Chronic Phase Chronic Myeloid Leukemia MedDRA version: 21.0 Level: LLT Classification code 10054352 Term: Chronic phase chronic myeloid leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Takeda Development Center Americas, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Have CP-CML and have received at least two prior TKI therapies and have demonstrated resistance to treatment OR Have documented history of presence of T315I mutation after receiving any number of prior TKI. a. The diagnosis of CML will be made using standard hematopathologic and cytogenetic criteria; CP-CML will be defined by all of the following: i. 95% Ph+) or failure to achieve CHR or new mutation ii. Six months after the initiation of prior TKI therapy: BCR-ABL1IS >10% and/or Ph+ >65% or new mutation iii. Twelve months after the initiation of prior TKI therapy: BCR-ABL1IS >10% and/or Ph+ >35% or new mutation. iv. At any time after the initiation of prior TKI therapy, the development of a new BCR-ABL1 kinase domain mutation(s). v. At any time after the initiation of prior TKI therapy, the development of new clonal evolution vi. At any time after the initiation of prior TKI therapy, the loss of CHR, or CCyR, or the confirmed loss of MMR in 2 consecutive tests, one of which has a BCR-ABL1IS transcript level of =1% or new mutation d. > 1% of BCR-ABL1IS as shown by real-time polymerase chain reaction 2. Age = 18 years old. 3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 4. Have adequate renal function as defined by the following criterion: a. Serum creatinine = 1.5 × upper limit of normal (ULN) for institution b. Estimated creatinine clearance = 30 mL/min (Cockcroft-Gault formula) 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. Alanine aminotransferase (ALT) = 2.5 × ULN, or = 5 × ULN if leukemic infiltration of the liver is present c. Aspartate aminotransferase (AST) = 2.5 × ULN, or = 5 × ULN if leukemic infiltration 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 QT interval corrected (Frederica) (QTcF) interval on screening electrocardiogram (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 a highly effective form of contraception with sexual partners from randomization through at least 4 months after the end of treatment (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 recovered from toxicities related to prior anticancer therapy to NCI CTCAE v 4.0 grade =1. 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 202 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects
Exclusion criteria
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 the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], v4.0) from AEs (except alopecia) due to agents previously administered. 3. Have undergone autologous or allogeneic stem cell transplant (SCT) 150 and >90 for SBP and DBP, respectively). Patients with hypertension should be under treatment at study entry to ensure blood pressure control. Those requiring 3 or more antihypertensive medications should be discussed with the medical monitor. 10. Have poorly controlled diabetes defined as HbA1c values of > 7.5%. Patients with preexisting, well-controlled, diabetes are not excluded. 11. Have a significant bleeding disorder unrelated to CML. 12. Have a history of alcohol abuse. 13. Have a history of either acute pancreatitis within 1 year of study enrollment or of chronic pancreatitis. 14. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug. 15. Have a history of another malignancy, other than cervical cancer in situ or 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. 16. Are pregnant or lactating. 17. Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days
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 CP-CML who are resistant to prior TKI therapy or have T315I mutation, as measured by = 1% BCR-ABL1IS at 12 months.;Secondary Objective: To characterize the rate of major molecular response (MMR) at 12 and 24 months and rate of major cytogenetic response (MCyR) by 12 months To evaluate duration of MMR To characterize the rates of AOEs, VTEs, AEs, and serious AEs (SAEs) To evaluate safety differences among the 3 starting dose cohorts, particularly for AOEs and VTEs To collect sparse PK samples to contribute to population PK and exposure-response analyses of safety and efficacy To characterize the rates of cytogenetic responses and molecular responses; durability will be assessed by evaluating = 1% BCR-ABL1IS response and major molecular response (MMR) at and by 6, 12, 18, and 24 months To characterize the rate of discontinuation, dose reductions, and interruptions To characterize the rates of hematologic responses To evaluate time to response, duration of response, and survival outcomes;Primary end point(s): = 1% BCR-ABL1IS ;Timepoint(s) of evaluation of this end point: At 12 months for each starting dose cohort. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Molecular response rates: MMR at 12 and 24 months Cytogenetic response rates: MCyR by 12 months Duration of MMR Safety: a. Rate of AOEs and VTEs in each dose cohort b. Rate of AEs in each dose cohort c. Rate of SAEs in each dose cohort Cytogenetic response rate: CCyR at 12 months Molecular response rates: MR4, and MR4.5 by and at 3-month intervals and MR1 (= 10% BCR-ABL1IS) at 3 months Hematologic response rates: Complete hematologic response (CHR) at 3 months Tolerability: a. Rate of discontinuation due to AEs in each dose cohort b. Dose reductions due to AE in each dose cohort c. Dose interruptions in each dose cohort Duration of response: a. Rate of =1% BCR-ABL1IS by 12 months and at and by 6, 18, and 24 months b. MMR at and by 6 and 18 months; and by 12 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, Czechia, Czech Republic, Denmark, Finland, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Netherlands, Norway, Poland, Portugal, Russian Federation, Singapore, Spain, Sweden, Taiwan, United Kingdom, United States
Contacts
Public ContactDrug Information Call Center
Takeda Development Center Americas, Inc.
Outcome results
None listed