Chronic Myeloid Leukemia (CML), Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Conditions
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
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.
Interventions
DRUGponatinib - Phase 1
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.
DRUGponatinib - Phase 2
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.
Sponsors
Ariad Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib | Cycle 1 (Cycle length= 28 days) | 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) | Baseline up to 60 months | 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) | Baseline up to 60 months | 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
| Measure | Time frame | Description |
|---|---|---|
| CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | Baseline up to 60 months | 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) | Baseline up to 60 months | 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) | From the first dose of study treatment until the criteria for response were first met (up to 60 months) | 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) | From the first assessment at which criteria for response was met until the criteria for progression was first met (up to 60 months) | 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). |
| Cmax: Maximum Observed Plasma Concentration for Ponatinib | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | From the first assessment at which criteria for response was met until the criteria for progression or death was met (up to 60 months) | 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). |
| AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Ponatinib | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| T1/2: Terminal Phase Elimination Half-life for Ponatinib | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| CP-CML and Advanced Phase Participants: Overall Survival (OS) | From the first dose of study treatment until death (up to 60 months) | 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). |
| Tmax: Time to Reach the Cmax for Ponatinib | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days) | — |
| CP-CML Participants: Percentage of Participants With CHR | Baseline up to 60 months | 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). |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 9 investigative sites in Japan from 31 August 2012 to 02 August 2018.
Pre-assignment details
Participants with CP-CML, AP-CML, or BP-CML, or with Ph+ALL were enrolled in Phase 1 (dose-escalation) to receive 30 or 45 mg of ponatinib and recommended phase 2 dose in Phase 2 (expansion). As there was no participant enrolled in Phase 1: BP-CML Ponatinib 30 milligram (mg) arm, therefore the arm is not reported in the result summary. Participants in Phase 1 with CP-CML or AP-CML, BP-CML or Ph+ ALL and who had T315I mutation and other mutations were analyzed as subgroups in the study.
Participants by arm
| Arm | Count |
|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML Ponatinib 30 mg, tablet, orally, once daily in a 28-day treatment cycle for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with CP-CML resistant or intolerant to dasatinib or nilotinib in Dose-escalation Phase 1. | 1 |
| Ponatinib 30 mg: Phase 1 AP-CML Ponatinib 30 mg, tablet, orally, once daily in a 28-day treatment cycle for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with AP-CML resistant or intolerant to dasatinib or nilotinib in Dose-escalation Phase 1. | 1 |
| Ponatinib 30 mg: Phase 1 Ph+ ALL Ponatinib 30 mg, tablet, orally, once daily in a 28-day treatment cycle for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with Ph+ ALL resistant or intolerant to prior TKIs in Dose-escalation Phase 1. | 4 |
| Ponatinib 45 mg: Phase 1 CP-CML Ponatinib 45 mg, tablet, orally, once daily in a 28-day treatment cycle for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with CP-CML resistant or intolerant to dasatinib or nilotinib in Dose-escalation Phase 1. | 3 |
| Ponatinib 45 mg: Phase 1 AP-CML Ponatinib 45 mg, tablet, orally, once daily in a 28-day treatment cycle 1 for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with AP-CML resistant or intolerant to dasatinib or nilotinib in Dose-escalation Phase 1. | 1 |
| Ponatinib 45 mg: Phase 1 BP-CML Ponatinib 45 mg, tablet, orally, once daily in a 28-day treatment cycle for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with BP-CML resistant or intolerant to dasatinib or nilotinib in Dose-escalation Phase 1. | 1 |
| Ponatinib 45 mg: Phase 1 Ph+ ALL Ponatinib 45 mg, tablet, orally, once daily in a 28-day treatment cycle for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with Ph+ ALL resistant or intolerant to prior TKIs in Dose-escalation Phase 1. | 1 |
| Ponatinib 15 mg: Phase 2 CP-CML Ponatinib 15 mg, tablet, orally, once daily for 7-days in a 28-day treatment cycle in participants with CP-CML resistant or intolerant to dasatinib or nilotinib in Expansion Phase 2. Dose was increased to ponatinib 45 mg in the same participants at the discretion of Investigator and was administered as tablet, orally, once daily in a 28-day treatment Cycle for up to unacceptable drug reaction or disease progression (up to 60 months). | 2 |
