Clinical trial NCT03589326: A Study of Ponatinib Versus Imatinib in Adults With Acute Lymphoblastic Leukemia
Official title: A Phase 3, Randomized, Open-label, Multicenter Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ALL)
Keywords: Ponatinib
Imatinib mesylate
Bcr-Abl Tyrosine Kinase
Bcr-abl fusion proteins
Iclusig
Gleevec
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2018-07-17
Enrollment: 245
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this study, adults with newly-diagnosed Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) will receive first-line therapy of ponatinib or imatinib.

The main aim of this study is to compare the number of participants on each treatment that show no signs of disease.

Participants will take tablets of either ponatinib or imatinib at the same time each day combined with reduced-intensity chemotherapy for up to 20 months. Then, they will continue with single-agent therapy (ponatinib or imatinib) until they meet the discontinuation criteria from the study.

Detailed description: The drug being tested in this study is called ponatinib. Ponatinib is being tested to treat people who have newly diagnosed Ph+ ALL. This study will look at the efficacy of ponatinib in participants in addition to standard care.

The study will enroll approximately 230 participants. Participants will be randomized in a 2:1 ratio to receive oral ponatinib or imatinib (Cohort A and Cohort B, respectively) daily throughout the study.

All participants will be asked to take ponatinib or imatinib at the same time each day with reduced-intensity chemotherapy in induction phase (Cycles 1 to 3), consolidation phase (Cycles 4 to 9) and maintenance phase (Cycles 10 to 20). At the end of the 20 cycles, participants will remain on ponatinib or imatinib (administered as a single agent). The dose of ponatinib in consolidation and maintenance phase will start with the last dose given in the previous phase. The dose can be modified based on MRD-negative CR results.

This multi-center trial will be conducted in Argentina, Australia, Austria, Belarus, Brazil, Bulgaria, Canada, Chile, France, Mexico, Greece, Italy, Japan, Korea, Republic Of, Poland, Romania, Russia, Spain, Taiwan, Province Of China, Turkey, Finland and the United States. Participants including those who achieve a clinical response, may receive study drug until they are deceased, have failed to achieve the primary endpoint, have experienced relapse from CR or have progressive disease, have an unacceptable toxicity, have withdrawn consent, have proceeded to HSCT, or until the sponsor terminates the study, whichever occurs first. After disease progression, all participants will be contacted every 3 months for survival follow-up. Participants will be followed until completion of the study or until the participant's death has been reported.

Eligibility criteria: Inclusion Criteria:

1. Newly diagnosed Philadelphia chromosome-positive (Ph+) or BCR-ABL1-positive ALL, as defined by the 2017 national comprehensive cancer network (NCCN) guidelines.
2. Eastern Cooperative Oncology Group (ECOG) performance status of \<=2.

Exclusion Criteria:

1. With a history or current diagnosis of chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML).
2. Prior/current treatment with any systemic anticancer therapy (including but not limited to any tyrosine kinase inhibitor \[TKI\]) and/or radiotherapy for ALL, with the exception of an optional prephase therapy or chemotherapy induction (no more than 1 cycle), which should be discussed with the sponsor's medical monitor/designee.
3. Currently taking drugs that are known to have a risk of causing prolonged corrected QT (QTc) or torsades de pointes (TdP) (unless these can be changed to acceptable alternatives or discontinued).
4. Taking any medications or herbal supplements that are known to be strong inhibitors or strong inducers of cytochrome P450 (CYP)3A4 within at least 14 days before the first dose of study drug.
5. Uncontrolled active serious infection that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
6. Major surgery within 28 days before randomization (minor surgical procedures such as catheter placement or BM biopsy are not exclusionary criteria).
7. Known human immunodeficiency virus (HIV) seropositivity, known active hepatitis B or C infection.
8. History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis.
9. Uncontrolled hypertriglyceridemia (triglycerides \>450 milligram per deciliter \[mg/dL\]).
10. Diagnosed and treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
11. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
12. Clinical manifestations of CNS or extramedullary involvement with ALL other than lymphadenopathy or hepatosplenomegaly.
13. Autoimmune disease with potential CNS involvement.
14. Known significant neuropathy of Grade \>=2 severity.
15. Clinically significant, uncontrolled, or active cardiovascular, cerebrovascular, or peripheral vascular disease, or history of or active venous thrombotic/embolic event (VTE) disease.
16. Have a significant bleeding disorder unrelated to ALL.

