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

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ClinicalTrials.gov Identifier: NCT02467270
Recruitment Status : Active, not recruiting
First Posted : June 10, 2015
Last Update Posted : July 3, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Ariad Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE June 2, 2015
First Posted Date  ICMJE June 10, 2015
Last Update Posted Date July 3, 2019
Actual Study Start Date  ICMJE June 30, 2015
Estimated Primary Completion Date May 13, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 1, 2019)
Percentage of Participants with <=1% BCR-ABL1IS at Month 12 [ Time Frame: Month 12 ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 5, 2015)
Major cytogenetic response (MCyR) [ Time Frame: 12 months ]
MCyR is the presence of 0-35% of Ph+ cells in bone marrow. Response is further defined as partial cytogenetic response (PCyR), complete cytogenetic response (CCyR), or ≤1% BCR ABL(IS) (i.e., MR2), which is equivalent to CCyR.
Change History Complete list of historical versions of study NCT02467270 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 1, 2019)
  • Percentage of Participants With Major Molecular Response (MMR) at Months 12 and 24 [ Time Frame: Months 12 and 24 ]
    MMR is defined as percentage of participants with major molecular response.
  • Major Cytogenetic Response (MCyR) Rates by Month 12 [ Time Frame: Up to Month 12 ]
    MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: 0% Ph + metaphases; PCyR: greater than (>) 0 to 35% Ph + metaphases.
  • Duration of MMR [ Time Frame: Baseline up to Month 24 ]
    Duration of MMR is defined as the interval between the first assessment at which the criteria for <=1% MMR are met until the earliest date at which loss of <=1% MMR occurs, or the criteria for progression are met.
  • Percentage of Participants with Adjusted Incidence Rates for Arterial Occlusive Events (AOEs) and Venous Thrombotic Events (VTEs), Adverse Events (AEs), and Serious AEs (SAEs) [ Time Frame: Baseline up to Month 24 ]
    Percentage of participants with adjusted incidence rates who developed AOEs and VTEs will be categorized according to arterial occlusive events (Cardiac occlusive/thrombotic events, cerebral occlusive/thrombotic events and peripheral occlusive/thrombotic events) and venous thrombotic events.
  • Percentage of Participants With CCyR at Month 12 [ Time Frame: Month 12 ]
    Cytogenetic response is the percentage of Ph+ metaphases in bone marrow (peripheral blood may not be used), with a review of a minimum of 20 metaphases. CCyR is defined as 0% Ph+ metaphases.
  • Percentage of Participants With Major Molecular Response (MMR), Molecular Response 4 (MR4) and Molecular Response (MR4.5) [ Time Frame: Baseline up to Month 24 ]
    MR4 is defined as <=0.01% BCR-ABL1IS. MR 4.5 is defined as <=0.0032% BCR-ALB1IS.
  • Percentage of Participants With Molecular Response 1 (MR1) at Month 3 [ Time Frame: Month 3 ]
    MR1 is defined as percentage of participants achieving a ratio of <=10% Breakpoint Cluster Region-abelson (BCR-ABL1) transcripts on the international scale.
  • Percentage of Participants With Complete hematologic Response (CHR) at Month 3 [ Time Frame: Month 3 ]
    CHR is defined as achieving all of the following measurements: white blood cells (WBC) <= institutional upper limit of normal (ULN), platelets less than (<) 450,000 per cubic millimeter (/mm^3), no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, and no extramedullary involvement (including no hepatomegaly or splenomegaly).
  • Percentage of Participants with AEs Leading to Discontinuation and Dose Reduction [ Time Frame: Baseline up to Month 24 ]
  • Percentage of Participants with Dose Interruptions [ Time Frame: Baseline up to Month 24 ]
  • Duration of Response (DOR) of <=1% BCR-ABL1 IS [ Time Frame: From the first assessment at which the criteria for <= 1% BCR-ABL1IS are met until the earliest date at which loss of <= 1% BCR-ABL1IS occurs, or the criteria for progression are met (up to 6.3 years) ]
    Duration of <=1% BCR-ABL1IS is defined as the interval between the first assessment at which the criteria for <=1% BCR-ABL1IS are met until the earliest date at which loss of <=1% BCR-ABL1IS occurs, or the criteria for progression (progression to accelerated phase [AP] or blast phase [BP] of CML) are met. Loss of <=1% BCR-ABL1IS is an increase to >1% of BCR-ABL1IS. Progression to AP is defined as: greater than or equal to (>=) 15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets per liter (/L) in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
  • DOR for MMR [ Time Frame: From the first assessment at which the criteria for MMR are met until the earliest date at which loss of MMR occurs, or the criteria for progression are met (up to 6.3 years) ]
    Duration of MMR is defined as the interval between the first assessment at which the criteria for MMR are met until the earliest date at which loss of MMR occurs, or the criteria for progression (progression to AP or BP of CML) are met. Participants remaining in MMR will be censored at the last date at which the criteria for MMR are met. Loss of MMR is an increase to >1% of BCR-ABL1IS. Progression to AP is defined as: >= 15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
  • DOR in Responders [ Time Frame: Baseline up to 6.3 years ]
    Responders are defined as those participants who meet all of the following: are randomized and treated, respond at 12 months after the initiation of study treatment, and undergo baseline polymerase chain reaction (PCR) assessment.
  • Time to Response [ Time Frame: Baseline up to 6.3 years ]
  • Percentage of Participants With Progression to AP or BP CML [ Time Frame: From first dose date of study treatment until death due to any cause, censored at the last response assessment (up to 6.3 years) ]
    Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
  • Progression-free Survival (PFS) [ Time Frame: From first dose date of study treatment until first date at which criteria for progression are met, or death due to any cause, censored at the last response assessment (up to 6.3 years) ]
    PFS is defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression are met (progression to the AP or BP of CML), or death due to any cause, censored at the last response assessment. Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
  • Overall Survival (OS) [ Time Frame: From first dose date of study treatment until death due to any cause, censored at the last contact date when the participant was alive (up to 6.3 years) ]
    OS is defined as the interval between the first does of study treatment and death due to any cause, censored at the last contact date when the participant was alive.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2015)
  • Rates of vascular occlusive events (VOEs), adverse events (AEs), and serious AEs (SAEs) [ Time Frame: 24 months ]
    VOEs will be categorized as arterial or venous and according to main vasculature affected (cardiovascular, cerebrovascular or peripheral vascular).
  • Safety measured by comparing frequencies of AEs, SAEs and VOEs [ Time Frame: 24 months ]
  • Analysis of the relationship between steady-state plasma ponatinib exposure [peak plasma concentration (CMAX) and area-under-the-curve (AUC)] and safety measures (VOEs and any AEs that occur in at least 30 patients) [ Time Frame: 24 months ]
  • Analysis of the relationship between steady-state plasma ponatinib exposure (AUC and CMAX) and efficacy measures (MCyR, MR2, and MMR) [ Time Frame: 24 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary The purpose of this study is to characterize the efficacy of ponatinib administered in 3 starting doses (45 milligram [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 less than or equal to (<=) 1 percent (%) 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 the 24-month main treatment period 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 60 months. Participants will make a final visit to the clinic approximately 30 days after the last dose of study treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Myeloid Leukemia, Chronic, Chronic Phase
Intervention  ICMJE
  • Drug: Ponatinib 45 mg
    45 mg tablet, taken orally once daily.
    Other Names:
    • Iclusig
    • AP24534
  • Drug: Ponatinib 30 mg
    30 mg tablet, taken orally once daily.
    Other Names:
    • Iclusig
    • AP24534
  • Drug: Ponatinib 15 mg
    15 mg tablet, taken orally once daily.
    Other Names:
    • Iclusig
    • AP24534
Study Arms  ICMJE
  • Experimental: Cohort A
    Ponatinib 45 mg once daily starting dose.
    Intervention: Drug: Ponatinib 45 mg
  • Experimental: Cohort B
    Ponatinib 30 mg once daily starting dose.
    Intervention: Drug: Ponatinib 30 mg
  • Experimental: Cohort C
    Ponatinib 15 mg once daily starting dose.
    Intervention: Drug: Ponatinib 15 mg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 30, 2019)
283
Original Estimated Enrollment  ICMJE
 (submitted: June 5, 2015)
450
Estimated Study Completion Date  ICMJE September 30, 2021
Estimated Primary Completion Date May 13, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Have CP-CML and have received at least two prior 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:

    • Serum creatinine <=1.5*ULN for institution
    • Estimated creatinine clearance >=30 milliliter per minute (mL/min) (Cockcroft-Gault formula)
  4. Have adequate hepatic function as defined by the following criteria:

    • Total serum bilirubin <=1.5*ULN, unless due to Gilbert's syndrome
    • Alanine transaminase (ALT) <=2.5*ULN, or <=5*ULN if leukemic infiltration of the liver is present
    • 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:

    • Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or Transient Ischemic Attack (TIA)
    • Any history of peripheral vascular infarction, including visceral infarction
    • Any revascularization procedure, including the placement of a stent
    • 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
    • History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia
    • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Chile,   Russian Federation,   Argentina,   Australia,   Canada,   Czechia,   Denmark,   France,   Germany,   Hong Kong,   Italy,   Korea, Republic of,   Poland,   Portugal,   Singapore,   Spain,   Sweden,   Switzerland,   Taiwan,   United Kingdom,   United States
Removed Location Countries Belgium,   China,   Czech Republic,   Finland,   Japan,   Norway
 
Administrative Information
NCT Number  ICMJE NCT02467270
Other Study ID Numbers  ICMJE AP24534-14-203
2014‐001617‐12 ( EudraCT Number )
15/LO/1192 ( Registry Identifier: NRES )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Responsible Party Takeda ( Ariad Pharmaceuticals )
Study Sponsor  ICMJE Ariad Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Clinical Science Takeda
PRS Account Takeda
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP