search
Back to results

A Study of Ponatinib in Japanese Participants With Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL)

Primary Purpose

Chronic Myeloid Leukemia (CML), Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Status
Completed
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
ponatinib - Phase 1
ponatinib - Phase 2
Sponsored by
Ariad Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Myeloid Leukemia (CML) focused on measuring Leukemia, Leukemia, Myeloid, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Neoplasms by Histologic Type, Neoplasms, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Myeloproliferative Disorders, Bone Marrow Diseases, Hematologic Diseases

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL, as follows:

    • All patients must have screening bone marrow (BM) cytogenetics with conventional banding performed within 42 days prior to beginning treatment.
    • Examination of at least 20 metaphases is required in patients in CP. If less than 20 metaphases are examined, the BM aspirate must be repeated.
    • Adequate BM aspirate with differential cell counts is required in patients with AP, BP, or Ph+ ALL. If an adequate aspirate is not obtained, the aspirate must be repeated.
  2. Be previously treated with and resistant, or intolerant, as defined in the protocol, to either dasatinib or nilotinib for CML or at least one TKI for Ph+ ALL, regardless of whether dasatinib or nilotinib or the prior TKI were used to treat newly diagnosed or resistant patients.
  3. Must be ≥ 18 years old.
  4. Provide written informed consent.
  5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  6. Minimum life expectancy of 3 months or more.
  7. Adequate renal function defined as serum creatinine < 1.5 × upper limit of normal (ULN) for institution.
  8. Adequate hepatic function defined as:

    1. Total bilirubin < 1.5 × ULN
    2. Alanine aminotransferase (ALT [SGPT]) and aspartate aminotransferase (AST [SGOT]) < 2.5 × ULN for institution (< 5 × ULN if liver involvement with leukemia)
    3. Prothrombin time < 1.5 × ULN
  9. Normal pancreatic status defined as:

    1. Lipase ≤ 1.5 × ULN for institution
    2. Amylase ≤ 1.5 × ULN for institution
  10. Normal QT interval corrected (Fridericia) (QTcF) interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
  11. For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment.
  12. Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study.
  13. Ability to comply with study procedures, in the Investigator's opinion.

Exclusion Criteria:

Patients are not eligible for participation in the study if they meet any of the following exclusion criteria:

  1. Received TKI therapy within 7 days prior to receiving the first dose of ponatinib, or have not recovered (> grade 1 by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [NCI CTCAE v.4.0]) from adverse events (AEs) (except alopecia) due to agents previously administered.
  2. Received other therapies as follows:

    1. For CP and AP patients, 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.
    2. For BP patients, received chemotherapy within 7 days prior to the first dose of ponatinib. Otherwise, 2a applies.
    3. For Ph+ ALL patients, received corticosteroids within 24 hours before the first dose of ponatinib and other chemotherapy within 7 days prior to the first dose of ponatinib. Otherwise, 2a applies.
    4. All patients are excluded if they have not recovered (> grade 1 by NCI CTCAE v.4.0) from AEs (except alopecia) due to agents previously administered.
  3. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of ponatinib; any evidence of ongoing graft versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy.
  4. Take medications that are known to be associated with Torsades de Pointes.
  5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
  6. Have previously been treated with ponatinib.
  7. Patients with CP-CML are excluded if they are in CCyR.
  8. Patients with CP-CML are excluded if a baseline BM aspirate adequate for conventional cytogenetic analysis with 20 metaphases examined is not available.
  9. Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if they are in MaHR.
  10. Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if a baseline BM aspirate adequate for cell count and differential report is not available. Patients with a fibrotic marrow or dry tap that does not yield adequate cell counts for diagnosis are not evaluable for classification, and endpoints are not eligible.
  11. Have active central nervous system (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.
  12. Have significant or active cardiovascular disease, specifically including, but not restricted to:

    1. Myocardial infarction within 3 months prior to first dose of ponatinib
    2. History of clinically significant atrial arrhythmia or any ventricular arrhythmia
    3. Unstable angina within 3 months prior to first dose of ponatinib
    4. Congestive heart failure within 3 months prior to first dose of ponatinib
  13. Have a significant bleeding disorder unrelated to CML or Ph+ ALL.
  14. Have a history of pancreatitis or alcohol abuse.
  15. Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL).
  16. Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered ponatinib.
  17. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years).
  18. Are pregnant or lactating. Women of childbearing potential must agree to an effective contraception from the time of signing the informed consent through the Follow-up Visit, approximately 30 days after last dose of ponatinib.
  19. Underwent 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.
  20. Have ongoing or active infection (including known history of human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]). Testing for these viruses is not required in the absence of history.
  21. Suffer from any condition or illness that, in the opinion of the Investigator or the Medical Monitor, would compromise patients safety or interfere with the evaluation of the safety of the study drug.

Sites / Locations

  • Aichi Cancer Center Hospital
  • Akita University Hospital
  • Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital
  • Kyushu University Hospital
  • Kinki University Hospital, Faculty of Medicine
  • The Cancer Institute Hospital Japanese Foundation for Cancer Research
  • The University of Tokyo, The Institute of Medical Science
  • Keio University Hospital
  • Osaka City University Hospital
  • National Cancer Center Hospital
  • Tokyo Medical University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Phase 1 dose escalation

Phase 2 expansion

Arm Description

Phase 1

Phase 2

Outcomes

Primary Outcome Measures

Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib
DLT was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 and was defined as any of the following events: 1. Grade greater than or equal to (>=) 3 non-hematologic, with the exception of medically controllable toxicities (example; nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting <=3 days, but excluding alopecia; 2. Missed doses: >25% of planned ponatinib doses over 28 days due to AEs in the first cycle; 3. Febrile neutropenia (the occurrence of an ANC <500/microliter concurrently with a temperature elevation of >101 degree Fahrenheit), when neutropenia is not related to underlying acute leukemia, as defined hematologic toxicity: Dose-limiting hematologic toxicity is the occurrence of a Grade 4 cytopenia >28 days, not related to underlying disease according to the investigator. Bone marrow examination must demonstrate <5% cellularity.
Phase 2, CP-CML Participants: Percentage of Participants With Major Cytogenetic Response (MCyR)
MCyR was defined as percentage of participants who achieved a complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) after the initiation of study treatment. Cytogenic response was the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow. CCyR: no Ph+ cells. PCyR: 1% to 35% Ph+ cells. Participants entering the study already in PCyR had to achieve a CCyR in order to be considered a success for the confirmed MCyR rate.
Phase 2, BP-CML and Ph+ALL: Percentage of Participants With Major Hematologic Response (MaHR)
MaHR was defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). MaHR response was confirmed by a peripheral blood complete blood count (CBC) and differential no earlier than 28 days after the response was observed. Response criteria for CHR was reported as white blood cells (WBC)<=institutional upper limit of normal (ULN), absolute neutrophil count (ANC)>=1000/mm^3, platelets>=100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts <=5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL reported as WBC<=institutional ULN, no blasts or promyelocytes in peripheral blood, BM blasts <=5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3<=platelets<100,000/mm^3; (ii) 500/mm^3<=ANC<1000/mm^3.

Secondary Outcome Measures

CP-CML Participants: Percentage of Participants With CHR
Hematologic response was defined as CHR for CP-CML participants. Participants who entered the trial in CHR and continued to meet the criteria for CHR on study were analyzed as responders. Response criteria for CHR was reported as WBC <=institutional ULN, platelets <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%, no extramedullary involvement (including no hepatomegaly or splenomegaly).
CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR
Confirmed MCyR was defined as 2 assessments of CCyR or PCyR at least 28 days apart. Participants entering the trial in PCyR must achieve two consecutive assessments of CCyR no fewer than 28 days apart in order to be considered as meeting the criteria for confirmed MCyR. Participants entering the trial in less than PCyR must achieve two consecutive assessments of PCyR or CCyR no fewer than 28 days apart in order to be considered as meeting the criteria for confirmed MCyR. CCyR: no Ph+ cells. PCyR: 1% to 35% Ph+ cells.
CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR)
MMR was defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL <=0.1% on the International scale (equivalent to a 3-log reduction in transcript). Participants were non-responders in any of the following situations: BCR-ABL or ABL levels not detectable at baseline, no valid baseline or post-baseline assessment, and baseline assessment for e1a2 variant only.
CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR)
Time to response was defined as the interval from the first dose of study treatment until the criteria for response were first met, censored at the last assessment of response. Median time to response was estimated by Kaplan-Meier method.
CP-CML and Advanced Phase Participants: Median Duration of Response (DOR)
DOR: interval between first assessment at which criteria for response was met, until criteria for progression was met, censored at last date at which criteria for response was met. DOR was estimated using the Kaplan-Meier method. Progression criteria for CP was: death, development of AP/BP, or loss of CHR (in absence of cytogenic response), or loss of MCyR, or increasing WBC in participant without CHR (doubling of WBCs to >20,000 on 2 occasions at least 4 weeks apart, after first week of therapy), as confirmed by development in complete blood cells (CBCs) at least 4 weeks apart; AP was: death, development of confirmed BP, loss of previous major/minor hematologic response over-2 week period, or no decrease from baseline levels in percentage blasts in peripheral blood/BM on all assessments over a 4-week period; and BP/Ph+ALL was: death/increasing blasts in peripheral blood or BM over a 4-week period. As planned, DOR is reported for all participants by entry mutation (T315I and Other).
CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS)
PFS: interval from the first dose of study treatment until the criteria for progression or death were met, censored at the last response assessment. PFS was estimated using the Kaplan-Meier method. Progression criteria for CP was: death, development of AP/BP, or loss of CHR (in absence of cytogenic response), or loss of MCyR, or increasing WBC in participant without CHR (doubling of WBCs to >20,000 on 2 occasions at least 4 weeks apart, after first week of therapy), as confirmed by development in CBCs at least 4 weeks apart; AP was: death, development of confirmed BP, loss of previous major/minor hematologic response over-2 week period, or no decrease from baseline levels in percentage blasts in peripheral blood/BM on all assessments over a 4-week period; BP/Ph+ALL was: death or increasing blasts in peripheral blood or BM over a 4-week period. As planned, PFS is reported for all participants by entry mutation (T315I and Other).
CP-CML and Advanced Phase Participants: Overall Survival (OS)
OS was defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive. Overall survival was estimated using the Kaplan-Meier method. As planned, OS is reported for all participants by entry mutation (T315I and Other).
Cmax: Maximum Observed Plasma Concentration for Ponatinib
Tmax: Time to Reach the Cmax for Ponatinib
AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Ponatinib
T1/2: Terminal Phase Elimination Half-life for Ponatinib

Full Information

First Posted
August 13, 2012
Last Updated
March 9, 2022
Sponsor
Ariad Pharmaceuticals
search

1. Study Identification

Unique Protocol Identification Number
NCT01667133
Brief Title
A Study of Ponatinib in Japanese Participants With Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL)
Official Title
A Phase 1/2 Multi-center, Open-label Study of Ponatinib in Japanese Patients With Chronic Myeloid Leukemia (CML) Who Have Failed Dasatinib or Nilotinib or Ph+ Acute Lymphoblastic Leukemia (ALL) Who Have Failed Prior Tyrosine Kinase Inhibitors (TKIs)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
August 31, 2012 (Actual)
Primary Completion Date
August 2, 2018 (Actual)
Study Completion Date
August 2, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ariad Pharmaceuticals