Primary outcomes:
measure: Number of Participants With Minimal Residual Disease (MRD)-Negative Complete Remission (CR) at The End of Induction Phase
timeFrame: From Cycle 1 through Cycle 3 (approximately 3 months) (Cycle length = 28 days)
Secondary outcomes:
measure: Event-free Survival (EFS)
timeFrame: Baseline up to approximately 3 to 6 years
measure: Percentage of Participants With CR and Incomplete Complete Remission (CRi)
timeFrame: End of Cycle 1 (approximately 1 month), Cycle 2 (approximately 2 months), Cycle 3 (approximately 3 months), and Cycle 9 (approximately 9 months) (Cycle length= 28 days)
measure: Percentage of Participants With Molecular Response
timeFrame: End of Cycle 1 (approximately 1 month), Cycle 2 (approximately 2 months), Cycle 3 (approximately 3 months), and Cycle 9 (approximately 9 months) (Cycle length= 28 days)
measure: Percentage of Participants With Primary Induction Failure (PIF)
timeFrame: Up to 3 months
measure: Percentage of Participants With Overall Response Rate (ORR)
timeFrame: Up to 3 months
measure: Percentage of MRD-Negative CR
timeFrame: Up to approximately 3 to 6 years
measure: Duration of MRD-Negative CR
timeFrame: Up to approximately 3 to 6 years
measure: Duration of CR
timeFrame: Up to approximately 3 to 6 years
measure: Time to Treatment Failure
timeFrame: Up to approximately 6 years
measure: Duration of MR4.5
timeFrame: Up to approximately 3 to 6 years
measure: Percentage of On-Study Participants With Overall Survival (OS)
timeFrame: Up to approximately 3 to 6 years
measure: Percentage of On-Study Participants With Relapse From CR
timeFrame: Up to approximately 3 to 6 years
measure: Overall Survival (OS)
timeFrame: Up to approximately 3 to 6 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope - Duarte
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Augusta
country: United States
facility: Augusta University Georgia Cancer Center
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Indianapolis
country: United States
facility: Indiana Blood & Marrow Transplantation
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center Research Institute
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New Hyde Park
country: United States
facility: Monter Cancer Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Hospital
state: Texas
city: Cordoba
country: Argentina
facility: Sanatorio Allende
city: Cordoba
country: Argentina
facility: Hospital Privado Centro Medico de Cordoba
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Linz
country: Austria
facility: Ordensklinikum Linz Elisabethinen
state: Upper Austria
city: Wien
country: Austria
facility: Hanusch Krankenhaus Wiener Gebietskrankenkasse
state: Vienna
city: Vienna
country: Austria
facility: Universitaetsklinik Fuer Innere Medizin I
city: Salvador
country: Brazil
facility: Hospital Sao Rafael-Monte Tabor
state: Bahia
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner
state: Parana
city: Passo Fundo
country: Brazil
facility: Hospital da Cidade
state: RIO Grande DO SUL
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
state: RIO Grande DO SUL
city: Campinas
country: Brazil
facility: Hemocentro Campinas Unicamp
state: SAO Paulo
city: Jau
country: Brazil
facility: Fundacao Doutor Amaral Carvalho
state: SAO Paulo
city: Ribeirao Preto
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da Riberao Preto da Universidade de Sao Paulo
state: SAO Paulo
city: Rio de Janeiro
country: Brazil
facility: HEMORIO Instituto Estadual de Hematologia
city: Sao Paulo
country: Brazil
facility: Instituto do Cancer do Estado de Sao Paulo
city: Sao Paulo
country: Brazil
facility: Fundacao Antonio Prudente - A.C.Camargo Cancer Center
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Saint Ivan Rilski
state: Sofiya
city: Vancouver
country: Canada
facility: 855 West 12th Avenue
state: British Columbia
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Greenfield Park
country: Canada
facility: Hopital Charles-LeMoyne
state: Quebec
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University/Suzhou First People's Hospital
state: Jiangsu
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University
state: Zhejiang
city: Tianjin
country: China
facility: Institute of Hematology & Blood Diseases Hospital of CAMS & PUMC
