Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses

NCT ID: NCT02467270

Last Updated: 2025-05-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 283 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-30
• Study Completion Date: 2025-04-23

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.

Conditions

Myeloid Leukemia, Chronic, Chronic Phase

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort A: Ponatinib 45 mg

Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Tablet, taken orally once daily.

Cohort B: Ponatinib 30 mg

Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Tablet, taken orally once daily.

Cohort C: Ponatinib 15 mg

Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Tablet, taken orally once daily.

Interventions

Ponatinib

Tablet, taken orally once daily.

Intervention Type: DRUG

Other Intervention Names

Iclusig; AP24534

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director Clinical Science

Role: STUDY_DIRECTOR

Takeda

Locations

Emory University Winship Cancer Institute

Atlanta, Georgia, United States

Indiana Blood & Marrow Transplantation

Indianapolis, Indiana, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Michigan Medicine

Ann Arbor, Michigan, United States

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States

University of Minnesota Medical School

Minneapolis, Minnesota, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Memorial Sloan-Kettering Cancer Center - New York

New York, New York, United States

NewYork-Presbyterian Weill Cornell Medical Center

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Cleveland Clinic Taussig Cancer Institute Main Campus

Cleveland, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Abramson Cancer Center

Philadelphia, Pennsylvania, United States

MD Anderson Cancer Center

Houston, Texas, United States

University of Utah Huntsman Cancer Institute

Salt Lake City, Utah, United States

Fundaleu

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

Hospital General de Agudo Jose Maria Ramos Mejia

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

Hospital Italiano La Plata

La Plata, Buenos Aires, Argentina

Royal North Shore Hospital

Saint Leonards, New South Wales, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Princess Margaret Hospital - Toronto

Toronto, Ontario, Canada

Jewish General Hospital

Montreal, Quebec, Canada

Saskatchewan Cancer Agency

Regina, Saskatchewan, Canada

Centro de Investigaciones Clinicas Vina del Mar

Viña del Mar, Región de Valparaíso, Chile

Hospital del Salvador

Providencia, Santiago Metropolitan, Chile

Ustav Hematologie a Krevni Transfuze Praha

Prague, Prague, Czechia

Fakultni Nemocnice Olomouc

Olomouc, , Czechia

Aarhus University Hospital

Aarhus C, \Aarhus, Denmark

Centre de Lutte Contre le Cancer - Institut Bergonie

Bordeaux, Aquitaine, France

Centre Hospitalier Regional Universitaire de Lille

Lille, Hauts-de-France, France

Centre Hospitalier Universitaire de Nancy Hopital de Brabois

Vandœuvre-lès-Nancy, Lorraine, France

Institut Universitaire du Cancer de Toulouse Oncopole

Toulouse, Midi-pyrenees, France

Center Hospitalier Universitaire d'Angers

Angers, Pays de la Loire Region, France

Centre Hospitalier Universitaire de Nantes Hotel Dieu

Nantes, Pays de la Loire Region, France

Centre Hospitalier Universitaire de Poitiers

Poitiers, Poitou-charentes, France

Centre Hospitalier Universitaire de Nice Hopital l'Archet

Nice, Provence-Alpes-Côte d'Azur Region, France

Universitaetsklinikum Heidelberg

Mannheim, Baden-Wurttemberg, Germany

Universitatsklinikum Ulm

Ulm, Baden-Wurttemberg, Germany

Universitatsmedizin Rostock

Rostock, Mecklenburg-Vorpommern, Germany

Uniklinik RWTH Aachen

Aachen, North Rhine-Westphalia, Germany

Universitaetsklinikum Essen

Essen, North Rhine-Westphalia, Germany

Universitatsklinikum Jena

Jena, Thuringia, Germany

Charite Universitatsmedizin Berlin

Berlin, , Germany

Universitatsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Queen Mary Hospital