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to assess the safety and efficacy of ponatinib in Japanese patients with chronic myeloid leukemia (CML) who have experienced failure of dasatinib or nilotinib or with Ph+ acute lymphoblastic leukemia (ALL) following failure of prior tyrosine kinase inhibitors (TKIs).
Detailed Description
This multi-center, phase 1/2, open-label study will consist of two phases. The first will be a dose escalation phase employing a modified 3+3 design with two dose cohorts (30mg and 45mg). After 6 patients complete the first cycle in a cohort, safety events will be evaluated before opening the next dose cohort. Patients will continue on treatment as long as it is tolerated and disease progression has not occurred. Phase 2 will occur at the recommended dose determined in phase 1 in an additional 25 patients. Another 3 patients will be dosed at 15mg for collection of pharmacokinetic data. These patients may also escalate to the recommended dose and be assessed for efficacy and safety as phase 2 patients. Efficacy measures include molecular, cytogenetic, and hematologic response rates at various time points; time to response; duration of response; and survival follow-up. Safety measures include routine physical and laboratory evaluations, adverse event monitoring, and ECGs. Other measures include mutation testing and molecular genetic assessment. Accrual is expected to take approximately 12 months, and patients will be followed for survival for up to 60 months from the last dose of study drug; therefore, the estimated duration of the trial is 72 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Myeloid Leukemia (CML), Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Keywords
Leukemia, Leukemia, Myeloid, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Neoplasms by Histologic Type, Neoplasms, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Myeloproliferative Disorders, Bone Marrow Diseases, Hematologic Diseases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
35 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase 1 dose escalation
Arm Type
Experimental
Arm Description
Phase 1
Arm Title
Phase 2 expansion
Arm Type
Experimental
Arm Description
Phase 2
Intervention Type
Drug
Intervention Name(s)
ponatinib - Phase 1
Other Intervention Name(s)
AP24534
Intervention Description
30 mg dose of ponatinib taken orally once daily for at least the first 6 patients. If no dose-limiting toxicities are observed, the next patients will receive 45 mg dose of ponatinib taken orally once daily. Once the recommended dose is confirmed, all patients may receive the recommended dose, at the investigators' discretion.
Intervention Type
Drug
Intervention Name(s)
ponatinib - Phase 2
Other Intervention Name(s)
AP24534
Intervention Description
Recommended dose of ponatinib as determined in the dose escalation phase. In addition, 3 patients will receive 15 mg dose once daily for 8 days for PK testing. These PK patients may be allowed to receive the recommended dose after PK testing is complete, at the investigators' discretion.
Primary Outcome Measure Information:
Title
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib
Description
DLT was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 and was defined as any of the following events: 1. Grade greater than or equal to (>=) 3 non-hematologic, with the exception of medically controllable toxicities (example; nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting <=3 days, but excluding alopecia; 2. Missed doses: >25% of planned ponatinib doses over 28 days due to AEs in the first cycle; 3. Febrile neutropenia (the occurrence of an ANC <500/microliter concurrently with a temperature elevation of >101 degree Fahrenheit), when neutropenia is not related to underlying acute leukemia, as defined hematologic toxicity: Dose-limiting hematologic toxicity is the occurrence of a Grade 4 cytopenia >28 days, not related to underlying disease according to the investigator. Bone marrow examination must demonstrate <5% cellularity.
Time Frame
Cycle 1 (Cycle length= 28 days)
Title
Phase 2, CP-CML Participants: Percentage of Participants With Major Cytogenetic Response (MCyR)
Description
MCyR was defined as percentage of participants who achieved a complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) after the initiation of study treatment. Cytogenic response was the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow. CCyR: no Ph+ cells. PCyR: 1% to 35% Ph+ cells. Participants entering the study already in PCyR had to achieve a CCyR in order to be considered a success for the confirmed MCyR rate.
Time Frame
Baseline up to 60 months
Title
Phase 2, BP-CML and Ph+ALL: Percentage of Participants With Major Hematologic Response (MaHR)
Description
MaHR was defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). MaHR response was confirmed by a peripheral blood complete blood count (CBC) and differential no earlier than 28 days after the response was observed. Response criteria for CHR was reported as white blood cells (WBC)<=institutional upper limit of normal (ULN), absolute neutrophil count (ANC)>=1000/mm^3, platelets>=100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts <=5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL reported as WBC<=institutional ULN, no blasts or promyelocytes in peripheral blood, BM blasts <=5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3<=platelets<100,000/mm^3; (ii) 500/mm^3<=ANC<1000/mm^3.
Time Frame
Baseline up to 60 months
Secondary Outcome Measure Information:
Title
CP-CML Participants: Percentage of Participants With CHR
Description