city: Helsinki
country: Finland
facility: Helsingin ja Uudenmaan sairaanhoitopiiri
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles Hopital Andre Mignot
state: Ile-de-france
city: Toulouse Cedex 09
country: France
facility: Institut Universitaire du Cancer de Toulouse Oncopole
state: Midi-pyrenees
city: Angers Cedex 9
country: France
facility: Center Hospitalier Universitaire d'Angers
state: PAYS DE LA Loire
city: Pierre Benite Cedex
country: France
facility: Centre Hospitalier Lyon Sud
state: Rhone-alpes
city: Athens
country: Greece
facility: Evaggelismos General Hospital
state: Attica
city: Chaidari
country: Greece
facility: University General Hospital of Athens Attikon
state: Attica
city: Patra
country: Greece
facility: University General Hospital of Patras Panagia I Voithia
state: Peloponnese
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
state: Forli-cesena
city: Genova
country: Italy
facility: Azienda Policlinico San Martino
state: Liguria
city: Monza
country: Italy
facility: Azienda Ospedaliera San Gerardo di Monza
state: Monza E Brianza
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova
state: Reggio Nella Emilia
city: Mestre
country: Italy
facility: Ospedale dell'Angelo
state: Venezia
city: Bologna
country: Italy
facility: Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi
city: Lecce
country: Italy
facility: Azienda Ospedaliera Vito Fazzi
city: Milano
country: Italy
facility: Istituto Scientifico Universitario San Raffaele
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria di Modena Policlinico
city: Palermo
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello
city: Ravenna
country: Italy
facility: Azienda USL della Romagna
city: Roma
country: Italy
facility: Centro di Ematologia Policlinico Umberto I Universita Sapienza di Roma
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Sapporo
country: Japan
facility: Aiiku Hospital
state: Hokkaido
city: Isehara City
country: Japan
facility: Tokai University Hospital
state: Kanagawa
city: Okayama-shi
country: Japan
facility: Okayama University Hospital
state: Okayama
city: Chiba
country: Japan
facility: Chiba Aoba Municipal Hospital
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
city: Suwon
country: Korea, Republic of
facility: The Catholic University of Korea St. Vincent's Hospital
state: Gyeonggi-do
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
state: Gyeongsangbuk-do
city: Jeonju
country: Korea, Republic of
facility: Chonbuk National University Hospital
state: Jeollabuk-do
city: Busan
country: Korea, Republic of
facility: Inje University Haeundae Paik Hospital
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Hospital
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. Jose Eleuterio Gonzalez
state: Nuevo LEON
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny we Wroclawiu
state: Dolnoslaskie
city: Krakow
country: Poland
facility: Szpital Uniwersytecki w Krakowie
state: Malopolskie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
state: Pomorskie
city: Olsztyn
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej Ministerstwa Spraw Wewnetrznych z Warminsko-Mazurs
state: Warminsko-mazurskie
city: Moscow
country: Russian Federation
facility: City Clinical Hospital named after Vikentiy Vikentyevich Veresaev
state: Moscow CITY
city: Ekaterinburg
country: Russian Federation
facility: Sverdlovsk Regional Clinical Hospital #1
state: Sverdlovsk
city: Moscow
country: Russian Federation
facility: National Research Center for Hematology, Dept. of Hematology/Oncology and BMT
city: Saint Petersburg
country: Russian Federation
facility: Almazov Federal North-West Medical Research Centre of Department of Health of Russian Federation
city: Badalona
country: Spain
facility: Institut Catala d'Oncologia Badalona - Hospital Germans Trias i Pujol
state: Cataluna
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Hualien City
country: Taiwan
facility: Hualien Tzu Chi Hospital
state: Hualien
city: Taichung
country: Taiwan
facility: China Medical University Hospital
state: Taichung CITY
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
state: Tainan CITY
city: Ankara
country: Turkey
facility: Ankara Universitesi Tp Fakultesi
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: