Clinical trial NCT02467270: Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses
Official title: A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients With Resistant Chronic Phase Chronic Myeloid Leukemia to Characterize the Efficacy and Safety of a Range of Doses
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myeloid Leukemia, Chronic, Chronic Phase
Keywords: Chronic Phase Chronic Myeloid Leukemia
Molecular Response
CML
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
CP-CML
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-06-10
Enrollment: 283
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: 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-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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. 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
2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
3. 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)
4. 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
5. Have normal pancreatic status as defined by the following criterion:

   o\] Serum lipase and amylase \<=1.5\*ULN
6. 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.
7. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
8. 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).
9. Provide written informed consent.
10. Be willing and able to comply with scheduled visits and study procedures.
11. 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.

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, version 4.0) from AEs (except alopecia), due to agents previously administered.
3. 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.
4. 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).
5. Are taking medications with a known risk of Torsades de Pointes.
6. Have previously been treated with ponatinib.
7. 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.
8. 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
9. 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.
10. Have poorly controlled diabetes defined as HbA1c values of \>7.5%. Participants 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 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.
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 prior to first dose of ponatinib.
18. Have an active infection which requires intravenous antibiotics.
19. Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.
20. Have any condition or illness that, in the opinion of the investigator, would compromise participant safety or interfere with the evaluation of the drug.
21. Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients.

