Myeloproliferative Neoplasms Clinical Trial
Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses
The purpose of this study is to characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 30 mg, and 15 mg daily) in participants with CP-leukemia-cml/" >CML who are resistant to prior tyrosine-kinase inhibitor (TKI) therapy or have T315I mutation, as measured by <=1 % Breakpoint Cluster Region-Abelson Transcript Level using International Scale (BCR-ABL1IS) at 12 months.
The drug being tested in this study is ponatinib. This study will characterize the safety and efficacy of ponatinib over a range of 3 starting doses.
The study will enroll 276 participants in 3 cohorts and each cohort will have 92 participants. All the participants will be randomized to receive once-daily oral administration of 1 of 3 starting doses of ponatinib:
Cohort A: 45 mg ponatinib tablet
Cohort B: 30 mg ponatinib tablet
Cohort C: 15 mg ponatinib tablet
The study is designed to consist of 2 periods: 24-cycle Main treatment period and optional treatment continuation period. Participants will be treated with their randomized dose of study drug in the Main Treatment Period until the occurrence of at least one of the following: absence of CHR by 3 months, absence of MCyR at 12 months, absence of <=1% BCR-ABL1IS at 12 months, loss of <=1% BCR-ABL1IS development of intolerance, or completion of all 24 cycles of treatment (whichever occurs first). Following completion of approximately 5 years or following early withdrawal, participants may enter into an optional treatment continuation period.
This multi-center trial will be conducted in the United States, United Kingdom, Republic of Korea, Spain, France, Taiwan, Australia, Canada, Italy, Chile, Japan, Germany, Argentina, Poland, Czech Republic, Denmark, Hong Kong, Portugal, Russia, Singapore, Switzerland, and Sweden. The overall time to participate in this study is approximately 96 months. Participants will make a final visit to the clinic approximately 30 days after the last dose of study treatment.
Have chronic phase-chronic myelogenous leukemia/chronic myeloid leukemia (CP-CML) and have received at least two prior tyrosine kinase inhibitor (TKI) therapies and have demonstrated resistance to treatment OR have documented history of presence of T315I mutation after receiving any number of prior TKI.
o] The diagnosis of chronic myeloid leukemia (CML) will be made using standard hematopathologic and cytogenetic criteria; CP-CML will be defined by all of the following: i <15% blasts in bone marrow ii <30% blasts plus promyelocytes in bone marrow iii <20% basophils in peripheral blood. iv >= 100*10^9/liter (L) platelets (>=100,000/mm^3). v No evidence of extramedullary disease except hepatosplenomegaly vi No prior diagnosis of AP-CML, and BP-CML o] Cytogenetic assessment at screening must demonstrate the BCR-ABL1 fusion by presence of the t(9;22) Philadelphia chromosome.
i Variant translocations are only allowed provided they meet inclusion criterion 1d.
o] Resistance to prior TKI therapy is defined as follows (participants must meet at least 1 criterion): i Three months after the initiation of prior TKI therapy: No cytogenetic response (>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 o] >1% of BCR-ABL1IS as shown by real-time polymerase chain reaction
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
Have adequate renal function as defined by the following criterion:
o] Serum creatinine <=1.5*ULN for institution o] Estimated creatinine clearance >=30 milliliter per minute (mL/min) (Cockcroft-Gault formula)
Have adequate hepatic function as defined by the following criteria:
o] Total serum bilirubin <=1.5*ULN, unless due to Gilbert's syndrome o] Alanine transaminase (ALT) <=2.5*ULN, or <=5*ULN if leukemic infiltration of the liver is present o] Aspartate transaminase (AST) <=2.5*ULN, or <=5*ULN if leukemic infiltration of the liver is present
Have normal pancreatic status as defined by the following criterion:
o] Serum lipase and amylase <=1.5*ULN
Have normal QT interval corrected (Frederica) (QTcF) interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of <=450 milliseconds (ms) in males or <=470 ms in females.
Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
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 participants who are fertile).
Provide written informed consent.
Be willing and able to comply with scheduled visits and study procedures.
Have recovered from toxicities related to prior anticancer therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 grade <=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.
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, version 4.0) from AEs (except alopecia), due to agents previously administered.
Have undergone autologous or allogeneic stem cell transplant <60 days prior to receiving the first dose of ponatinib; have any evidence of ongoing graft-versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy.
Are being considered for hematopoietic stem cell transplant (HSCT) within 6-12 months of enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial).
Are taking medications with a known risk of Torsades de Pointes.
Have previously been treated with ponatinib.
Have active CNS disease as evidenced by cytology or pathology; in the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.
Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
o] Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or Transient Ischemic Attack (TIA) o] Any history of peripheral vascular infarction, including visceral infarction o] Any revascularization procedure, including the placement of a stent o] Congestive heart failure (CHF) (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal, per local institutional standards, within 6 months prior to enrollment o] History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia o] Venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 6 months prior to enrollment
Have uncontrolled hypertension (that is, >150 and >90 for systolic blood pressure (SBP) and diastolic blood pressure (DBP) respectively). Participants 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.
Have poorly controlled diabetes defined as HbA1c values of >7.5%. Participants with preexisting, well-controlled diabetes are not excluded.
Have a significant bleeding disorder unrelated to CML.
Have a history of alcohol abuse.
Have a history of either acute pancreatitis within 1 year of study enrollment or of chronic pancreatitis.
Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
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 participants 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.
Are pregnant or lactating.
Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.
Have an active infection which requires intravenous antibiotics.
Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.
Have any condition or illness that, in the opinion of the investigator, would compromise participant safety or interfere with the evaluation of the drug.
Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients.
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There are 85 Locations for this study
Atlanta Georgia, 30322, United States
Indianapolis Indiana, 46237, United States
Baltimore Maryland, 21201, United States
Ann Arbor Michigan, 48109, United States
Detroit Michigan, 48201, United States
Minneapolis Minnesota, 55455, United States
Omaha Nebraska, 68198, United States
Hackensack New Jersey, 07601, United States
New York New York, 10065, United States
New York New York, 10065, United States
Durham North Carolina, 27710, United States
Cleveland Ohio, 44195, United States
Portland Oregon, 97239, United States
Philadelphia Pennsylvania, 19104, United States
Houston Texas, 77030, United States
Salt Lake City Utah, 84112, United States
Ciudad Autonoma de Buenos Aires Buenos Aires, C1114, Argentina
Ciudad Autonoma de Buenos Aires Buenos Aires, C1221, Argentina
La Plata Buenos Aires, B1900, Argentina
Saint Leonards New South Wales, 2065, Australia
Adelaide South Australia, 5000, Australia
Toronto Ontario, M5G 2, Canada
Montreal Quebec, H3T 1, Canada
Regina Saskatchewan, S4T 7, Canada
Providencia Santiago, 75009, Chile
Vina del Mar Valparaiso, 25403, Chile
Prague Praha, 12820, Czechia
Olomouc , 772 0, Czechia
Aarhus C Aarhus, DK-80, Denmark
Bordeaux Aquitaine, 33076, France
Vandoeuvre les Nancy Lorraine, 54511, France
Toulouse Cedex 9 Midi-pyrenees, 31059, France
Lille cedex NORD Pas-de-calais, 59037, France
Angers Cedex 9 PAYS DE LA Loire, 49933, France
Nantes Cedex 1 PAYS DE LA Loire, 44093, France
Poitiers Cedex Poitou-charentes, 86021, France
Nice Cedex 3 Provence Alpes COTE D'azur, 06202, France
Mannheim Baden-wuerttemberg, 68169, Germany
Ulm Baden-wuerttemberg, 89081, Germany
Rostock Mecklenburg-vorpommern, 18057, Germany
Aachen Nordrhein-westfalen, 52074, Germany
Essen Nordrhein-westfalen, 45147, Germany
Jena Thuringen, 07747, Germany
Berlin , 13353, Germany
Hamburg , 20246, Germany
Hong Kong , 852, Hong Kong
Monza Monza E Brianza, 20090, Italy
Pesaro Pesaro E Urbino, 61100, Italy
Catania , 95124, Italy
Genova , 16132, Italy
Pescara , 65124, Italy
Roma , 00161, Italy
Verona , 37134, Italy
Seoul , 6591, Korea, Republic of
Wroclaw Dolnoslaskie, 50-36, Poland
Lodz Lodzkie, 93-51, Poland
Krakow Malopolskie, 30-51, Poland
Warszawa Mazowieckie, 02-77, Poland
Gdansk Pomorskie, 80-95, Poland
Lisboa , 1090-, Portugal
Porto , 4200-, Portugal
Rostov-na-Donu Rostov, 34402, Russian Federation
Chelyabinsk , 45407, Russian Federation
Kemerovo , 65006, Russian Federation
Moscow , 11112, Russian Federation
Moscow , 12516, Russian Federation
Saint Petersburg , 19102, Russian Federation
Saint Petersburg , 19734, Russian Federation
Samara , 44309, Russian Federation
Saratov , 35501, Russian Federation
Singapore , 16985, Singapore
Malaga Andalucia, 29010, Spain
Las Palmas de Gran Canaria LAS Palmas, 35010, Spain
Barcelona , 08036, Spain
Madrid , 28006, Spain
Madrid , 28034, Spain
Valencia , 46010, Spain
Uppsala , 751 8, Sweden
Zurich , 8091, Switzerland
Taipei , 100, Taiwan
Liverpool England, L7 8X, United Kingdom
London England, SE5 9, United Kingdom
London England, W12 0, United Kingdom
Nottingham England, NG5 1, United Kingdom
Oxford England, OX3 7, United Kingdom
Glasgow Scotland, G12 0, United Kingdom
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