| Ponatinib 15 mg: Phase 2 Ph+ ALL Ponatinib 15 mg, tablet, orally, once daily for 7-days in a 28-day treatment cycle in participants with Ph+ ALL resistant or intolerant to prior TKIs in Expansion Phase 2. Dose was increased to ponatinib 45 mg in the same participants at the discretion of Investigator and was administered as tablet, orally, once daily in a 28-day treatment Cycle 1 for up to unacceptable drug reaction or disease progression (up to 60 months). | 1 |
| Ponatinib 45 mg: Phase 2 CP-CML Ponatinib 45 mg, tablet, orally, once daily in a 28-day treatment cycle for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with CP-CML resistant or intolerant to dasatinib or nilotinib in Expansion Phase 2. | 11 |
| Ponatinib 45 mg: Phase 2 BP-CML Ponatinib 45 mg, tablet, orally, once daily in a 28-day treatment cycle for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with BP-CML resistant or intolerant to dasatinib or nilotinib in Expansion Phase 2. | 3 |
| Ponatinib 45 mg: Phase 2 PH+ ALL Ponatinib 45 mg, tablet, orally, once daily in a 28-day treatment cycle for up to unacceptable drug reaction or disease progression (up to 60 months) in participants with PH+ ALL resistant or intolerant to prior TKI in Expansion Phase 2. | 6 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1: Dose-escalation | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1: Dose-escalation | Lack of Efficacy | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1: Dose-escalation | Progressive Disease | 0 | 1 | 2 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Phase 1: Dose-escalation | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 2: Dose-expansion | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 1 | 0 | 0 |
| Phase 2: Dose-expansion | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Phase 2: Dose-expansion | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
| Phase 2: Dose-expansion | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Phase 2: Dose-expansion | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 5 |
| Phase 2: Dose-expansion | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Ponatinib 30 mg: Phase 1 Ph+ ALL | Ponatinib 45 mg: Phase 1 CP-CML | Ponatinib 45 mg: Phase 1 AP-CML | Ponatinib 45 mg: Phase 1 BP-CML | Ponatinib 45 mg: Phase 1 Ph+ ALL | Ponatinib 30 mg: Phase 1 CP-CML | Ponatinib 15 mg: Phase 2 CP-CML | Ponatinib 15 mg: Phase 2 Ph+ ALL | Ponatinib 30 mg: Phase 1 AP-CML | Ponatinib 45 mg: Phase 2 CP-CML | Ponatinib 45 mg: Phase 2 BP-CML | Ponatinib 45 mg: Phase 2 PH+ ALL |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.4 years STANDARD_DEVIATION 12.44 | 56.5 years STANDARD_DEVIATION 11.73 | 60.7 years STANDARD_DEVIATION 12.86 | 57.0 years | 58.0 years | 30.0 years | 61.0 years | 61.5 years STANDARD_DEVIATION 14.85 | 76.0 years | 62.0 years | 59.1 years STANDARD_DEVIATION 13.78 | 67.7 years STANDARD_DEVIATION 4.04 | 58.3 years STANDARD_DEVIATION 13.78 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 = Fully Active | 28 Participants | 2 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 11 Participants | 1 Participants | 6 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 = Restricted in Physical Activity; Ambulatory | 7 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Height | 162.5 centimeter (cm) STANDARD_DEVIATION 8.95 | 165.1 centimeter (cm) STANDARD_DEVIATION 8.89 | 172.4 centimeter (cm) STANDARD_DEVIATION 6.61 | 170.5 centimeter (cm) | 156.4 centimeter (cm) | 170.7 centimeter (cm) | 163.6 centimeter (cm) | 169.5 centimeter (cm) STANDARD_DEVIATION 2.83 | 166.0 centimeter (cm) | 155.9 centimeter (cm) | 159.5 centimeter (cm) STANDARD_DEVIATION 10.15 | 162.4 centimeter (cm) STANDARD_DEVIATION 6.92 | 158.0 centimeter (cm) STANDARD_DEVIATION 8.95 |
| Participants with BCR-ABL Ratio >10% | 19 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 7 Participants | 2 Participants | 2 Participants |
| Participants with BCR-ABL Ratio >1 to <=10 percent (%) | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants |
| Participants with BCR-ABL Ratio e1a2 variant | 10 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants |
| Participants with BCR-ABL Ratio Greater than (>)0.1 - less than or equal to (<=)1% | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Participants with Extramedullary Involvement Hepatomegaly | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Participants with Extramedullary Involvement No extramedullary involvement | 33 Participants | 4 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 11 Participants | 2 Participants | 6 Participants |
| Participants with Extramedullary Involvement Splenomegaly | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Participants with Initial Diagnosis of Leukemia AP-CML | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Participants with Initial Diagnosis of Leukemia BP-CML | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Participants with Initial Diagnosis of Leukemia CP-CML | 20 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 11 Participants | 1 Participants | 0 Participants |
| Participants with Initial Diagnosis of Leukemia Ph+ ALL | 12 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian | 35 Participants | 4 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 11 Participants | 3 Participants | 6 Participants |
| Region of Enrollment Japan | 35 Participants | 4 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 11 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Female | 15 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 6 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 20 Participants | 2 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants | 2 Participants | 2 Participants |
| Time Since Diagnosis to Date of First Dose | 2.11 years | 1.51 years | 3.47 years | 10.87 years | 0.53 years | 3.00 years | 10.29 years | 12.98 years | 0.73 years | 21.65 years | 3.76 years | 1.69 years | 0.91 years |
| Weight | 57.5 kilogram (kg) STANDARD_DEVIATION 10.54 | 45.8 kilogram (kg) STANDARD_DEVIATION 3.93 | 74.1 kilogram (kg) STANDARD_DEVIATION 6.49 | 55.8 kilogram (kg) | 60.0 kilogram (kg) | 54.6 kilogram (kg) | 67.0 kilogram (kg) | 60.0 kilogram (kg) STANDARD_DEVIATION 8.49 | 60.5 kilogram (kg) | 57.0 kilogram (kg) | 59.0 kilogram (kg) STANDARD_DEVIATION 9.93 | 54.0 kilogram (kg) STANDARD_DEVIATION 10.99 | 53.7 kilogram (kg) STANDARD_DEVIATION 11.84 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 4 / 4 | 0 / 3 | 1 / 1 | 0 / 1 | 1 / 1 | 0 / 2 | 1 / 1 | 1 / 11 | 3 / 3 | 6 / 6 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 3 / 4 | 3 / 3 | 1 / 1 | 1 / 1 | 1 / 1 | 2 / 2 | 1 / 1 | 11 / 11 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 1 / 1 | 0 / 1 | 2 / 4 | 2 / 3 | 1 / 1 | 0 / 1 | 0 / 1 | 1 / 2 | 1 / 1 | 6 / 11 | 2 / 3 | 1 / 6 |
Outcome results
Primary
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.
Time frame: Cycle 1 (Cycle length= 28 days)
Population: DLT evaluable population (Phase 1 only) included all participants who had completed at least 75% of their planned doses during Cycle 1, unless missed doses were due to adverse events (AEs).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib | 0 Participants |
| Ponatinib 30 mg: Phase 1 AP-CML | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib | 0 Participants |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib | 1 Participants |
| Ponatinib 45 mg: Phase 1 CP-CML | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib | 1 Participants |
| Ponatinib 45 mg: Phase 1 AP CML | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib | 0 Participants |
| Ponatinib 45 mg: Phase 1 BP-CML | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib | 0 Participants |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib | 0 Participants |
Primary
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.
Time frame: Baseline up to 60 months
Population: Treated population included all participants who had received at least 1 dose of study drug. This outcome measure was planned to be assessed only in BP-CML and Ph+ALL participants of Phase 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | Phase 2, BP-CML and Ph+ALL: Percentage of Participants With Major Hematologic Response (MaHR) | 0 percentage of participants |
| Ponatinib 30 mg: Phase 1 AP-CML | Phase 2, BP-CML and Ph+ALL: Percentage of Participants With Major Hematologic Response (MaHR) | 33.3 percentage of participants |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | Phase 2, BP-CML and Ph+ALL: Percentage of Participants With Major Hematologic Response (MaHR) | 83.3 percentage of participants |
Primary
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.
Time frame: Baseline up to 60 months
Population: Treated population included all participants who had received at least 1 dose of study drug. This outcome measure was planned to be assessed only in CP-CML participants of Phase 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | Phase 2, CP-CML Participants: Percentage of Participants With Major Cytogenetic Response (MCyR) | 50 percentage of participants |
| Ponatinib 30 mg: Phase 1 AP-CML | Phase 2, CP-CML Participants: Percentage of Participants With Major Cytogenetic Response (MCyR) | 63.6 percentage of participants |
Secondary
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)
Population: Treated population include all participants who had received at least 1 dose of study drug and for whom PK samples were collected. As planned, PK samples were analyzed per dose level.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Ponatinib | 336.00 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 129.55 |
| Ponatinib 30 mg: Phase 1 AP-CML | AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Ponatinib | 495.98 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 154.09 |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Ponatinib | 1385.5 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 456.2 |
Secondary
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)
Population: Treated population include all participants who had received at least 1 dose of study drug and for whom PK samples were collected. As planned, PK samples were analyzed per dose level.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | Cmax: Maximum Observed Plasma Concentration for Ponatinib | 23.67 nanogram per milliliter (ng/mL) | Standard Deviation 7.136 |
| Ponatinib 30 mg: Phase 1 AP-CML | Cmax: Maximum Observed Plasma Concentration for Ponatinib | 31.55 nanogram per milliliter (ng/mL) | Standard Deviation 9.072 |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | Cmax: Maximum Observed Plasma Concentration for Ponatinib | 89.13 nanogram per milliliter (ng/mL) | Standard Deviation 24.63 |
Secondary
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).
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)
Population: Treated population by entry mutation. Here number analyzed n are the participants who were evaluable for this outcome measure for given categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Cytogenic response | 1513.0 days |
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | NA days |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Molecular response | NA days |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | NA days |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Cytogenic response | NA days |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | NA days |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Cytogenic response | NA days |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Molecular response | NA days |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | NA days |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Cytogenic response | NA days |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Molecular response | NA days |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Cytogenic response | NA days |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Molecular response | NA days |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | NA days |
| Ponatinib 15 mg: Phase 2 Ph+ ALL | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | 56.5 days |
| Ponatinib 45 mg: Phase 2 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Cytogenic response | NA days |
| Ponatinib 45 mg: Phase 2 CP-CML | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | NA days |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Cytogenic response | 31.0 days |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | 50.5 days |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Molecular response | 168.0 days |
| Ponatinib 30 mg: Phase 1 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | NA days |
| Ponatinib 45 mg: Phase 1 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Cytogenic response | 169.0 days |
| Ponatinib 45 mg: Phase 1 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | 226.0 days |
| Ponatinib 45 mg: Phase 2 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Hematologic response | 113.5 days |
| Ponatinib 45 mg: Phase 2 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Median Duration of Response (DOR) | Cytogenic response | 205.0 days |
Secondary
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).
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)
Population: Treated population by entry mutation. Here overall number analyzed N are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | 1597.0 days |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | NA days |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | NA days |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | NA days |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | NA days |
| Ponatinib 15 mg: Phase 2 Ph+ ALL | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | 51.0 days |
| Ponatinib 45 mg: Phase 2 CP-CML | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | 320.0 days |
| Ponatinib 45 mg: Phase 2 BP-CML | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | 33.0 days |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | 100.0 days |
| Ponatinib 30 mg: Phase 1 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | 56.5 days |
| Ponatinib 45 mg: Phase 1 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | 281.0 days |
| Ponatinib 45 mg: Phase 2 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS) | 127.5 days |
Secondary
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).
Time frame: From the first dose of study treatment until death (up to 60 months)
Population: Treated population by entry mutation. Here overall number analyzed N are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML and Advanced Phase Participants: Overall Survival (OS) | NA days |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML and Advanced Phase Participants: Overall Survival (OS) | NA days |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML and Advanced Phase Participants: Overall Survival (OS) | NA days |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML and Advanced Phase Participants: Overall Survival (OS) | NA days |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML and Advanced Phase Participants: Overall Survival (OS) | NA days |
| Ponatinib 15 mg: Phase 2 Ph+ ALL | CP-CML and Advanced Phase Participants: Overall Survival (OS) | 201.0 days |
| Ponatinib 45 mg: Phase 2 CP-CML | CP-CML and Advanced Phase Participants: Overall Survival (OS) | NA days |
| Ponatinib 45 mg: Phase 2 BP-CML | CP-CML and Advanced Phase Participants: Overall Survival (OS) | 109.0 days |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML and Advanced Phase Participants: Overall Survival (OS) | 264.0 days |
| Ponatinib 30 mg: Phase 1 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Overall Survival (OS) | 131.0 days |
| Ponatinib 45 mg: Phase 1 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Overall Survival (OS) | 382.0 days |
| Ponatinib 45 mg: Phase 2 Advanced Phase Participants With Other Mutations | CP-CML and Advanced Phase Participants: Overall Survival (OS) | 550.5 days |
Secondary
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.
Time frame: From the first dose of study treatment until the criteria for response were first met (up to 60 months)
Population: Treated population included all participants who had received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | NA days |
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | NA days |
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | 85.0 days |
| Ponatinib 30 mg: Phase 1 AP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | NA days |
| Ponatinib 30 mg: Phase 1 AP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | 22 days |
| Ponatinib 30 mg: Phase 1 AP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | NA days |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | 14.5 days |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | NA days |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | NA days |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | 85 days |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | NA days |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | 85 days |
| Ponatinib 45 mg: Phase 1 AP CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | NA days |
| Ponatinib 45 mg: Phase 1 AP CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | 56 days |
| Ponatinib 45 mg: Phase 1 AP CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | 113 days |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | 15 days |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | 29 days |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | NA days |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | NA days |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | 28 days |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | NA days |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | 84 days |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | 84 days |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | NA days |
| Ponatinib 15 mg: Phase 2 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | NA days |
| Ponatinib 15 mg: Phase 2 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | NA days |
| Ponatinib 15 mg: Phase 2 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | NA days |
| Ponatinib 45 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | 167 days |
| Ponatinib 45 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | NA days |
| Ponatinib 45 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | 253.0 days |
| Ponatinib 45 mg: Phase 2 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | 31 days |
| Ponatinib 45 mg: Phase 2 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | 17 days |
| Ponatinib 45 mg: Phase 2 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | 58 days |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Hematologic response | 15 days |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Cytogenic response | 29 days |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR) | Molecular response | NA days |
Secondary
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.
Time frame: Baseline up to 60 months
Population: Treated population included all participants who had received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 100 percentage of participants |
| Ponatinib 30 mg: Phase 1 AP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 0 percentage of participants |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 0 percentage of participants |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 100 percentage of participants |
| Ponatinib 45 mg: Phase 1 AP CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 100 percentage of participants |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 100 percentage of participants |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 100 percentage of participants |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 0 percentage of participants |
| Ponatinib 15 mg: Phase 2 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 0 percentage of participants |
| Ponatinib 45 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 63.6 percentage of participants |
| Ponatinib 45 mg: Phase 2 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 33.3 percentage of participants |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR | 16.7 percentage of participants |
Secondary
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.
Time frame: Baseline up to 60 months
Population: Treated population included all participants who had received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 0 percentage of participants |
| Ponatinib 30 mg: Phase 1 AP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 0 percentage of participants |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 0 percentage of participants |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 100 percentage of participants |
| Ponatinib 45 mg: Phase 1 AP CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 0 percentage of participants |
| Ponatinib 45 mg: Phase 1 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 0 percentage of participants |
| Ponatinib 45 mg: Phase 1 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 0 percentage of participants |
| Ponatinib 15 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 50.0 percentage of participants |
| Ponatinib 15 mg: Phase 2 Ph+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 9 percentage of participants |
| Ponatinib 45 mg: Phase 2 CP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 27.3 percentage of participants |
| Ponatinib 45 mg: Phase 2 BP-CML | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 33.3 percentage of participants |
| Ponatinib 45 mg: Phase 2 PH+ ALL | CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR) | 0 percentage of participants |
Secondary
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).
Time frame: Baseline up to 60 months
Population: Treated population included all participants who had received at least 1 dose of study drug. This outcome measure was planned to be assessed only in CP-CML Participants of Phase 1 and 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | CP-CML Participants: Percentage of Participants With CHR | 100 percentage of participants |
| Ponatinib 30 mg: Phase 1 AP-CML | CP-CML Participants: Percentage of Participants With CHR | 100 percentage of participants |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | CP-CML Participants: Percentage of Participants With CHR | 100 percentage of participants |
| Ponatinib 45 mg: Phase 1 CP-CML | CP-CML Participants: Percentage of Participants With CHR | 90.9 percentage of participants |
Secondary
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)
Population: Treated population include all participants who had received at least 1 dose of study drug and for whom PK samples were collected. As planned, PK samples were analyzed per dose level.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | T1/2: Terminal Phase Elimination Half-life for Ponatinib | NA hours |
| Ponatinib 30 mg: Phase 1 AP-CML | T1/2: Terminal Phase Elimination Half-life for Ponatinib | NA hours |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | T1/2: Terminal Phase Elimination Half-life for Ponatinib | NA hours |
Secondary
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)
Population: Treated population include all participants who had received at least 1 dose of study drug and for whom PK samples were collected. As planned, PK samples were analyzed per dose level.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ponatinib 30 mg: Phase 1 CP-CML | Tmax: Time to Reach the Cmax for Ponatinib | 4.00 hour |
| Ponatinib 30 mg: Phase 1 AP-CML | Tmax: Time to Reach the Cmax for Ponatinib | 6.75 hour |
| Ponatinib 30 mg: Phase 1 Ph+ ALL | Tmax: Time to Reach the Cmax for Ponatinib | 5.00 hour |