Primary outcomes:
measure: Percentage of Participants With Molecular Response (MR2: <=1% Breakpoint Cluster Region-Abelson Transcript Level) as Measured by the International Scale (BCR-ABL1IS) at Month 12
timeFrame: 12 months after the first dose of study treatment
Secondary outcomes:
measure: Percentage of Participants With Major Molecular Response (MMR/MR3)
timeFrame: 12 months after the first dose of study treatment
measure: Percentage of Participants With Major Cytogenetic Response (MCyR)
timeFrame: 12 months after the first dose of study treatment
measure: Duration of Major Molecular Response (MMR/MR3)
timeFrame: Baseline up to approximately 8 years
measure: Percentage of Participants With Adjusted Incidence Rates for Treatment Emergent Arterial Occlusive Events (AOEs), Venous Thrombotic Events (VTEs), Adverse Events (AEs), and Serious AEs (SAEs)
timeFrame: From first dose up to 30 days after last dose of the study drug up to data cut-off date: 31 May 2020 (Up to approximately 5 years)
measure: Percentage of Participants With Complete Cytogenetic Response (CCyR)
timeFrame: Month 12
measure: Percentage of Participants With Molecular Response 4 (MR4) and Molecular Response (MR4.5)
timeFrame: Up to approximately 8 years
measure: Percentage of Participants With Molecular Response 1 (MR1)
timeFrame: 3 months after the first dose of study treatment
measure: Percentage of Participants With Complete Hematologic Response (CHR)
timeFrame: 3 months after the first dose of study treatment
measure: Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption
timeFrame: Up to data cut-off: 31 May 2020 (Approximately 5 years)
measure: Kaplan-Meier Estimate of Duration of Response (DOR) of <=1% BCR-ABL1 IS (MR2) at Months 12 and 24
timeFrame: 12 and 24 months after the first dose of study treatment
measure: Kaplan-Meier Estimate of Duration of Response (DOR) of Major Molecular Response (MMR/MR3)
timeFrame: 12 and 24 months after the first dose of study treatment
measure: Duration of Response in Responders
timeFrame: Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)
measure: Time to Response
timeFrame: Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)
measure: Percentage of Participants With Progression to Accelerated Phase (AP)-Chronic Myeloid Leukemia (CML) or Blast Phase (BP)-CML
timeFrame: From first dose date of study treatment up to data cut-off: 31 May 2020 (Approximately 5 years)
measure: Progression-free Survival (PFS)
timeFrame: Up to data cut-off: 31 May 2020 (Up to approximately 5 years)
measure: Overall Survival (OS)
timeFrame: Up to data cut-off: 31 May 2020 (Up to approximately 5 years)
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Indianapolis
country: United States
facility: Indiana Blood & Marrow Transplantation
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Ann Arbor
country: United States
facility: Michigan Medicine
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical School
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center - New York
state: New York
city: New York
country: United States
facility: NewYork-Presbyterian Weill Cornell Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Institute Main Campus
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Abramson Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Huntsman Cancer Institute
state: Utah
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Fundaleu
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Hospital General de Agudo Jose Maria Ramos Mejia
state: Buenos Aires
city: La Plata
country: Argentina
facility: Hospital Italiano La Plata
state: Buenos Aires
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Toronto
country: Canada
facility: Princess Margaret Hospital - Toronto
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Regina
country: Canada
facility: Saskatchewan Cancer Agency
state: Saskatchewan
city: Providencia
country: Chile
facility: Hospital del Salvador
state: Santiago
city: Vina del Mar
country: Chile
facility: Centro de Investigaciones Clinicas Vina del Mar
state: Valparaiso
city: Prague
country: Czechia
facility: Ustav Hematologie a Krevni Transfuze Praha
state: Praha
city: Olomouc
country: Czechia
facility: Fakultni Nemocnice Olomouc
city: Aarhus C
country: Denmark
facility: Aarhus University Hospital
state: \Aarhus
city: Bordeaux
country: France
facility: Centre de Lutte Contre le Cancer - Institut Bergonie
state: Aquitaine
city: Vandoeuvre les Nancy
country: France
facility: Centre Hospitalier Universitaire de Nancy Hopital de Brabois
state: Lorraine
city: Toulouse Cedex 9
country: France
facility: Institut Universitaire du Cancer de Toulouse Oncopole
state: Midi-pyrenees
city: Lille cedex
country: France
facility: Centre Hospitalier Regional Universitaire de Lille
state: NORD Pas-de-calais
city: Angers Cedex 9
country: France
facility: Center Hospitalier Universitaire d'Angers
state: PAYS DE LA Loire
city: Nantes Cedex 1
country: France
facility: Centre Hospitalier Universitaire de Nantes Hotel Dieu
state: PAYS DE LA Loire
city: Poitiers Cedex
country: France
facility: Centre Hospitalier Universitaire de Poitiers
state: Poitou-charentes
city: Nice Cedex 3
country: France
facility: Centre Hospitalier Universitaire de Nice Hopital l'Archet
state: Provence Alpes COTE D'azur
city: Mannheim
country: Germany
facility: Universitaetsklinikum Heidelberg
state: Baden-wuerttemberg
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
state: Baden-wuerttemberg
city: Rostock
country: Germany
facility: Universitatsmedizin Rostock
state: Mecklenburg-vorpommern
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
state: Nordrhein-westfalen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
state: Nordrhein-westfalen
city: Jena
country: Germany
facility: Universitatsklinikum Jena
state: Thuringen
city: Berlin
country: Germany
facility: Charite Universitatsmedizin Berlin
city: Hamburg
country: Germany
facility: Universitatsklinikum Hamburg-Eppendorf
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Monza
country: Italy
facility: Azienda Ospedaliera San Gerardo di Monza
state: Monza E Brianza
city: Pesaro
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Marche Nord
state: Pesaro E Urbino
city: Catania
country: Italy
facility: Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele
city: Genova
country: Italy
facility: Azienda Ospedaliera Universitaria San Martino
city: Pescara
country: Italy
facility: Azienda Sanitaria Locale di Pescara Ospedale Civile Dello Spirito Santo
city: Roma
country: Italy
facility: Sapienza Universita Di Roma
city: Verona
country: Italy
facility: AOUI - Ospedale Policlinico "Giambattista Rossi" di Borgo Roma
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Wroclaw
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu
state: Dolnoslaskie
city: Lodz
country: Poland
facility: Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
state: Lodzkie
city: Krakow
country: Poland
facility: Malopolskie Centrum Medyczne
state: Malopolskie
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
state: Mazowieckie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
state: Pomorskie
city: Lisboa
country: Portugal
facility: Instituto Portugues de Oncologia de Lisboa Francisco Gentil
city: Porto
country: Portugal
facility: Centro Hospitalar Sao Joao
city: Rostov-na-Donu
country: Russian Federation
facility: Rostov State Medical University
state: Rostov
city: Chelyabinsk
country: Russian Federation
facility: Chelyabinsk Regional Clinical Hospital
city: Kemerovo
country: Russian Federation
facility: Kemerovo Regional Clinical Hospital
city: Moscow
country: Russian Federation
facility: GBUZ Moscow Clinical Scientific Center DZM
city: Moscow
country: Russian Federation
facility: Russian Academy of Medical Science
city: Saint Petersburg
country: Russian Federation
facility: FGU Russian Scientific Research Institute of Hematology and Transfusiology
city: Saint Petersburg
country: Russian Federation
facility: Almazov Federal North-West Medical Research Centre of Department of Health of Russian Federation
city: Samara
country: Russian Federation
facility: Samara State Medical University
city: Saratov
country: Russian Federation
facility: Saratov State Medical University
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Malaga
country: Spain
facility: Hospital Regional Universitario Carlos Haya
state: Andalucia
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Doctor Nergrin
state: LAS Palmas
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Ramon Y Cajal
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset
city: Zurich
country: Switzerland
facility: University Hospital Zurich
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital NHS Trust
state: England
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital NHS Trust
state: England
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: England
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
state: Scotland
Study officials:
affiliation: Takeda
name: Study Director Clinical Science
role: STUDY_DIRECTOR
References:
citation: Cortes J, Apperley J, Lomaia E, Moiraghi B, Undurraga Sutton M, Pavlovsky C, Chuah C, Sacha T, Lipton JH, Schiffer CA, McCloskey J, Hochhaus A, Rousselot P, Rosti G, de Lavallade H, Turkina A, Rojas C, Arthur CK, Maness L, Talpaz M, Mauro M, Hall T, Lu V, Srivastava S, Deininger M. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood. 2021 Nov 25;138(21):2042-2050. doi: 10.1182/blood.2021012082.