 30 patients) Cytogenetic response rates: CCyR by and at 12 months Molecular response rates: MR2, MR3/MMR, MR4, and MR4.5 at 3-month intervals and MR1 (= 10% BCR-ABLIS) at 3 months Hematologic response rates: Complete hematologic response (CHR) Tolerability: a. Rate of discontinuation due to AEs in each dose cohort b. Dose reductions (prior to response) in each dose cohort c. Dose interruptions in each dose cohort Duration of response: a. Rates of MR2 and MMR at 12, 18, and 24 months b. Rate of MCyR at 12, 18, and 24 months Duration of response in responders Time to response Rate of progression to accelerated phase (AP-) or blast phase (BP-) CML Progression Free Survival Overall Survival;Timepoint(s) of evaluation of this end point: At each visit and the final analysis will be done at the end of the study. | — |
Countries
Argentina, Australia, Belgium, Canada, Chile, Czech Republic, Denmark, Finland, France, Germany, Hong Kong, Italy, Korea, Republic of, Netherlands, Norway, Poland, Portugal, Singapore, Spain, Sweden, Taiwan, United Kingdom, United States
Contacts
Public ContactSara Green
ARIAD Pharmaceuticals, Inc.
Outcome results
None listed