Hong Kong, , Hong Kong

Azienda Ospedaliera San Gerardo di Monza

Monza, Monza E Brianza, Italy

Azienda Ospedaliera Ospedali Riuniti Marche Nord

Pesaro, Pesaro E Urbino, Italy

Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele

Catania, , Italy

Azienda Ospedaliera Universitaria San Martino

Genova, , Italy

Azienda Sanitaria Locale di Pescara Ospedale Civile Dello Spirito Santo

Pescara, , Italy

Sapienza Universita Di Roma

Roma, , Italy

AOUI - Ospedale Policlinico "Giambattista Rossi" di Borgo Roma

Verona, , Italy

Malopolskie Centrum Medyczne

Krakow, Lesser Poland Voivodeship, Poland

Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu

Wroclaw, Lower Silesian Voivodeship, Poland

Instytut Hematologii i Transfuzjologii

Warsaw, Masovian Voivodeship, Poland

Uniwersyteckie Centrum Kliniczne

Gdansk, Pomeranian Voivodeship, Poland

Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi

Lodz, Łódź Voivodeship, Poland

Instituto Portugues de Oncologia de Lisboa Francisco Gentil

Lisbon, , Portugal

Centro Hospitalar Sao Joao

Porto, , Portugal

Rostov State Medical University

Rostov-on-Don, Rostov Oblast, Russia

Chelyabinsk Regional Clinical Hospital

Chelyabinsk, , Russia

Kemerovo Regional Clinical Hospital

Kemerovo, , Russia

GBUZ Moscow Clinical Scientific Center DZM

Moscow, , Russia

Russian Academy of Medical Science

Moscow, , Russia

FGU Russian Scientific Research Institute of Hematology and Transfusiology

Saint Petersburg, , Russia

Almazov Federal North-West Medical Research Centre of Department of Health of Russian Federation

Saint Petersburg, , Russia

Samara State Medical University

Samara, , Russia

Saratov State Medical University

Saratov, , Russia

Singapore General Hospital

Singapore, , Singapore

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, , South Korea

Hospital Regional Universitario Carlos Haya

Málaga, Andalusia, Spain

Hospital Universitario de Gran Canaria Doctor Nergrin

Las Palmas de Gran Canaria, LAS Palmas, Spain

Hospital Clinic i Provincial de Barcelona

Barcelona, , Spain

Hospital Universitario de La Princesa

Madrid, , Spain

Hospital Universitario Ramon Y Cajal

Madrid, , Spain

Hospital Clinico Universitario de Valencia

Valencia, , Spain

Akademiska Sjukhuset

Uppsala, , Sweden

University Hospital Zurich

Zurich, , Switzerland

National Taiwan University Hospital

Taipei, , Taiwan

Royal Liverpool University Hospital NHS Trust

Liverpool, England, United Kingdom

King's College Hospital NHS Foundation Trust

London, England, United Kingdom

Imperial College Healthcare NHS Trust

London, England, United Kingdom

Nottingham City Hospital NHS Trust

Nottingham, England, United Kingdom

Churchill Hospital

Oxford, England, United Kingdom

Beatson West of Scotland Cancer Centre

Glasgow, Scotland, United Kingdom

Countries

United States; Argentina; Australia; Canada; Chile; Czechia; Denmark; France; Germany; Hong Kong; Italy; Poland; Portugal; Russia; Singapore; South Korea; Spain; Sweden; Switzerland; Taiwan; United Kingdom

References

Kantarjian HM, Jabbour E, Deininger M, Abruzzese E, Apperley J, Cortes J, Chuah C, DeAngelo DJ, DiPersio J, Hochhaus A, Lipton J, Nicolini FE, Pinilla-Ibarz J, Rea D, Rosti G, Rousselot P, Shah NP, Talpaz M, Srivastava S, Ren X, Mauro M. Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia. Am J Hematol. 2022 Nov;97(11):1419-1426. doi: 10.1002/ajh.26686. Epub 2022 Aug 30.

Reference Type: DERIVED

PMID: 36054756 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34407543 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203469s009lbl.pdf

Iclusig® (ponatinib) US Prescribing Information

Other Identifiers

2014-001617-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

15/LO/1192

Identifier Type: REGISTRY

Identifier Source: secondary_id

U1111-1238-0007

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

AP24534-14-203

Identifier Type: -

Identifier Source: org_study_id