Myeloproliferative Neoplasms Clinical Trial
Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs
Summary
The purpose of this pivotal study was to compare the efficacy of asciminib (ABL001) with that of bosutinib in the treatment of patients with leukemia-cml/" >CML-CP having previously been treated with a minimum of two prior ATP-binding site TKIs.
Patients intolerant to the most recent TKI therapy must have had BCR-ABL1 ratio > 0.1% IS at screening and patients failing their most recent TKI therapy must have met the definition of treatment failure as per the 2013 European LeukemiaNet (ELN) recommendations.
Patients with documented treatment failure as per 2013 ELN recommendations while on bosutinib treatment had the option to switch to asciminib treatment within 96 weeks after the last patient has been randomized on study.
Full Description
Patients were randomized in a 2:1 ratio to asciminib 40 mg BID or bosutinib 500 mg QD. Randomization was stratified by major cytogenetic response (MCyR) at screening. Patients with documented treatment failure (specifically meeting lack of efficacy criteria adapted from the 2013 ELN recommendations) while on bosutinib treatment were offered the option to switch to asciminib treatment within 96 weeks after the last patient was randomized to the study.
Eligibility Criteria
Inclusion Criteria:
Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
Patients must meet all of the following laboratory values at the screening visit:
< 15% blasts in peripheral blood and bone marrow
< 30% blasts plus promyelocytes in peripheral blood and bone marrow
< 20% basophils in the peripheral blood
≥ 50 x 109/L (≥ 50,000/mm3) platelets
Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior to screening) is acceptable
No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
BCR-ABL1 ratio > 0.1% IS according to central laboratory at the screening examination for patients intolerant to the most recent TKI therapy
Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib, dasatinib, radotinib or ponatinib)
Failure (adapted from the 2013 ELN Guidelines Bacarrani 2013) or intolerance to the most recent TKI therapy at the time of screening
Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as follows. Patients must meet at least 1 of the following criteria.
Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases
Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases
Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases
At any time after the initiation of therapy, loss of CHR, CCyR or PCyR
At any time after the initiation of therapy, the development of new BCR-ABL1 mutations which potentially cause resistance to study treatment
At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS
At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+
Intolerance is defined as:
Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal)
Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer
Exclusion Criteria:
Known presence of the T315I or V299L mutation at any time prior to study entry Known second chronic phase of CML after previous progression to AP/BC Previous treatment with a hematopoietic stem-cell transplantation Patient planning to undergo allogeneic hematopoietic stem cell transplantation
Cardiac or cardiac repolarization abnormality, including any of the following:
History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients)
Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
Concomitant medication(s) with a known risk of Torsades de Pointes per www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.
Inability to determine the QTcF interval
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, active or uncontrolled infection, pulmonary hypertension)
History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
History of acute or chronic liver disease
Treatment with medications that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of treatment with study treatment
Moderate or strong inducers of CYP3A
Moderate or strong inhibitors of CYP3A
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 days after last dose of ABL001 and one month after last dose of bosutinib. Highly effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy (with or without hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks before taking study treatment). In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject.
Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before taking study medication. In the case of oophorectomy alone, women are considered post-menopausal and not of child bearing potential only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
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There are 88 Locations for this study
Chicago Illinois, 60637, United States
Beech Grove Indiana, 46107, United States
Baltimore Maryland, 21205, United States
Boston Massachusetts, 02215, United States
Ann Arbor Michigan, 48109, United States
Buffalo New York, 14263, United States
New York New York, 10021, United States
New York New York, 10065, United States
Houston Texas, 77030, United States
Salt Lake City Utah, 84112, United States
Caba Buenos Aires, C1221, Argentina
Capital Federal , C1114, Argentina
Cordoba , X5016, Argentina
Adelaide South Australia, 5000, Australia
Melbourne Victoria, 3000, Australia
Murdoch Western Australia, 6150, Australia
Rio de Janeiro RJ, 20.21, Brazil
Sao Paulo SP, 05403, Brazil
Sao Paulo SP, 08270, Brazil
Porto Alegre , 90035, Brazil
Plovdiv , 4002, Bulgaria
Varna , 9000, Bulgaria
Toronto Ontario, M5G 2, Canada
Ostrava Poruba, 708 5, Czechia
Brno Bohunice , 625 0, Czechia
Bordeaux , 33076, France
Lyon , 69373, France
Marseille , 13273, France
Paris Cedex 10 , 75475, France
Vandoeuvre les Nancy , 54511, France
Mannheim Baden-Wuerttemberg, 68305, Germany
Berlin , 13353, Germany
Duesseldorf , 40225, Germany
Frankfurt , 60590, Germany
Heidelberg , 69120, Germany
Jena , 07740, Germany
Kiel , 24116, Germany
Budapest , 1097, Hungary
Debrecen , 4032, Hungary
Jerusalem , 91120, Israel
Zrifin , 70300, Israel
Bari BA, 70124, Italy
Milano MI, 20122, Italy
Napoli , 80132, Italy
Nagoya Aichi, 453-8, Japan
Toyoake city Aichi, 470 1, Japan
Kashiwa Chiba, 277 8, Japan
Kobe-shi Hyogo, 650-0, Japan
Osaka Sayama Osaka, 589 8, Japan
Suita Osaka, 565 0, Japan
Bunkyo ku Tokyo, 113-8, Japan
Chuo-city Yamanashi, 409-3, Japan
Akita , 010-8, Japan
Aomori , 030 8, Japan
Uijeongbu si Gyeonggi Do, 11759, Korea, Republic of
Seoul Seocho Gu, 06591, Korea, Republic of
Busan , 49201, Korea, Republic of
Jeollanam , 51976, Korea, Republic of
Ashrafieh , 16683, Lebanon
Beirut , 1107 , Lebanon
Monterrey Nuevo Leon, 64460, Mexico
Amsterdam , 1081 , Netherlands
Dordrecht , 3318A, Netherlands
Cluj-Napoca , 40012, Romania
Timisoara , 30007, Romania
Moscow , 12516, Russian Federation
Moscow , 12528, Russian Federation
Saint Petersburg , 19102, Russian Federation
Saint Petersburg , 19734, Russian Federation
Riyadh , 11211, Saudi Arabia
Belgrade , 11000, Serbia
Novi Sad , 40010, Serbia
Toledo Castilla La Mancha, 45071, Spain
Barcelona Catalunya, 08036, Spain
Hospitalet de LLobregat Catalunya, 08907, Spain
Bilbao Pais Vasco, 48013, Spain
Madrid , 28034, Spain
Zürich , 8091, Switzerland
Istanbul TUR, 34098, Turkey
Adana , 01330, Turkey
Istanbul , 34093, Turkey
Izmir , 35040, Turkey
Samsun , 55139, Turkey
Wirral Merseyside, CH63 , United Kingdom
Glasgow Scotland, G12 0, United Kingdom
Cardiff , CF4 4, United Kingdom
London , W12 0, United Kingdom
Oxford , OX3 7, United Kingdom
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