Hematologic response was defined as CHR for CP-CML participants. Participants who entered the trial in CHR and continued to meet the criteria for CHR on study were analyzed as responders. Response criteria for CHR was reported as WBC <=institutional ULN, platelets <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%, no extramedullary involvement (including no hepatomegaly or splenomegaly).
Time Frame
Baseline up to 60 months
Title
CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR
Description
Confirmed MCyR was defined as 2 assessments of CCyR or PCyR at least 28 days apart. Participants entering the trial in PCyR must achieve two consecutive assessments of CCyR no fewer than 28 days apart in order to be considered as meeting the criteria for confirmed MCyR. Participants entering the trial in less than PCyR must achieve two consecutive assessments of PCyR or CCyR no fewer than 28 days apart in order to be considered as meeting the criteria for confirmed MCyR. CCyR: no Ph+ cells. PCyR: 1% to 35% Ph+ cells.
Time Frame
Baseline up to 60 months
Title
CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR)
Description
MMR was defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL <=0.1% on the International scale (equivalent to a 3-log reduction in transcript). Participants were non-responders in any of the following situations: BCR-ABL or ABL levels not detectable at baseline, no valid baseline or post-baseline assessment, and baseline assessment for e1a2 variant only.
Time Frame
Baseline up to 60 months
Title
CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR)
Description
Time to response was defined as the interval from the first dose of study treatment until the criteria for response were first met, censored at the last assessment of response. Median time to response was estimated by Kaplan-Meier method.
Time Frame
From the first dose of study treatment until the criteria for response were first met (up to 60 months)
Title
CP-CML and Advanced Phase Participants: Median Duration of Response (DOR)
Description
DOR: interval between first assessment at which criteria for response was met, until criteria for progression was met, censored at last date at which criteria for response was met. DOR was estimated using the Kaplan-Meier method. Progression criteria for CP was: death, development of AP/BP, or loss of CHR (in absence of cytogenic response), or loss of MCyR, or increasing WBC in participant without CHR (doubling of WBCs to >20,000 on 2 occasions at least 4 weeks apart, after first week of therapy), as confirmed by development in complete blood cells (CBCs) at least 4 weeks apart; AP was: death, development of confirmed BP, loss of previous major/minor hematologic response over-2 week period, or no decrease from baseline levels in percentage blasts in peripheral blood/BM on all assessments over a 4-week period; and BP/Ph+ALL was: death/increasing blasts in peripheral blood or BM over a 4-week period. As planned, DOR is reported for all participants by entry mutation (T315I and Other).
Time Frame
From the first assessment at which criteria for response was met until the criteria for progression was first met (up to 60 months)
Title
CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS)
Description
PFS: interval from the first dose of study treatment until the criteria for progression or death were met, censored at the last response assessment. PFS was estimated using the Kaplan-Meier method. Progression criteria for CP was: death, development of AP/BP, or loss of CHR (in absence of cytogenic response), or loss of MCyR, or increasing WBC in participant without CHR (doubling of WBCs to >20,000 on 2 occasions at least 4 weeks apart, after first week of therapy), as confirmed by development in CBCs at least 4 weeks apart; AP was: death, development of confirmed BP, loss of previous major/minor hematologic response over-2 week period, or no decrease from baseline levels in percentage blasts in peripheral blood/BM on all assessments over a 4-week period; BP/Ph+ALL was: death or increasing blasts in peripheral blood or BM over a 4-week period. As planned, PFS is reported for all participants by entry mutation (T315I and Other).
Time Frame
From the first assessment at which criteria for response was met until the criteria for progression or death was met (up to 60 months)
Title
CP-CML and Advanced Phase Participants: Overall Survival (OS)
Description
OS was defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive. Overall survival was estimated using the Kaplan-Meier method. As planned, OS is reported for all participants by entry mutation (T315I and Other).
Time Frame
From the first dose of study treatment until death (up to 60 months)
Title
Cmax: Maximum Observed Plasma Concentration for Ponatinib
Time Frame
Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Title
Tmax: Time to Reach the Cmax for Ponatinib
Time Frame
Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Title
AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Ponatinib
Time Frame
Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Title
T1/2: Terminal Phase Elimination Half-life for Ponatinib
Time Frame
Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL, as follows: All patients must have screening bone marrow (BM) cytogenetics with conventional banding performed within 42 days prior to beginning treatment. Examination of at least 20 metaphases is required in patients in CP. If less than 20 metaphases are examined, the BM aspirate must be repeated. Adequate BM aspirate with differential cell counts is required in patients with AP, BP, or Ph+ ALL. If an adequate aspirate is not obtained, the aspirate must be repeated. Be previously treated with and resistant, or intolerant, as defined in the protocol, to either dasatinib or nilotinib for CML or at least one TKI for Ph+ ALL, regardless of whether dasatinib or nilotinib or the prior TKI were used to treat newly diagnosed or resistant patients. Must be ≥ 18 years old. Provide written informed consent. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Minimum life expectancy of 3 months or more. Adequate renal function defined as serum creatinine < 1.5 × upper limit of normal (ULN) for institution. Adequate hepatic function defined as: Total bilirubin < 1.5 × ULN Alanine aminotransferase (ALT [SGPT]) and aspartate aminotransferase (AST [SGOT]) < 2.5 × ULN for institution (< 5 × ULN if liver involvement with leukemia) Prothrombin time < 1.5 × ULN Normal pancreatic status defined as: Lipase ≤ 1.5 × ULN for institution Amylase ≤ 1.5 × ULN for institution Normal QT interval corrected (Fridericia) (QTcF) interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females. For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment. Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study. Ability to comply with study procedures, in the Investigator's opinion. Exclusion Criteria: Patients are not eligible for participation in the study if they meet any of the following exclusion criteria: Received TKI therapy within 7 days prior to receiving the first dose of ponatinib, or have not recovered (> grade 1 by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [NCI CTCAE v.4.0]) from adverse events (AEs) (except alopecia) due to agents previously administered. Received other therapies as follows: For CP and AP patients, 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. For BP patients, received chemotherapy within 7 days prior to the first dose of ponatinib. Otherwise, 2a applies. For Ph+ ALL patients, received corticosteroids within 24 hours before the first dose of ponatinib and other chemotherapy within 7 days prior to the first dose of ponatinib. Otherwise, 2a applies. All patients are excluded if they have not recovered (> grade 1 by NCI CTCAE v.4.0) from AEs (except alopecia) due to agents previously administered. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of ponatinib; any evidence of ongoing graft versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy. Take medications that are known to be associated with Torsades de Pointes. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy. Have previously been treated with ponatinib. Patients with CP-CML are excluded if they are in CCyR. Patients with CP-CML are excluded if a baseline BM aspirate adequate for conventional cytogenetic analysis with 20 metaphases examined is not available. Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if they are in MaHR. Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if a baseline BM aspirate adequate for cell count and differential report is not available. Patients with a fibrotic marrow or dry tap that does not yield adequate cell counts for diagnosis are not evaluable for classification, and endpoints are not eligible. Have active central nervous system (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. Have significant or active cardiovascular disease, specifically including, but not restricted to: Myocardial infarction within 3 months prior to first dose of ponatinib History of clinically significant atrial arrhythmia or any ventricular arrhythmia Unstable angina within 3 months prior to first dose of ponatinib Congestive heart failure within 3 months prior to first dose of ponatinib Have a significant bleeding disorder unrelated to CML or Ph+ ALL. Have a history of pancreatitis or alcohol abuse. Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL). Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered ponatinib. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years). Are pregnant or lactating. Women of childbearing potential must agree to an effective contraception from the time of signing the informed consent through the Follow-up Visit, approximately 30 days after last dose of ponatinib. Underwent 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. Have ongoing or active infection (including known history of human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]). Testing for these viruses is not required in the absence of history. Suffer from any condition or illness that, in the opinion of the Investigator or the Medical Monitor, would compromise patients safety or interfere with the evaluation of the safety of the study drug.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
Facility Name
Aichi Cancer Center Hospital
City
Nagoya-shi
State/Province
Aichi
ZIP/Postal Code
464-8681
Country
Japan
Facility Name
Akita University Hospital
City
Akita-shi
State/Province
Akita
ZIP/Postal Code
010-8543
Country
Japan
Facility Name
Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital
City
Hiroshima-shi
State/Province
Hiroshima
ZIP/Postal Code
730-8619
Country
Japan
Facility Name
Kyushu University Hospital
City
Hukuoka-shi
State/Province
Hukuoka
Country
Japan
Facility Name
Kinki University Hospital, Faculty of Medicine
City
Osakasayama-shi
State/Province
Osaka
ZIP/Postal Code
589-8511
Country
Japan
Facility Name
The Cancer Institute Hospital Japanese Foundation for Cancer Research
City
Koto
State/Province
Tokyo
Country
Japan
Facility Name
The University of Tokyo, The Institute of Medical Science
City
Minato-ku
State/Province
Tokyo
Country
Japan
Facility Name
Keio University Hospital
City
Shinjuku-ku
State/Province
Tokyo
Country
Japan
Facility Name
Osaka City University Hospital
City
Shinjuku-ku
State/Province
Tokyo
Country
Japan
Facility Name
National Cancer Center Hospital
City
Chuo-ku, Tokyo
Country
Japan
Facility Name
Tokyo Medical University Hospital
City
Shinjuku-ku, Tokyo
Country
Japan

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
IPD Sharing Access Criteria
IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
IPD Sharing URL
https://vivli.org/ourmember/takeda/
Citations:
PubMed Identifier
34699069
Citation
Hanley MJ, Diderichsen PM, Narasimhan N, Srivastava S, Gupta N, Venkatakrishnan K. Population Pharmacokinetics of Ponatinib in Healthy Adult Volunteers and Patients With Hematologic Malignancies and Model-Informed Dose Selection for Pediatric Development. J Clin Pharmacol. 2022 Apr;62(4):555-567. doi: 10.1002/jcph.1990. Epub 2021 Dec 16.
Results Reference
derived
PubMed Identifier
28444644
Citation
Tojo A, Kyo T, Yamamoto K, Nakamae H, Takahashi N, Kobayashi Y, Tauchi T, Okamoto S, Miyamura K, Hatake K, Iwasaki H, Matsumura I, Usui N, Naoe T, Tugnait M, Narasimhan NI, Lustgarten S, Farin H, Haluska F, Ohyashiki K. Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study. Int J Hematol. 2017 Sep;106(3):385-397. doi: 10.1007/s12185-017-2238-9. Epub 2017 Apr 25.
Results Reference
derived

Learn more about this trial

A Study of Ponatinib in Japanese Participants With Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL)

We'll reach out to this number within 24 hrs